1 1427 151 DIFFERENTIAL EFFECTS OF CHRONIC IMMUNOSUPPRESSION ON BEHAVIORAL, EPIGENETIC, AND ALZHEIMER'S DISEASE-ASSOCIATED MARKERS IN 3XTG-AD MICE. BACKGROUND: CIRCULATING AUTOANTIBODIES AND SEX-DEPENDENT DISCREPANCY IN PREVALENCE ARE UNEXPLAINED PHENOMENA OF ALZHEIMER'S DISEASE (AD). USING THE 3XTG-AD MOUSE MODEL, WE REPORTED THAT ADULT MALES SHOW EARLY MANIFESTATIONS OF SYSTEMIC AUTOIMMUNITY, INCREASED EMOTIONAL REACTIVITY, ENHANCED EXPRESSION OF THE HISTONE VARIANT MACROH2A1 IN THE CEREBRAL CORTEX, AND LOSS OF PLAQUE/TANGLE PATHOLOGY. CONVERSELY, ADULT FEMALES DISPLAY LESS SEVERE AUTOIMMUNITY AND RETAIN THEIR AD-LIKE PHENOTYPE. THIS STUDY EXAMINES THE LINK BETWEEN IMMUNITY AND OTHER TRAITS OF THE CURRENT 3XTG-AD MODEL. METHODS: YOUNG 3XTG-AD AND WILD-TYPE MICE DRANK A SUCROSE-LACED 0.4 MG/ML SOLUTION OF THE IMMUNOSUPPRESSANT CYCLOPHOSPHAMIDE ON WEEKENDS FOR 5 MONTHS. AFTER BEHAVIORAL PHENOTYPING AT 2 AND 6 MONTHS OF AGE, WE ASSESSED ORGAN MASS, SEROLOGIC MARKERS OF AUTOIMMUNITY, MOLECULAR MARKERS OF EARLY AD PATHOLOGY, AND EXPRESSION OF GENES ASSOCIATED WITH NEURODEGENERATION. RESULTS: CHRONIC IMMUNOSUPPRESSION PREVENTED HEMATOCRIT DROP AND REDUCED SOLUBLE ABETA IN 3XTG-AD MALES WHILE NORMALIZING THE EXPRESSION OF HISTONE VARIANT MACROH2A1 IN 3XTG-AD FEMALES. THIS TREATMENT ALSO REDUCED HEPATOSPLENOMEGALY, LOWERED AUTOANTIBODY LEVELS, AND INCREASED THE EFFECTOR T CELL POPULATION WHILE DECREASING THE PROPORTION OF REGULATORY T CELLS IN BOTH SEXES. EXPOSURE TO CYCLOPHOSPHAMIDE, HOWEVER, NEITHER PREVENTED REDUCED BRAIN MASS AND BDNF EXPRESSION NOR NORMALIZED INCREASED TAU AND ANXIETY-RELATED BEHAVIORS. CONCLUSION: THE RESULTS SUGGEST THAT SYSTEMIC AUTOIMMUNITY INCREASES SOLUBLE ABETA PRODUCTION AND AFFECTS TRANSCRIPTIONAL REGULATION OF MACROH2A1 IN A SEX-RELATED MANNER. DESPITE THE COMPLEXITY OF MULTISYSTEM INTERACTIONS, 3XTG-AD MICE CAN BE A USEFUL IN VIVO MODEL FOR EXPLORING THE REGULATORY ROLE OF AUTOIMMUNITY IN THE ETIOLOGY OF AD-LIKE NEURODEGENERATIVE DISORDERS. 2021 2 1584 26 DNA METHYLATION PROFILES OF SELECTED PRO-INFLAMMATORY CYTOKINES IN ALZHEIMER DISEASE. BY MEANS OF FUNCTIONAL GENOMICS ANALYSIS, WE RECENTLY DESCRIBED THE MRNA EXPRESSION PROFILES OF VARIOUS GENES INVOLVED IN THE NEUROINFLAMMATORY RESPONSE IN THE BRAINS OF SUBJECTS WITH LATE-ONSET ALZHEIMER DISEASE (LOAD). SOME OF THESE GENES, NAMELY INTERLEUKIN (IL)-1BETA AND IL-6, SHOWED DISTINCT EXPRESSION PROFILES WITH PEAK EXPRESSION DURING THE FIRST STAGES OF THE DISEASE AND CONTROL-LIKE LEVELS AT LATER STAGES. IL-1BETA AND IL-6 GENES ARE MODULATED BY DNA METHYLATION IN DIFFERENT CHRONIC AND DEGENERATIVE DISEASES; IT IS ALSO WELL KNOWN THAT LOAD MAY HAVE AN EPIGENETIC BASIS. INDEED, WE AND OTHERS HAVE PREVIOUSLY REPORTED GENE-SPECIFIC DNA METHYLATION ALTERATIONS IN LOAD AND IN RELATED ANIMAL MODELS. BASED ON THESE DATA, WE STUDIED THE DNA METHYLATION PROFILES, AT SINGLE CYTOSINE RESOLUTION, OF IL-1BETA AND IL-6 5'-FLANKING REGION BY BISULPHITE MODIFICATION IN THE CORTEX OF HEALTHY CONTROLS AND LOAD PATIENTS AT 2 DIFFERENT DISEASE STAGES: BRAAK I-II/A AND BRAAK V-VI/C. OUR ANALYSIS PROVIDES EVIDENCE THAT NEUROINFLAMMATION IN LOAD IS ASSOCIATED WITH (AND POSSIBLY MEDIATED BY) EPIGENETIC MODIFICATIONS. 2017 3 6895 23 [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 3093 27 GENOMIC AND EPIGENOMIC RESPONSES TO CHRONIC STRESS INVOLVE MIRNA-MEDIATED PROGRAMMING. STRESS REPRESENTS A CRITICAL INFLUENCE ON MOTOR SYSTEM FUNCTION AND HAS BEEN SHOWN TO IMPAIR MOVEMENT PERFORMANCE. WE HYPOTHESIZED THAT STRESS-INDUCED MOTOR IMPAIRMENTS ARE DUE TO BRAIN-SPECIFIC CHANGES IN MIRNA AND PROTEIN-ENCODING GENE EXPRESSION. HERE WE SHOW A CAUSAL LINK BETWEEN STRESS-INDUCED MOTOR IMPAIRMENT AND ASSOCIATED GENETIC AND EPIGENETIC RESPONSES IN RELEVANT CENTRAL MOTOR AREAS IN A RAT MODEL. EXPOSURE TO TWO WEEKS OF MILD RESTRAINT STRESS ALTERED THE EXPRESSION OF 39 GENES AND NINE MIRNAS IN THE CEREBELLUM. IN LINE WITH PERSISTENT BEHAVIOURAL IMPAIRMENTS, SOME CHANGES IN GENE AND MIRNA EXPRESSION WERE RESISTANT TO RECOVERY FROM STRESS. INTERESTINGLY, STRESS UP-REGULATED THE EXPRESSION OF ADIPOQ AND PROLACTIN RECEPTOR MRNAS IN THE CEREBELLUM. STRESS ALSO ALTERED THE EXPRESSION OF PRLR, MIR-186, AND MIR-709 IN HIPPOCAMPUS AND PREFRONTAL CORTEX. IN ADDITION, OUR FINDINGS DEMONSTRATE THAT MIR-186 TARGETS THE GENE EPS15. FURTHERMORE, WE FOUND AN AGE-DEPENDENT INCREASE IN EPHRINB3 AND GABAA4 RECEPTORS. THESE DATA SHOW THAT EVEN MILD STRESS RESULTS IN SUBSTANTIAL GENOMIC AND EPIGENOMIC CHANGES INVOLVING MIRNA EXPRESSION AND ASSOCIATED GENE TARGETS IN THE MOTOR SYSTEM. THESE FINDINGS SUGGEST A CENTRAL ROLE OF MIRNA-REGULATED GENE EXPRESSION IN THE STRESS RESPONSE AND IN ASSOCIATED NEUROLOGICAL FUNCTION. 2012 5 20 30 5-HYDROXYMETHYLATION-ASSOCIATED EPIGENETIC MODIFIERS OF ALZHEIMER'S DISEASE MODULATE TAU-INDUCED NEUROTOXICITY. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISORDER CHARACTERIZED BY PROGRESSIVE DETERIORATION OF COGNITIVE FUNCTION. PATHOGENESIS OF AD IS INCOMPLETELY UNDERSTOOD; EVIDENCE SUGGESTS A ROLE FOR EPIGENETIC REGULATION, IN PARTICULAR THE CYTOSINE MODIFICATIONS 5-METHYLCYTOSINE AND 5-HYDROXYMETHYLCYTOSINE (5HMC). 5HMC IS ENRICHED IN THE NERVOUS SYSTEM AND DISPLAYS NEURODEVELOPMENT AND AGE-RELATED CHANGES. TO DETERMINE THE ROLE OF 5HMC IN AD, WE PERFORMED GENOME-WIDE ANALYSES OF 5HMC IN DNA FROM PREFRONTAL CORTEX OF POST-MORTEM AD PATIENTS, AND RNA-SEQ TO CORRELATE CHANGES IN 5HMC WITH TRANSCRIPTIONAL CHANGES. WE IDENTIFIED 325 GENES CONTAINING DIFFERENTIALLY HYDROXYMETHYLATED LOCI (DHMLS) IN BOTH DISCOVERY AND REPLICATION DATASETS. THESE ARE ENRICHED FOR PATHWAYS INVOLVED IN NEURON PROJECTION DEVELOPMENT AND NEUROGENESIS. OF THESE, 140 SHOWED CHANGES IN GENE EXPRESSION. PROTEINS ENCODED BY THESE GENES FORM DIRECT PROTEIN-PROTEIN INTERACTIONS WITH AD-ASSOCIATED GENES, EXPANDING THE NETWORK OF GENES IMPLICATED IN AD. WE IDENTIFIED AD-ASSOCIATED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) LOCATED WITHIN OR NEAR DHMLS, SUGGESTING THESE SNPS MAY IDENTIFY REGIONS OF EPIGENETIC GENE REGULATION THAT PLAY A ROLE IN AD PATHOGENESIS. FINALLY, USING AN EXISTING AD FLY MODEL, WE SHOWED SOME OF THESE GENES MODULATE AD-ASSOCIATED TOXICITY. OUR DATA IMPLICATE NEURONAL PROJECTION DEVELOPMENT AND NEUROGENESIS PATHWAYS AS POTENTIAL TARGETS IN AD. BY INCORPORATING EPIGENOMIC AND TRANSCRIPTOMIC DATA WITH GENOME-WIDE ASSOCIATION STUDIES DATA, WITH VERIFICATION IN THE DROSOPHILA MODEL, WE CAN EXPAND THE KNOWN NETWORK OF GENES INVOLVED IN DISEASE PATHOGENESIS AND IDENTIFY EPIGENETIC MODIFIERS OF ALZHEIMER'S DISEASE. 2016 6 1182 40 CONVERGING AND DIFFERENTIAL BRAIN PHOSPHOLIPID DYSREGULATION IN THE PATHOGENESIS OF REPETITIVE MILD TRAUMATIC BRAIN INJURY AND ALZHEIMER'S DISEASE. REPETITIVE MILD TRAUMATIC BRAIN INJURY (RMTBI) IS A MAJOR EPIGENETIC RISK FACTOR FOR ALZHEIMER'S DISEASE (AD). THE PRECISE NATURE OF HOW RMTBI LEADS TO OR PRECIPITATES AD PATHOLOGY IS CURRENTLY UNKNOWN. NUMEROUS NEUROLOGICAL CONDITIONS HAVE SHOWN AN IMPORTANT ROLE FOR DYSFUNCTIONAL PHOSPHOLIPID METABOLISM AS A DRIVING FACTOR FOR THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES. HOWEVER, THE PRECISE ROLE IN RMTBI AND AD REMAINS ELUSIVE. WE HYPOTHESIZED THAT A DETAILED PHOSPHOLIPID CHARACTERIZATION WOULD REVEAL PROFILES OF RESPONSE TO INJURY IN TBI THAT OVERLAP WITH AGE-DEPENDENT CHANGES IN AD AND THUS PROVIDE INSIGHTS INTO THE TBI-AD RELATIONSHIP. WE EMPLOYED A LIPIDOMIC APPROACH EXAMINING BRAIN PHOSPHOLIPID PROFILES FROM MOUSE MODELS OF RMTBI AND AD. CORTEX AND HIPPOCAMPAL TISSUE WERE COLLECTED AT 24 H, 3, 6, 9, AND 12 MONTHS POST-RMTBI, AND AT AGES REPRESENTING 'PRE', 'PERI' AND 'POST' ONSET OF AMYLOID PATHOLOGY (I.E., 3, 9, 15 MONTHS-OLD). TOTAL LEVELS OF PHOSPHATIDYLCHOLINE (PC), PHOSPHATIDYLETHANOLAMINE (PE), LYSOPE, AND PHOSPHATIDYLINOSITOL (PI), INCLUDING THEIR MONOUNSATURATED, POLYUNSATURATED AND SATURATED FATTY ACID (FA) CONTAINING SPECIES WERE SIGNIFICANTLY INCREASED AT ACUTE AND/OR CHRONIC TIME POINTS POST-INJURY IN BOTH BRAIN REGIONS. HOWEVER, LEVELS OF MOST PHOSPHOLIPID SPECIES IN PS1/APP MICE WERE NOMINAL IN THE HIPPOCAMPUS, WHILE IN THE CORTEX, LEVELS WERE SIGNIFICANTLY DECREASED AT AGES POST-ONSET OF AMYLOID PATHOLOGY. SPHINGOMYELIN AND LYSOPC LEVELS SHOWED COINCIDENTAL TRENDS IN OUR RMTBI AND AD MODELS WITHIN THE HIPPOCAMPUS, AN INCREASE AT ACUTE AND/OR CHRONIC TIME POINTS EXAMINED. THE RATIO OF ARACHIDONIC ACID (OMEGA-6 FA) TO DOCOSAHEXAENOIC ACID (OMEGA-3 FA)-CONTAINING PE SPECIES WAS INCREASED AT EARLY TIME POINTS IN THE HIPPOCAMPUS OF INJURED VERSUS SHAM MICE, AND IN PS1/APP MICE THERE WAS A COINCIDENTAL INCREASE COMPARED TO WILD TYPE LITTERMATES AT ALL TIME POINTS. THIS STUDY DEMONSTRATES SOME OVERLAPPING AND DIVERSE PHOSPHOLIPID PROFILES IN RMTBI AND AD MODELS. FUTURE STUDIES ARE REQUIRED TO CORROBORATE OUR FINDINGS IN HUMAN POST-MORTEM TISSUE. INVESTIGATION OF SECONDARY MECHANISMS TRIGGERED BY ABERRANT DOWNSTREAM ALTERATIONS IN BIOACTIVE METABOLITES OF THESE PHOSPHOLIPIDS, AND THEIR MODULATION AT THE APPROPRIATE TIME-WINDOWS OF OPPORTUNITY COULD HELP FACILITATE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES TO AMELIORATE THE NEURODEGENERATIVE CONSEQUENCES OF RMTBI OR THE POTENTIAL TRIGGERING OF AD PATHOGENESIS BY RMTBI. 2019 7 2442 34 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 8 2776 39 EXTRAUTERINE GROWTH RESTRICTION ON PULMONARY VASCULAR ENDOTHELIAL DYSFUNCTION IN ADULT MALE RATS: THE ROLE OF EPIGENETIC MECHANISMS. OBJECTIVE: EARLY POSTNATAL LIFE IS CONSIDERED AS A CRITICAL TIME WINDOW FOR THE DETERMINATION OF LONG-TERM METABOLIC STATES AND ORGAN FUNCTIONS. EXTRAUTERINE GROWTH RESTRICTION (EUGR) CAUSES THE DEVELOPMENT OF ADULT-ONSET CHRONIC DISEASES, INCLUDING PULMONARY HYPERTENSION. HOWEVER, THE EFFECTS OF NUTRITIONAL DISADVANTAGES DURING THE EARLY POSTNATAL PERIOD ON PULMONARY VASCULAR CONSEQUENCES IN LATER LIFE ARE NOT FULLY UNDERSTOOD. OUR STUDY WAS DESIGNED TO TEST WHETHER EPIGENETICS DYSREGULATION MEDIATES THE CELLULAR MEMORY OF THIS EARLY POSTNATAL EVENT. METHODS AND RESULTS: TO TEST THIS HYPOTHESIS, WE ISOLATED PULMONARY VASCULAR ENDOTHELIAL CELLS BY MAGNETIC-ACTIVATED CELL SORTING FROM EUGR AND CONTROL RATS. A POSTNATAL INSULT, NUTRITIONAL RESTRICTION-INDUCED EUGR CAUSED DEVELOPMENT OF AN INCREASED PULMONARY ARTERY PRESSURE AT 9 WEEKS OF AGE IN MALE SPRAGUE-DAWLEY RATS. METHYL-DNA IMMUNE PRECIPITATION CHIP, GENOME-SCALE MAPPING STUDIES TO SEARCH FOR DIFFERENTIALLY METHYLATED LOCI BETWEEN CONTROL AND EUGR RATS, REVEALED SIGNIFICANT DIFFERENCE IN CYTOSINE METHYLATION BETWEEN EUGR AND CONTROL RATS. EUGR CHANGES THE CYTOSINE METHYLATION AT APPROXIMATELY 500 LOCI IN MALE RATS AT 9 WEEKS OF AGE, PRECEDING THE DEVELOPMENT OF PULMONARY HYPERTENSION AND THESE REPRESENT THE CANDIDATE LOCI FOR MEDIATING THE PATHOGENESIS OF PULMONARY VASCULAR DISEASE THAT OCCURS LATER IN LIFE. GENE ONTOLOGY ANALYSIS ON DIFFERENTIALLY METHYLATED GENES SHOWED THAT HYPERMETHYLATED GENES IN EUGR ARE VASCULAR DEVELOPMENT-ASSOCIATED GENES AND HYPOMETHYLATED GENES IN EUGR ARE LATE-DIFFERENTIATION-ASSOCIATED AND SIGNAL TRANSDUCTION GENES. WE VALIDATED CANDIDATE DYSREGULATED LOCI WITH THE QUANTITATIVE ASSAYS OF CYTOSINE METHYLATION AND GENE EXPRESSIONS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT EPIGENETICS DYSREGULATION IS A STRONG MECHANISM FOR PROPAGATING THE CELLULAR MEMORY OF EARLY POSTNATAL EVENTS, CAUSING CHANGES IN THE EXPRESSION OF GENES AND LONG-TERM SUSCEPTIBILITY TO PULMONARY HYPERTENSION, AND FURTHER PROVIDING A NEW INSIGHT INTO THE PREVENTION AND TREATMENT OF EUGR-RELATED PULMONARY HYPERTENSION. 2014 9 4528 21 MULTIGENERATIONAL EFFECTS OF CADMIUM ON THE LIFESPAN AND FERTILITY OF DROSOPHILA MELANOGASTER. ALTHOUGH THE DAMAGE AND TOLERANCE MECHANISMS OF CD STRESS ARE KNOWN, THE DATA ON GENETIC RISK ARE LIMITED. THE AIM OF THIS STUDY WAS TO ASSESS THE CHRONIC TOXICITY OF CD, GENETIC RESPONSES, AND MULTIGENERATIONAL EFFECTS IN FIVE GENERATIONS OF DROSOPHILA MELANOGASTER. FOR EACH GENERATION, LIFESPAN AND FERTILITY WERE STATISTICALLY ANALYSED AND THE EXPRESSION OF APOPTOSIS- (P53 AND CASPASE-3) AND EPIGENESIS-RELATED (DDNMT2 AND DMBD2/3) GENES WAS EXAMINED. LIFESPAN AND FERTILITY SIGNIFICANTLY DECLINED UNDER CD STRESS AND THESE EFFECTS WERE MAINTAINED FOR TWO GENERATIONS AND ONE GENERATION, RESPECTIVELY, WHEN CD STRESS WAS REMOVED. THE EXPRESSION OF P53 AND CASPASE-3 WAS SIGNIFICANTLY UP-REGULATED AFTER EXPOSURE, SUGGESTING THAT APOPTOSIS CONTRIBUTES TO THE RESISTANCE MECHANISM. THEIR ALTERED EXPRESSION WAS RETAINED FOR TWO GENERATIONS. FURTHERMORE, HIGH EXPRESSION OF DDNMT2 AND DMBD2/3 ACCOMPANIED CD EXPOSURE, WHICH WAS PASSED ON TO THREE GENERATIONS, SUGGESTING THAT GENETIC MODIFICATIONS IN APOPTOSIS-RELATED GENES ARE CARRIED TO THE OFFSPRING THROUGH EPIGENETIC REGULATION. 2020 10 2119 30 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 11 989 30 CHRONIC SOCIAL DEFEAT STRESS DIFFERENTIALLY REGULATES THE EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE. OBJECTIVES: ALTHOUGH STRESS IS CONSIDERED A PRIMARY RISK FACTOR FOR NEUROPSYCHIATRIC DISORDERS, A MAJORITY OF INDIVIDUALS ARE RESILIENT TO THE EFFECTS OF STRESS EXPOSURE AND SUCCESSFULLY ADAPT TO ADVERSE LIFE EVENTS, WHILE OTHERS, THE SO-CALLED SUSCEPTIBLE INDIVIDUALS, MAY HAVE PROBLEMS TO PROPERLY ADAPT TO ENVIRONMENTAL CHANGES. HOWEVER, THE MECHANISMS UNDERLYING THESE DIFFERENT RESPONSES TO STRESS EXPOSURE ARE POORLY UNDERSTOOD.METHODS: ADULT MALE C57BL/6J MICE WERE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS PROTOCOL AND LEVELS OF BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES WERE ANALYSED BY REAL-TIME PCR IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) OF SUSCEPTIBLE AND RESILIENT MICE.RESULTS: WE FOUND A SELECTIVE REDUCTION OF BDNF-6 TRANSCRIPT IN THE HPC AND AN INCREASE OF BDNF-4 TRANSCRIPT IN THE PFC OF SUSCEPTIBLE MICE. MOREOVER, SUSCEPTIBLE MICE SHOWED A SELECTIVE REDUCTION OF THE G9A MRNA LEVELS IN THE HPC, WHILE HDAC-5 AND DNMT3A MRNA LEVELS WERE SPECIFICALLY REDUCED IN THE PFC.CONCLUSIONS: OVERALL, OUR RESULTS, SHOWING A DIFFERENT EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE, SUGGEST THAT STRESS RESILIENCE IS NOT SIMPLY A LACK OF ACTIVATION OF STRESS-RELATED PATHWAYS, BUT IS RELATED TO THE ACTIVATION OF ADDITIONAL DIFFERENT SPECIFIC MECHANISMS. 2019 12 6794 32 [EFFECT OF BENZO(A)PYRENE ON THE EXPRESSION OF AHR-REGULATED MICRORNA IN FEMALE AND MALE RAT LUNGS]. SMOKING IS THE MAIN RISK FACTOR FOR LUNG CANCER, MAINLY DUE TO PRESENCE OF NITROSAMINES AND POLYCYCLIC AROMATIC HYDROCARBONS, INCLUDING BENZO[A]PYRENE (BP) IN TOBACCO SMOKE COMPOSITION. THE GENOTOXIC EFFECT OF BP IS BASED ON THE HIGH DNA-BINDING ABILITY OF ITS METABOLITES, WHILE THE EPIGENETIC EFFECTS ARE MEDIATED BY A CHANGE IN THE EXPRESSION OF CANCER RELATED GENES OR REGULATORY RNAS. IT HAS BEEN SHOWN THAT WOMEN HAVE A HIGHER RISK TO DEVELOP LUNG CANCER UPON SMOKING RATHER THAN MEN. WE HYPOTHESIZED THAT CROSSTALK BETWEEN SIGNALING PATHWAYS ACTIVATED BY BP AND ESTROGENS COULD UNDERLIE THE SEX-DEPENDENT DIFFERENCES IN MIRNAS EXPRESSION. TO TEST THIS HYPOTHESIS, MALE AND FEMALE RATS WERE SUBJECTED TO SHORT-TERM OR LONG-TERM BP EXPOSURE. USING IN SILICO ANALYSIS, MIRNAS CONTAINING THE ER- AND AHR-BINDING SITES IN THE PROMOTERS OF THE GENES (OR HOST GENES) WERE SELECTED. DURING CHRONIC EXPOSURE OF BP THE EXPRESSION OF MIR-22-3P, -29A-3P, -126A-3P, -193B-5P IN THE LUNGS OF MALE RATS WERE SIGNIFICANTLY INCREASED, WHILE THE LEVEL OF MIRNA-483-3P WERE DECREASED. EXPRESSION OF MIRNA-483-3P WAS UP-REGULATED DURING CHRONIC BP EXPOSURE IN THE LUNGS OF FEMALE RATS AND THE LEVELS OF OTHER STUDIED MIRNAS WERE UNCHANGED. IN TURN, CHANGES IN THE EXPRESSION OF MIRNAS WERE FOLLOWED BY CHANGES IN THE EXPRESSION OF THEIR TARGET GENES, INCLUDING PTEN, EMP2, IGF1, ITGA6, SLC34A2, AND THE OBSERVED CHANGES IN FEMALE AND MALE RAT LUNGS WERE VARIED. THUS, OUR RESULTS SUGGEST THAT SEX-DEPENDENT EPIGENETIC EFFECTS OF BP MAY BE BASED ON DIFFERENT EXPRESSION OF AHR- AND ER- REGULATED MIRNAS. 2020 13 1162 37 CONTRASTING EFFECTS OF ACUTE AND CHRONIC STRESS ON THE TRANSCRIPTOME, EPIGENOME, AND IMMUNE RESPONSE OF ATLANTIC SALMON. STRESS EXPERIENCED DURING EARLY LIFE MAY HAVE LASTING EFFECTS ON THE IMMUNE SYSTEM, WITH IMPACTS ON HEALTH AND DISEASE DEPENDENT ON THE NATURE AND DURATION OF THE STRESSOR. THE EPIGENOME IS ESPECIALLY SENSITIVE TO ENVIRONMENTAL STIMULI DURING EARLY LIFE AND REPRESENTS A POTENTIAL MECHANISM THROUGH WHICH STRESS MAY CAUSE LONG-LASTING HEALTH EFFECTS. HOWEVER, THE EXTENT TO WHICH THE EPIGENOME RESPONDS DIFFERENTLY TO CHRONIC VS ACUTE STRESSORS IS UNCLEAR, ESPECIALLY FOR NON-MAMMALIAN SPECIES. WE EXAMINED THE EFFECTS OF ACUTE STRESS (COLD-SHOCK DURING EMBRYOGENESIS) AND CHRONIC STRESS (ABSENCE OF TANK ENRICHMENT DURING LARVAL-STAGE) ON GLOBAL GENE EXPRESSION (USING RNA-SEQ) AND DNA METHYLATION (USING RRBS) IN THE GILLS OF ATLANTIC SALMON (SALMO SALAR) FOUR MONTHS AFTER HATCHING. CHRONIC STRESS INDUCED PRONOUNCED TRANSCRIPTIONAL DIFFERENCES, WHILE ACUTE STRESS CAUSED FEW LASTING TRANSCRIPTIONAL EFFECTS. HOWEVER, BOTH ACUTE AND CHRONIC STRESS CAUSED LASTING AND CONTRASTING CHANGES IN THE METHYLOME. CRUCIALLY, WE FOUND THAT ACUTE STRESS ENHANCED TRANSCRIPTIONAL IMMUNE RESPONSE TO A PATHOGENIC CHALLENGE (BACTERIAL LIPOPOLYSACCHARIDE, LPS), WHILE CHRONIC STRESS SUPPRESSED IT. WE IDENTIFIED STRESS-INDUCED CHANGES IN PROMOTER AND GENE-BODY METHYLATION THAT WERE ASSOCIATED WITH ALTERED EXPRESSION FOR A SMALL PROPORTION OF IMMUNE-RELATED GENES, AND EVIDENCE OF WIDER EPIGENETIC REGULATION WITHIN SIGNALLING PATHWAYS INVOLVED IN IMMUNE RESPONSE. OUR RESULTS SUGGEST THAT STRESS CAN AFFECT IMMUNO-COMPETENCE THROUGH EPIGENETIC MECHANISMS, AND HIGHLIGHT THE MARKEDLY DIFFERENT EFFECTS OF CHRONIC LARVAL AND ACUTE EMBRYONIC STRESS. THIS KNOWLEDGE COULD BE USED TO HARNESS THE STIMULATORY EFFECTS OF ACUTE STRESS ON IMMUNITY, PAVING THE WAY FOR IMPROVED STRESS AND DISEASE MANAGEMENT THROUGH EPIGENETIC CONDITIONING. 2018 14 2246 29 EPIGENETIC MODULATION OF INFLAMMATION AND SYNAPTIC PLASTICITY PROMOTES RESILIENCE AGAINST STRESS IN MICE. MAJOR DEPRESSIVE DISORDER IS ASSOCIATED WITH ABNORMALITIES IN THE BRAIN AND THE IMMUNE SYSTEM. CHRONIC STRESS IN ANIMALS SHOWED THAT EPIGENETIC AND INFLAMMATORY MECHANISMS PLAY IMPORTANT ROLES IN MEDIATING RESILIENCE AND SUSCEPTIBILITY TO DEPRESSION. HERE, THROUGH A HIGH-THROUGHPUT SCREENING, WE IDENTIFY TWO PHYTOCHEMICALS, DIHYDROCAFFEIC ACID (DHCA) AND MALVIDIN-3'-O-GLUCOSIDE (MAL-GLUC) THAT ARE EFFECTIVE IN PROMOTING RESILIENCE AGAINST STRESS BY MODULATING BRAIN SYNAPTIC PLASTICITY AND PERIPHERAL INFLAMMATION. DHCA/MAL-GLUC ALSO SIGNIFICANTLY REDUCES DEPRESSION-LIKE PHENOTYPES IN A MOUSE MODEL OF INCREASED SYSTEMIC INFLAMMATION INDUCED BY TRANSPLANTATION OF HEMATOPOIETIC PROGENITOR CELLS FROM STRESS-SUSCEPTIBLE MICE. DHCA REDUCES PRO-INFLAMMATORY INTERLEUKIN 6 (IL-6) GENERATIONS BY INHIBITING DNA METHYLATION AT THE CPG-RICH IL-6 SEQUENCES INTRONS 1 AND 3, WHILE MAL-GLUC MODULATES SYNAPTIC PLASTICITY BY INCREASING HISTONE ACETYLATION OF THE REGULATORY SEQUENCES OF THE RAC1 GENE. PERIPHERAL INFLAMMATION AND SYNAPTIC MALADAPTATION ARE IN LINE WITH NEWLY HYPOTHESIZED CLINICAL INTERVENTION TARGETS FOR DEPRESSION THAT ARE NOT ADDRESSED BY CURRENTLY AVAILABLE ANTIDEPRESSANTS. 2018 15 1567 32 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D. 2018 16 5189 27 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 17 280 38 AGE-RELATED MIRNAS DYSREGULATION AND ABNORMAL BACE1 EXPRESSION FOLLOWING PB EXPOSURE IN ADOLESCENT MICE. NUMBERS OF EMERGING EVIDENCE SUGGEST THAT LEAD (PB) EXPOSURE CONTRIBUTES TO COGNITIVE DECLINE AND MIGHT ALSO INCREASE THE RISK OF ALZHEIMER'S DISEASE (AD) DEMENTIA IN THE ELDERLY BY INCREASING THE BETA-AMYLOID BURDEN. HERE, WE AIMED TO CHARACTERIZE THE EFFECTS OF PB ON THE POST-TRANSCRIPTIONAL REGULATORS, MICRORNAS (MIRNAS), WHICH MAY PARTICIPATE IN AD PATHOGENESIS. AT FIRST, EARLY CHRONIC PB EXPOSURE ON NEURONAL MIRNAS EXPRESSION WITH INCREASING AGING WAS PROFILED TO ELUCIDATE THE ASSOCIATION OF THREE SELECTED MIRNAS WITH BETA-SITE APP-CLEAVING ENZYME 1(BACE1), A RATE-LIMITING ENZYME FOR BETA-AMYLOID (ABETA) PRODUCTION. NEXT, WE VERIFIED CHANGES IN BACE1 WERE OBSERVED BY REGULATING MIRNAS EXPRESSION IN VITRO. WHILE PB PROMOTED BACE1 LEVELS, BACE1 LEVELS WERE REDUCED IN SH-SY5Y CELLS WITH MIR-124-3P MIMIC, SUGGESTING FOR THE FIRST TIME THAT MIR-124-3P/BACE1 PATHWAY MODULATION IS CRITICALLY INVOLVED IN PB-INDUCED AD-LIKE AMYLOIDOGENIC PROCESSING. FINDINGS FROM THIS STUDY COULD PROVIDE NEW INSIGHT INTO THE MOLECULAR MECHANISMS OF PB-ASSOCIATED NEURODEGENERATIVE PATHOGENESIS FROM AN EPIGENETIC PERSPECTIVE. 2022 18 5468 27 RESISTANCE TRAINING AND REDOX HOMEOSTASIS: CORRELATION WITH AGE-ASSOCIATED GENOMIC CHANGES. REGULAR PHYSICAL ACTIVITY IS EFFECTIVE AS PREVENTION AND TREATMENT FOR DIFFERENT CHRONIC CONDITIONS RELATED TO THE AGEING PROCESSES. IN FACT, A SEDENTARY LIFESTYLE HAS BEEN LINKED TO A WORSENING OF CELLULAR AGEING BIOMARKERS SUCH AS TELOMERE LENGTH (TL) AND/OR SPECIFIC EPIGENETIC CHANGES (E.G. DNA METHYLATION), WITH INCREASE OF THE PROPENSITY TO AGING-RELATED DISEASES AND PREMATURE DEATH. EXTENDING OUR PREVIOUS FINDINGS, WE AIMED TO TEST THE HYPOTHESIS THAT 12 WEEKS OF LOW FREQUENCY, MODERATE INTENSITY, EXPLOSIVE-TYPE RESISTANCE TRAINING (EMRT) MAY ATTENUATE AGE-ASSOCIATED GENOMIC CHANGES. TO THIS AIM, TL, GLOBAL DNA METHYLATION, TRF2, KU80, SIRT1, SIRT2 AND GLOBAL PROTEIN ACETYLATION, AS WELL AS OTHER PROTEINS INVOLVED IN APOPTOTIC PATHWAY (BCL-2, BAX AND CASPASE-3), ANTIOXIDANT RESPONSE (TRXR1 AND MNSOD) AND OXIDATIVE DAMAGE (MYELOPEROXIDASE) WERE EVALUATED BEFORE AND AFTER EMRT IN WHOLE BLOOD OR PERIPHERAL MONONUCLEAR CELLS (PBMCS) OF ELDERLY SUBJECTS. OUR FINDINGS CONFIRM THE POTENTIAL OF EMRT TO INDUCE AN ADAPTIVE CHANGE IN THE ANTIOXIDANT PROTEIN SYSTEMS AT SYSTEMIC LEVEL AND SUGGEST A PUTATIVE ROLE OF RESISTANCE TRAINING IN THE REDUCTION OF GLOBAL DNA METHYLATION. MOREOVER, WE OBSERVED THAT EMRT COUNTERACTS THE TELOMERES' SHORTENING IN A MANNER THAT PROVED TO BE DIRECTLY CORRELATED WITH THE AMELIORATION OF REDOX HOMEOSTASIS AND EFFICACY OF TRAINING REGIME, EVALUATED AS IMPROVEMENT OF BOTH MUSCLE'S POWER/STRENGTH AND FUNCTIONAL PARAMETERS. 2016 19 4405 33 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 20 276 30 AGE-RELATED DIFFERENCES IN MONOCYTE DNA METHYLATION AND IMMUNE FUNCTION IN HEALTHY KENYAN ADULTS AND CHILDREN. BACKGROUND: AGE-RELATED CHANGES IN ADAPTIVE AND INNATE IMMUNE CELLS HAVE BEEN ASSOCIATED WITH A DECLINE IN EFFECTIVE IMMUNITY AND CHRONIC, LOW-GRADE INFLAMMATION. EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL CHANGES IN MONOCYTES OCCUR WITH AGING, THOUGH MOST STUDIES TO DATE HAVE FOCUSED ON DIFFERENCES BETWEEN YOUNG ADULTS AND THE ELDERLY IN POPULATIONS WITH EUROPEAN ANCESTRY; FEW DATA EXIST REGARDING CHANGES THAT OCCUR IN CIRCULATING MONOCYTES DURING THE FIRST FEW DECADES OF LIFE OR IN AFRICAN POPULATIONS. WE ANALYZED DNA METHYLATION PROFILES, CYTOKINE PRODUCTION, AND INFLAMMATORY GENE EXPRESSION PROFILES IN MONOCYTES FROM YOUNG ADULTS AND CHILDREN FROM WESTERN KENYA. RESULTS: WE IDENTIFIED SEVERAL HYPO- AND HYPER-METHYLATED CPG SITES IN MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN THAT REPLICATED FINDINGS IN THE CURRENT LITERATURE OF DIFFERENTIAL DNA METHYLATION IN MONOCYTES FROM ELDERLY PERSONS VS. YOUNG ADULTS ACROSS DIVERSE POPULATIONS. DIFFERENTIALLY METHYLATED CPG SITES WERE ALSO NOTED IN GENE REGIONS IMPORTANT TO INFLAMMATION AND INNATE IMMUNE RESPONSES. MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN DISPLAYED INCREASED PRODUCTION OF IL-8, IL-10, AND IL-12P70 IN RESPONSE TO TLR4 AND TLR2/1 STIMULATION AS WELL AS DISTINCT INFLAMMATORY GENE EXPRESSION PROFILES. CONCLUSIONS: THESE FINDINGS COMPLEMENT PREVIOUS REPORTS OF AGE-RELATED METHYLATION CHANGES IN ISOLATED MONOCYTES AND PROVIDE NOVEL INSIGHTS INTO THE ROLE OF AGE-ASSOCIATED CHANGES IN INNATE IMMUNE FUNCTIONS. 2021