1 1201 160 CORTICOTROPIN-RELEASING FACTOR RECEPTOR-1 MODULATES BIOMARKERS OF DNA OXIDATION IN ALZHEIMER'S DISEASE MICE. INCREASED PRODUCTION OF HYDROXYL RADICAL IS THE MAIN SOURCE OF OXIDATIVE DAMAGE IN MAMMALIAN DNA THAT ACCUMULATES IN ALZHEIMER'S DISEASE (AD). REACTIVE OXYGEN SPECIES (ROS) REACT WITH BOTH NUCLEAR DNA (NDNA) AND MITOCHONDRIAL DNA (MTDNA) TO GENERATE 8-HYDROXY-2'-DEOXYGUANOSINE (8-OHDG), BOTH OF WHICH CAN BE MEASURED IN THE URINE. KNOWLEDGE OF THIS PATHWAY HAS POSITIONED MEASUREMENT OF URINE 8-OHDG AS A RELIABLE INDEX OF DNA OXIDATION AND A POTENTIAL BIOMARKER TARGET FOR TRACKING EARLY CELLULAR DYSFUNCTION IN AD. FURTHERMORE, EPIGENETIC STUDIES DEMONSTRATE DECREASED GLOBAL DNA METHYLATION LEVELS (E.G. 5-METHYL-2'-DEOXYCYTIDINE, 5-MDC) IN AD TISSUES. MOREOVER, STRESS HORMONES CAN ACTIVATE NEURONAL OXIDATIVE STRESS WHICH WILL STIMULATE THE RELEASE OF ADDITIONAL STRESS HORMONES AND RESULT IN DAMAGES TO HIPPOCAMPAL NEURONS IN THE AD BRAIN. OUR PREVIOUS WORK SUGGESTS THAT TREATING AD TRANSGENIC MICE THE TYPE-1 CORTICOTROPIN-RELEASING FACTOR RECEPTOR (CRFR1) ANTAGONIST, R121919, TO REDUCE STRESS SIGNALING, PREVENTED ONSET OF COGNITIVE IMPAIRMENT, SYNAPTIC/DENDRITIC LOSS AND ABETA PLAQUE ACCUMULATION. THEREFORE, TO INVESTIGATE WHETHER LEVELS OF DNA OXIDATION CAN BE IMPACTED BY THE SAME THERAPEUTIC APPROACH, URINE LEVELS OF HYDROGEN PEROXIDE, 8-OHDG, 5-MDC AND TOTAL ANTIOXIDANT CAPACITY (TAC) WERE ANALYZED USING AN AD TG MOUSE MODEL. WE FOUND THAT TG ANIMALS HAD AN 80% INCREASE IN HYDROGEN PEROXIDE LEVELS COMPARED TO WILD TYPE (WT) COUNTERPARTS, AN EFFECT THAT COULD BE DRAMATICALLY REVERSED BY THE CHRONIC ADMINISTRATION WITH R121919. A SIGNIFICANT DECREASE OF 8-OHDG LEVELS WAS OBSERVED IN TG MICE TREATED WITH CRFR1 ANTAGONIST. COLLECTIVELY OUR DATA SUGGEST THAT THE BENEFICIAL EFFECTS OF CRFR1 ANTAGONISM SEEN IN TG MICE MAY BE MECHANISTICALLY LINKED TO THE MODULATION OF OXIDATIVE STRESS PATHWAYS. 2017 2 920 29 CHRONIC HYPOXIA FACILITATES ALZHEIMER'S DISEASE THROUGH DEMETHYLATION OF GAMMA-SECRETASE BY DOWNREGULATING DNA METHYLTRANSFERASE 3B. INTRODUCTION: ENVIRONMENTAL FACTORS AND EPIGENETIC MECHANISMS ARE BELIEVED TO CONTRIBUTE TO ALZHEIMER'S DISEASE (AD). WE PREVIOUSLY DOCUMENTED THAT PRENATAL HYPOXIA AGGRAVATED THE COGNITIVE IMPAIRMENT AND NEUROPATHOLOGY IN OFFSPRING MICE. HERE, WE INVESTIGATE THE CHRONIC HYPOXIA-INDUCED EPIGENETIC MODIFICATIONS IN AD. METHODS: THE 3-MONTH-OLD APP(SWE)/PS1(DE9) MICE WERE EXPOSED TO HYPOXIC ENVIRONMENT 6 HOUR/DAY FOR 30 DAYS, FOLLOWED BY LEARNING AND MEMORY TESTS AND BIOCHEMICAL AND NEUROPATHOLOGY MEASUREMENT AT THE AGE OF 4, 6, AND 9 MONTHS. RESULTS: WE FOUND HYPOXIA EXAGGERATED THE NEUROPATHOLOGY AND COGNITIVE IMPAIRMENT IN AD MICE. CHRONIC HYPOXIA INDUCED DEMETHYLATION ON GENOMIC DNA AND DECREASED THE EXPRESSION OF DNA METHYLTRANSFERASE 3B (DNMT3B) IN VIVO. WE FURTHER FOUND THAT DNMTS INHIBITION ELEVATED THE PROTEIN LEVELS OF AMYLOID PRECURSOR PROTEIN, BETA- AND GAMMA-SECRETASES, WHEREAS OVEREXPRESSION OF DNMT3B SUPPRESSED THE LEVELS OF THEM IN VITRO. DISCUSSION: OUR STUDY SUGGESTS CHRONIC HYPOXIA CAN AGGRAVATE AD PROGRESSION THROUGH DEMETHYLATION OF GENES ENCODING GAMMA-SECRETASE COMPONENTS BY DOWNREGULATION OF DNMT3B. 2016 3 948 30 CHRONIC METABOLIC DERANGEMENT-INDUCED COGNITIVE DEFICITS AND NEUROTOXICITY ARE ASSOCIATED WITH REST INACTIVATION. CHRONIC METABOLIC ALTERATIONS MAY REPRESENT A RISK FACTOR FOR THE DEVELOPMENT OF COGNITIVE IMPAIRMENT, DEMENTIA, OR NEURODEGENERATIVE DISEASES. HYPERGLYCEMIA AND OBESITY ARE KNOWN TO IMPRINT EPIGENETIC MARKERS THAT COMPROMISE THE PROPER EXPRESSION OF CELL SURVIVAL GENES. HERE, WE SHOWED THAT CHRONIC HYPERGLYCEMIA (60 DAYS) INDUCED BY A SINGLE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN COMPROMISED COGNITION BY REDUCING HIPPOCAMPAL ERK SIGNALING AND BY INDUCING NEUROTOXICITY IN RATS. THE MECHANISMS APPEAR TO BE LINKED TO REDUCED ACTIVE DNA DEMETHYLATION AND DIMINISHED EXPRESSION OF THE NEUROPROTECTIVE TRANSCRIPTION FACTOR REST. THE IMPACT OF THE RELATIONSHIP BETWEEN ADIPOSITY AND DNA HYPERMETHYLATION ON REST EXPRESSION WAS ALSO DEMONSTRATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN OBESE CHILDREN WITH REDUCED LEVELS OF BLOOD ASCORBATE. THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS AND THE COGNITIVE IMPAIRMENT REPORTED IN OBESE CHILDREN, ADOLESCENTS, AND ADULTS SUGGEST THAT THE CORRECTION OF THE ANTHROPOMETRY AND THE PERIPHERAL METABOLIC ALTERATIONS WOULD PROTECT BRAIN HOMEOSTASIS AND REDUCE THE RISK OF DEVELOPING NEURODEGENERATIVE DISEASES. 2019 4 5710 25 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 2119 31 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 6 2297 35 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 7 988 34 CHRONIC SLEEP DISTURBANCES ALTERS SLEEP STRUCTURE AND TAU PHOSPHORYLATION IN ABETAPP/PS1 AD MICE AND THEIR WILD-TYPE LITTERMATES. BACKGROUND: EMERGING EVIDENCE INDICATES THAT SLEEP DISORDERS ARE THE COMMON NON-COGNITIVE SYMPTOMS OF ALZHEIMER'S DISEASE (AD), AND THEY MAY CONTRIBUTE TO THE PATHOGENESIS OF THIS DISEASE. OBJECTIVE: IN THIS STUDY, WE AIM TO INVESTIGATE THE EFFECT OF CHRONIC SLEEP DEPRIVATION (CSD) ON AD-RELATED PATHOLOGIES WITH A FOCUS ON TAU PHOSPHORYLATION AND THE UNDERLYING DNA METHYLATION REGULATION. METHODS: ABETAPPSWE/PS1DELTAE9 AD MICE AND THEIR WILD-TYPE (WT) LITTERMATES WERE SUBJECTED TO A TWO-MONTH CSD FOLLOWED BY ELECTROENCEPHALOGRAPHY AND ELECTROMYOGRAPHY RECORDING. THE MICE WERE EXAMINED FOR LEARNING AND MEMORY EVALUATION, THEN PATHOLOGICAL, BIOCHEMICAL, AND EPIGENETIC ASSESSMENTS INCLUDING WESTERN BLOTTING, IMMUNOFLUORESCENCE, DOT BLOTTING, AND BISULFITE SEQUENCING. RESULTS: THE RESULTS SHOW THAT CSD CAUSED SLEEP DISTURBANCES SHOWN AS SLEEP PATTERN CHANGE, POOR SLEEP MAINTENANCE, AND INCREASED SLEEP FRAGMENTATION. CSD INCREASED TAU PHOSPHORYLATION AT DIFFERENT SITES AND INCREASED THE LEVEL OF TAU KINASES IN AD AND WT MICE. THE INCREASED EXPRESSION OF CYCLIN-DEPENDENT KINASE 5 (CDK5) MAY RESULT FROM DECREASED DNA METHYLATION OF CPG SITES IN THE PROMOTER REGION OF CDK5 GENE, WHICH MIGHT BE ASSOCIATED WITH THE DOWNREGULATION OF DNA METHYLTRANSFERASE 3A AND 3B. CONCLUSION: CSD ALTERED AD-RELATED TAU PHOSPHORYLATION THROUGH EPIGENETIC MODIFICATION OF TAU KINASE GENE. THE FINDINGS IN THIS STUDY MAY GIVE INSIGHTS INTO THE MECHANISMS UNDERLYING THE EFFECTS OF SLEEP DISTURBANCES ON AD PATHOLOGY AND PROVIDE NEW THERAPEUTIC TARGETS FOR THE TREATMENT OF THIS DISEASE. 2023 8 2417 38 EPIGENETIC SIGNATURE OF CHRONIC CEREBRAL HYPOPERFUSION AND BENEFICIAL EFFECTS OF S-ADENOSYLMETHIONINE IN RATS. CHRONIC CEREBRAL HYPOPERFUSION IS ASSOCIATED WITH COGNITIVE DECLINE IN AGING AND AGE-RELATED NEURODEGENERATIVE DISEASE. EPIGENETIC MECHANISMS ARE INVOLVED IN THE MAINTENANCE OF LONG-TERM HYPOXIA-ADAPTED CELLULAR PHENOTYPES. IN THE PRESENT STUDY, THE EPIGENETIC SIGNATURES SUCH AS DNA METHYLATION AND HISTONE ACETYLATION, AS WELL AS S-ADENOSYLMETHIONINE (SAM) CYCLE USING CHRONIC CEREBRAL HYPOPERFUSION RAT MODEL WERE EXPLORED. CHRONIC CEREBRAL HYPOXIA-INDUCED GLOBAL DNA HYPERMETHYLATION ASSOCIATED WITH THE INCREASE OF DNA METHYLTRANSFERASE (DNMT) 3A AS WELL AS ALTERATION OF SAM CYCLE. MEANWHILE, AN ENHANCED LEVEL OF GLOBAL HISTONE H4 ACETYLATION ACCOMPANIED WITH THE UPREGULATION OF HISTONE ACETYLTRANSFERASE, P300/CREB-BINDING PROTEIN (CBP), AND THE DOWNREGULATION OF HISTONE DEACETYLASES (HDACS), WAS ALSO OBSERVED. SAM COULD IMPROVE SPATIAL CAPACITY THROUGH THE UPREGULATION OF ACETYLCHOLINE AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) RATHER THAN ALTERATION OF DNA METHYLATION LEVELS. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC CEREBRAL HYPOXIC CONDITIONS IN A RAT'S BRAIN. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR RESPONDS WITH A POTENTIAL ROLE IN MEMORY DEFICITS. 2014 9 3341 35 HISTONE DEACETYLASE-2 IS INVOLVED IN STRESS-INDUCED COGNITIVE IMPAIRMENT VIA HISTONE DEACETYLATION AND PI3K/AKT SIGNALING PATHWAY MODIFICATION. EXPOSURE TO CHRONIC STRESS UPREGULATES BLOOD GLUCOCORTICOID LEVELS AND IMPAIRS COGNITION VIA DIVERSE EPIGENETIC MECHANISMS, SUCH AS HISTONE DEACETYLATION. HISTONE DEACETYLATION CAN LEAD TO TRANSCRIPTIONAL SILENCING OF MANY PROTEINS INVOLVED IN COGNITION AND MAY ALSO CAUSE LEARNING AND MEMORY DYSFUNCTION. HISTONE DEACETYLASE?2 (HDAC2) HAS BEEN DEMONSTRATED TO EPIGENETICALLY BLOCK COGNITION VIA A REDUCTION IN THE HISTONE ACETYLATION LEVEL; HOWEVER, IT IS UNKNOWN WHETHER HDAC2 IS INVOLVED IN THE COGNITIVE DECLINE INDUCED BY CHRONIC STRESS. TO THE BEST OF AUTHORS' KNOWLEDGE, THIS IS THE FIRST STUDY TO DEMONSTRATE THAT THE STRESS HORMONE CORTICOSTEROID UPREGULATE HDAC2 PROTEIN LEVELS IN NEURO?2A CELLS AND CAUSE CELL INJURIES. HDAC2 KNOCKDOWN RESULTED IN A SIGNIFICANT AMELIORATION OF THE PATHOLOGICAL CHANGES IN N2A CELLS VIA THE UPREGULATION OF HISTONE ACETYLATION AND MODIFICATIONS IN THE PHOSPHOINOSITIDE 3?KINASE/PROTEIN KINASE B SIGNALING PATHWAY. IN ADDITION, THE HDAC2 PROTEIN LEVELS WERE UPREGULATED IN 12?MONTH?OLD FEMALE C57BL/6J MICE UNDER CHRONIC STRESS IN VIVO. TAKEN TOGETHER, THESE FINDINGS SUGGESTED THAT HDAC2 MAY BE AN IMPORTANT NEGATIVE REGULATOR INVOLVED IN CHRONIC STRESS?INDUCED COGNITIVE IMPAIRMENT. 2017 10 3587 38 IMPACT OF TLR4 ON BEHAVIORAL AND COGNITIVE DYSFUNCTIONS ASSOCIATED WITH ALCOHOL-INDUCED NEUROINFLAMMATORY DAMAGE. TOLL-LIKE RECEPTORS (TLRS) PLAY AN IMPORTANT ROLE IN THE INNATE IMMUNE RESPONSE, AND EMERGING EVIDENCE INDICATES THEIR ROLE IN BRAIN INJURY AND NEURODEGENERATION. OUR RECENT RESULTS HAVE DEMONSTRATED THAT ETHANOL IS CAPABLE OF ACTIVATING GLIAL TLR4 RECEPTORS AND THAT THE ELIMINATION OF THESE RECEPTORS IN MICE PROTECTS AGAINST ETHANOL-INDUCED GLIAL ACTIVATION, INDUCTION OF INFLAMMATORY MEDIATORS AND APOPTOSIS. THIS STUDY WAS DESIGNED TO ASSESS WHETHER ETHANOL-INDUCED INFLAMMATORY DAMAGE CAUSES BEHAVIORAL AND COGNITIVE CONSEQUENCES, AND IF BEHAVIORAL ALTERATIONS ARE DEPENDENT OF TLR4 FUNCTIONS. HERE WE SHOW IN MICE DRINKING ALCOHOL FOR 5MONTHS, FOLLOWED BY A 15-DAY WITHDRAWAL PERIOD, THAT ACTIVATION OF THE ASTROGLIAL AND MICROGLIAL CELLS IN FRONTAL CORTEX AND STRIATUM IS MAINTAINED AND THAT THESE EVENTS ARE ASSOCIATED WITH COGNITIVE AND ANXIETY-RELATED BEHAVIORAL IMPAIRMENTS IN WILD-TYPE (WT) MICE, AS DEMONSTRATED BY TESTING THE ANIMALS WITH OBJECT MEMORY RECOGNITION, CONDITIONED TASTE AVERSION AND DARK AND LIGHT BOX ANXIETY TASKS. MICE LACKING TLR4 RECEPTORS ARE PROTECTED AGAINST ETHANOL-INDUCED INFLAMMATORY DAMAGE, AND BEHAVIORAL ASSOCIATED EFFECTS. WE FURTHER ASSESS THE POSSIBILITY OF THE EPIGENETIC MODIFICATIONS PARTICIPATING IN SHORT- OR LONG-TERM BEHAVIORAL EFFECTS ASSOCIATED WITH NEUROINFLAMMATORY DAMAGE. WE SHOW THAT CHRONIC ALCOHOL TREATMENT DECREASES H4 HISTONE ACETYLATION AND HISTONE ACETYLTRANSFERASES ACTIVITY IN FRONTAL CORTEX, STRIATUM AND HIPPOCAMPUS OF WT MICE. ALTERATIONS IN CHROMATIN STRUCTURE WERE NOT OBSERVED IN TLR4(-/-) MICE. THESE RESULTS PROVIDE THE FIRST EVIDENCE OF THE ROLE THAT TLR4 FUNCTIONS PLAY IN THE BEHAVIORAL CONSEQUENCES OF ALCOHOL-INDUCED INFLAMMATORY DAMAGE AND SUGGEST THAT THE EPIGENETIC MODIFICATIONS MEDIATED BY TLR4 COULD CONTRIBUTE TO SHORT- OR LONG-TERM ALCOHOL-INDUCED BEHAVIORAL OR COGNITIVE DYSFUNCTIONS. 2011 11 3837 37 IONIZING RADIATION-INDUCED OXIDATIVE STRESS, EPIGENETIC CHANGES AND GENOMIC INSTABILITY: THE PIVOTAL ROLE OF MITOCHONDRIA. PURPOSE: TO REVIEW THE DATA CONCERNING THE ROLE OF ENDOGENOUSLY GENERATED REACTIVE OXYGEN SPECIES (ROS) IN THE NON-TARGETED IONIZING RADIATION (IR) EFFECTS AND IN DETERMINATION OF THE CELL POPULATION'S FATE, BOTH EARLY AFTER EXPOSURE AND AFTER MANY GENERATIONS. CONCLUSIONS: THE SHORT-TERM AS WELL AS CHRONIC OXIDATIVE STRESS RESPONSES MAINLY ARE PRODUCED DUE TO ROS GENERATION BY THE ELECTRON TRANSPORT CHAIN (ETC) OF THE MITOCHONDRIA AND BY THE CYTOPLASMIC NADPH OXIDASES. WHETHER THE INDUCTION OF THE OXIDATIVE STRESS AND ITS CONSEQUENCES OCCUR OR ARE HAMPERED IN A SINGLE CELL LARGELY DEPENDS ON THE INTERACTION BETWEEN THE NUCLEUS AND THE CELLULAR POPULATION OF SEVERAL HUNDRED OR THOUSANDS OF MITOCHONDRIA THAT ARE GENETICALLY HETEROGENEOUS. HIGH INTRA-MITOCHONDRIAL ROS LEVEL IS DAMAGING THE MITOCHONDRIAL (MT) DNA AND ITS MUTATIONS AFFECT THE EPIGENETIC CONTROL MECHANISMS OF THE NUCLEAR (N) DNA, BY DECREASING THE ACTIVITY OF METHYLTRANSFERASES AND THUS, CAUSING GLOBAL DNA HYPOMETHYLATION. THESE CHANGES ARE TRANSMITTED TO THE PROGENY OF THE IRRADIATED CELLS. THE CHRONIC OXIDATIVE STRESS IS THE MAIN CAUSE OF THE LATE POST-RADIATION EFFECTS, INCLUDING CANCER, AND THIS MAKES IT AN IMPORTANT ADVERSE EFFECT OF EXPOSURE TO IR AND A TARGET FOR RADIOLOGICAL PROTECTION. 2015 12 5818 37 STRESS AND TRAUMA: BDNF CONTROL OF DENDRITIC-SPINE FORMATION AND REGRESSION. CHRONIC RESTRAINT STRESS LEADS TO INCREASES IN BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA AND PROTEIN IN SOME REGIONS OF THE BRAIN, E.G. THE BASAL LATERAL AMYGDALA (BLA) BUT DECREASES IN OTHER REGIONS SUCH AS THE CA3 REGION OF THE HIPPOCAMPUS AND DENDRITIC SPINE DENSITY INCREASES OR DECREASES IN LINE WITH THESE CHANGES IN BDNF. GIVEN THE POWERFUL INFLUENCE THAT BDNF HAS ON DENDRITIC SPINE GROWTH, THESE OBSERVATIONS SUGGEST THAT THE FUNDAMENTAL REASON FOR THE DIRECTION AND EXTENT OF CHANGES IN DENDRITIC SPINE DENSITY IN A PARTICULAR REGION OF THE BRAIN UNDER STRESS IS DUE TO THE CHANGES IN BDNF THERE. THE MOST LIKELY CAUSE OF THESE CHANGES IS PROVIDED BY THE STRESS INITIATED RELEASE OF STEROIDS, WHICH READILY ENTER NEURONS AND ALTER GENE EXPRESSION, FOR EXAMPLE THAT OF BDNF. OF PARTICULAR INTEREST IS HOW GLUCOCORTICOIDS AND MINERALOCORTICOIDS TEND TO HAVE OPPOSITE EFFECTS ON BDNF GENE EXPRESSION OFFERING THE POSSIBILITY THAT DIFFERENCES IN THE DISTRIBUTION OF THEIR RECEPTORS AND OF THEIR DOWNSTREAM EFFECTS MIGHT PROVIDE A BASIS FOR THE DIFFERENTIAL TRANSCRIPTION OF THE BDNF GENES. ALTERNATIVELY, DIFFERENCES IN THE EXTENT OF METHYLATION AND ACETYLATION IN THE EPIGENETIC CONTROL OF BDNF TRANSCRIPTION ARE POSSIBLE IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS. ALTHOUGH PRESENT EVIDENCE POINTS TO CHANGES IN BDNF TRANSCRIPTION BEING THE MAJOR CAUSAL AGENT FOR THE CHANGES IN SPINE DENSITY IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS, STEROIDS HAVE SIGNIFICANT EFFECTS ON DOWNSTREAM PATHWAYS FROM THE TRKB RECEPTOR ONCE IT IS ACTED UPON BY BDNF, INCLUDING THOSE THAT MODULATE THE DENSITY OF DENDRITIC SPINES. FINALLY, ALTHOUGH GLUCOCORTICOIDS PLAY A CANONICAL ROLE IN DETERMINING BDNF MODULATION OF DENDRITIC SPINES, RECENT STUDIES HAVE SHOWN A ROLE FOR CORTICOTROPHIN RELEASING FACTOR (CRF) IN THIS REGARD. THERE IS CONSIDERABLE IMPROVEMENT IN THE EXTENT OF CHANGES IN SPINE SIZE AND DENSITY IN RODENTS WITH FOREBRAIN SPECIFIC KNOCKOUT OF CRF RECEPTOR 1 (CRFR1) EVEN WHEN THE GLUCOCORTICOID PATHWAYS ARE LEFT INTACT. IT SEEMS THEN THAT CRF DOES HAVE A ROLE TO PLAY IN DETERMINING BDNF CONTROL OF DENDRITIC SPINES. 2014 13 3148 40 GLUCOCORTICOID INDUCED LOSS OF OESTROGEN RECEPTOR ALPHA GENE METHYLATION AND RESTORATION OF SENSITIVITY TO FULVESTRANT IN TRIPLE NEGATIVE BREAST CANCER. THE RESPONSE TO PSYCHOLOGICAL STRESS CAN DIFFER DEPENDING ON THE TYPE AND DURATION OF THE STRESSOR. ACUTE STRESS CAN FACILITATE A "FIGHT OR FLIGHT RESPONSE" AND AID SURVIVAL, WHEREAS CHRONIC LONG-TERM STRESS WITH THE PERSISTENT RELEASE OF STRESS HORMONES SUCH AS CORTISOL HAS BEEN SHOWN TO BE DETRIMENTAL TO HEALTH. WE ARE NOW BEGINNING TO UNDERSTAND HOW THIS STRESS HORMONE RESPONSE IMPACTS IMPORTANT PROCESSES SUCH AS DNA REPAIR AND CELL PROLIFERATION PROCESSES IN BREAST CANCER. HOWEVER, IT IS NOT KNOWN WHAT EPIGENETIC CHANGES STRESS HORMONES INDUCE IN BREAST CANCER. EPIGENETIC MECHANISMS INCLUDE MODIFICATION OF DNA AND HISTONES WITHIN CHROMATIN THAT MAY BE INVOLVED IN GOVERNING THE TRANSCRIPTIONAL PROCESSES IN CANCER CELLS IN RESPONSE TO CHANGES BY ENDOGENOUS STRESS HORMONES. THE CONTRIBUTION OF ENDOGENOUS ACUTE OR LONG-TERM EXPOSURE OF GLUCOCORTICOID STRESS HORMONES, AND EXOGENOUS GLUCOCORTICOIDS TO METHYLATION PATTERNS IN BREAST CANCER TISSUES WITH DIFFERENT AETIOLOGIES REMAINS TO BE EVALUATED. IN VITRO AND IN VIVO MODELS WERE DEVELOPED TO INVESTIGATE THE EPIGENETIC MODIFICATIONS AND THEIR CONTRIBUTION TO BREAST CANCER PROGRESSION AND AETIOLOGY. A PANEL OF TRIPLE NEGATIVE BREAST CANCER CELL LINES WERE TREATED WITH THE GLUCOCORTICOID, CORTISOL WHICH RESULTED IN EPIGENETIC ALTERATION CHARACTERISED BY LOSS OF METHYLATION ON PROMOTER REGIONS OF TUMOUR SUPPRESSOR GENES INCLUDING ESR1, AND LOSS OF METHYLATION ON LINE-1 REPETITIVE ELEMENT USED AS A SURROGATE MARKER FOR GLOBAL METHYLATION. THIS WAS VERIFIED IN VIVO IN MDA-MB-231 XENOGRAFTS; THE MODEL VERIFIED THE LOSS OF METHYLATION ON ESR1 PROMOTER, AND SUBSEQUENT INCREASE IN ESR1 EXPRESSION IN PRIMARY TUMOURS IN MICE SUBJECTED TO RESTRAINT STRESS. OUR STUDY HIGHLIGHTS THAT DNA METHYLATION LANDSCAPE IN BREAST CANCER CAN BE ALTERED IN RESPONSE TO STRESS AND GLUCOCORTICOID TREATMENT. 2023 14 978 44 CHRONIC OXIDATIVE STRESS CAUSES ESTROGEN-INDEPENDENT AGGRESSIVE PHENOTYPE, AND EPIGENETIC INACTIVATION OF ESTROGEN RECEPTOR ALPHA IN MCF-7 BREAST CANCER CELLS. THE ROLE OF CHRONIC OXIDATIVE STRESS IN THE DEVELOPMENT AND AGGRESSIVE GROWTH OF ESTROGEN RECEPTOR (ER)-POSITIVE BREAST CANCER IS WELL KNOWN; HOWEVER, THE MECHANISTIC UNDERSTANDING IS NOT CLEAR. ESTROGEN-INDEPENDENT GROWTH IS ONE OF THE FEATURES OF AGGRESSIVE SUBTYPE OF BREAST CANCER. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECT OF OXIDATIVE STRESS ON ESTROGEN SENSITIVITY AND EXPRESSION OF NUCLEAR ESTROGEN RECEPTORS IN ER-POSITIVE BREAST CANCER CELLS. MCF-7 CELLS CHRONICALLY EXPOSED TO HYDROGEN PEROXIDE WERE USED AS A CELL MODEL IN THIS STUDY, AND THEIR GROWTH IN RESPONSE TO 17-BETA ESTRADIOL WAS EVALUATED BY CELL VIABILITY, CELL CYCLE, AND CELL MIGRATION ANALYSIS. RESULTS WERE FURTHER CONFIRMED AT MOLECULAR LEVEL BY ANALYSIS OF GENE EXPRESSIONS AT TRANSCRIPT AND PROTEIN LEVELS. HISTONE H3 MODIFICATIONS, EXPRESSION OF EPIGENETIC REGULATORY GENES, AND THE EFFECT OF DNA DEMETHYLATION WERE ALSO ANALYZED. LOSS OF GROWTH IN RESPONSE TO ESTROGEN WITH A DECREASE IN ERALPHA EXPRESSION WAS OBSERVED IN MCF-7 CELLS ADAPTED TO CHRONIC OXIDATIVE STRESS. INCREASES IN MTTFA AND NRF1 IN THESE CELLS FURTHER SUGGESTED THE ROLE OF MITOCHONDRIA-DEPENDENT REDOX-SENSITIVE GROWTH SIGNALING AS AN ALTERNATIVE PATHWAY TO ESTROGEN-DEPENDENT GROWTH. CHANGES IN EXPRESSION OF EPIGENETIC REGULATORY GENES, LEVELS OF HISTONE H3 MODIFICATIONS AS WELL AS SIGNIFICANT RESTORATIONS OF BOTH ERALPHA EXPRESSION AND ESTROGEN RESPONSE BY 5-AZA-2'-DEOXYCYTIDINE FURTHER CONFIRMED THE EPIGENETIC BASIS FOR ESTROGEN-INDEPENDENT GROWTH IN THESE CELLS. IN CONCLUSION, RESULTS OF THIS STUDY SUGGEST THAT CHRONIC OXIDATIVE STRESS CAN CONVERT ESTROGEN-DEPENDENT NONAGGRESSIVE BREAST CANCER CELLS INTO ESTROGEN-INDEPENDENT AGGRESSIVE FORM POTENTIALLY BY EPIGENETIC MECHANISM. 2015 15 331 38 ALTERATION IN MITOCHONDRIAL DYNAMICS PROMOTES THE PROINFLAMMATORY RESPONSE OF MICROGLIA AND IS INVOLVED IN CEREBELLAR DYSFUNCTION OF YOUNG AND AGED MICE FOLLOWING LPS EXPOSURE. CEREBELLAR DYSFUNCTION IS IMPLICATED IN IMPAIRED MOTOR COORDINATION AND BALANCE, THUS DISTURBING THE DYNAMICS OF SENSORIMOTOR INTEGRATION. NEUROINFLAMMATION AND AGING COULD BE PROMINENT CONTRIBUTORS TO CEREBELLAR ABERRATION. ADDITIONALLY, CHANGES IN MITOCHONDRIAL DYNAMICS MAY PRECEDE MICROGLIA ACTIVATION IN SEVERAL CHRONIC NEURODEGENERATIVE DISEASES; HOWEVER, THE UNDERLYING MECHANISM REMAINS LARGELY UNKNOWN. HERE USING LPS (1 MG/KG I.P. FOR FOUR CONSECUTIVE DAYS) STIMULATION IN BOTH YOUNG (3 MONTHS OLD) AND AGED (12 MONTHS OLD) MICE, FOLLOWED BY MOLECULAR ANALYSIS ON THE 21ST DAY, WE HAVE EXPLORED THE CORRELATION BETWEEN AGING AND MITOCHONDRIAL DYNAMIC ALTERATION IN THE BACKDROP OF CHRONIC NEUROINFLAMMATION. FOLLOWING LPS STIMULATION, WE OBSERVED MICROGLIA ACTIVATION AND SUBSEQUENT ELEVATION IN PROINFLAMMATORY CYTOKINES (M1; TNF-ALPHA, IFN-GAMMA) WITH NLRP3 ACTIVATION AND A CONCOMITANT REDUCTION IN THE EXPRESSION OF ANTI-INFLAMMATORY MARKERS (M2; YM1, TGF-BETA1) IN THE CEREBELLAR TISSUE OF AGED MICE COMPARED WITH THE YOUNG LPS AND AGED CONTROLS. REMARKABLY, SENESCENCE (P21, P27, P53) AND EPIGENETIC (HDAC2) MARKERS WERE FOUND UPREGULATED IN THE CEREBELLUM TISSUE OF THE AGED LPS GROUP, SUGGESTING THEIR CRUCIAL ROLE IN LPS-INDUCED CEREBELLAR DEFICIT. FURTHER, WE DEMONSTRATED ALTERATION IN THE ANTAGONISTIC FORCES OF MITOCHONDRIAL FUSION AND FISSION WITH INCREASED EXPRESSION OF THE MITOCHONDRIAL FISSION-RELATED GENE [FIS1] AND DECREASED FUSION-RELATED GENES [MFN1 AND MFN2]. WE NOTED INCREASED MTDNA COPY NUMBER, MICROGLIA ACTIVATION, AND INFLAMMATORY RESPONSE OF IL1-BETA AND IFN-GAMMA POST-CHRONIC NEUROINFLAMMATION IN AGED LPS GROUP. OUR RESULTS SUGGEST THAT THE CROSSTALK BETWEEN MITOCHONDRIAL DYNAMICS AND ALTERED MICROGLIAL ACTIVATION PARADIGM IN CHRONIC NEUROINFLAMMATORY CONDITIONS MAY BE THE KEY TO UNDERSTANDING THE CEREBELLAR MOLECULAR MECHANISM. 2023 16 4093 26 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 17 5193 35 PRENATAL EXPOSURE TO ENVIRONMENTAL PRO-OXIDANTS INDUCES MITOCHONDRIA-MEDIATED EPIGENETIC CHANGES: A CROSS-SECTIONAL PILOT STUDY. MITOCHONDRIA PLAY A CENTRAL ROLE IN MAINTAINING CELLULAR AND METABOLIC HOMEOSTASIS DURING VITAL DEVELOPMENT CYCLES OF FOETAL GROWTH. OPTIMAL MITOCHONDRIAL FUNCTIONS ARE IMPORTANT NOT ONLY TO SUSTAIN ADEQUATE ENERGY PRODUCTION BUT ALSO FOR REGULATED EPIGENETIC PROGRAMMING. HOWEVER, THESE ORGANELLES ARE SUBTLE TARGETS OF ENVIRONMENTAL EXPOSURES, AND ANY PERTURBANCE IN THE DEFINED MITOCHONDRIAL MACHINERY DURING THE DEVELOPMENTAL STAGE CAN LEAD TO THE RE-PROGRAMMING OF THE FOETAL EPIGENETIC LANDSCAPE. AS THESE MODIFICATIONS CAN BE TRANSFERRED TO SUBSEQUENT GENERATIONS, WE HEREIN PERFORMED A CROSS-SECTIONAL STUDY TO HAVE AN IN-DEPTH UNDERSTANDING OF THIS INTRICATE PHENOMENON. THE STUDY WAS CONDUCTED WITH TWO ARMS: WHEREAS THE FIRST GROUP CONSISTED OF IN UTERO PRO-OXIDANT EXPOSED INDIVIDUALS AND THE SECOND GROUP INCLUDED CONTROLS. OUR RESULTS SHOWED HIGHER LEVELS OF OXIDATIVE MTDNA DAMAGE AND ASSOCIATED INTEGRATED STRESS RESPONSE AMONG THE EXPOSED INDIVIDUALS. THESE DISTURBANCES WERE FOUND TO BE CLOSELY RELATED TO THE OBSERVED DISCREPANCIES IN MITOCHONDRIAL BIOGENESIS. THE EXPOSED GROUP SHOWED MTDNA HYPERMETHYLATION AND CHANGES IN ALLIED MITOCHONDRIAL FUNCTIONING. ALTERED EXPRESSION OF MITOMIRS AND THEIR RESPECTIVE TARGET GENES IN THE EXPOSED GROUP INDICATED THE POSSIBILITIES OF A DISTURBED MITOCHONDRIAL-NUCLEAR CROSS TALK. THIS WAS FURTHER CONFIRMED BY THE MODIFIED ACTIVITY OF THE MITOCHONDRIAL STRESS REGULATORS AND PRO-INFLAMMATORY MEDIATORS AMONG THE EXPOSED GROUP. IMPORTANTLY, THE DISTURBED DNMT FUNCTIONING, HYPERMETHYLATION OF NUCLEAR DNA, AND HIGHER DEGREE OF POST-TRANSLATIONAL HISTONE MODIFICATIONS ESTABLISHED THE EXISTENCE OF ABERRANT EPIGENETIC MODIFICATIONS IN THE EXPOSED INDIVIDUALS. OVERALL, OUR RESULTS DEMONSTRATE THE FIRST MOLECULAR INSIGHTS OF IN UTERO PRO-OXIDANT EXPOSURE ASSOCIATED CHANGES IN THE MITOCHONDRIAL-EPIGENETIC AXIS. ALTHOUGH, OUR STUDY MIGHT NOT CEMENT AN EXPOSURE-RESPONSE RELATIONSHIP FOR ANY PARTICULAR ENVIRONMENTAL PRO-OXIDANT, BUT SUFFICE TO ESTABLISH A DOGMA OF MITO-EPIGENETIC REPROGRAMMING AT INTRAUTERINE MILIEU WITH CHRONIC ILLNESS, A HITHERTO UNREPORTED INTERACTION. 2022 18 4604 31 NEGATIVE EVIDENCE FOR A FUNCTIONAL ROLE OF NEURONAL DNMT3A IN PERSISTENT PAIN. TRADITIONALLY, NEUROSCIENCE HAS HAD TO RELY ON MIXED TISSUE ANALYSIS TO EXAMINE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN THE CONTEXT OF NERVOUS SYSTEM FUNCTION OR PATHOLOGY. HOWEVER, PARTICULARLY WHEN STUDYING CHRONIC PAIN CONDITIONS, THIS APPROACH CAN BE FLAWED, SINCE IT NEGLECTS TO TAKE INTO ACCOUNT THE SHIFTING CONTRIBUTION OF DIFFERENT CELL TYPES ACROSS EXPERIMENTAL CONDITIONS. HERE, WE DEMONSTRATE THIS USING THE EXAMPLE OF DNA METHYLTRANSFERASES (DNMTS) - A GROUP OF EPIGENETIC MODIFIERS CONSISTING OF DNMT1, DNMT3A, AND DNMT3B IN MAMMALIAN CELLS. WE USED SENSORY NEURON-SPECIFIC KNOCKOUT MICE FOR DNMT3A/3B AS WELL AS PHARMACOLOGICAL BLOCKADE OF DNMT1 TO STUDY THEIR ROLE IN NOCICEPTION. IN CONTRAST TO PREVIOUS ANALYSES ON WHOLE TISSUE, WE FIND THAT DNMT3A AND 3B PROTEIN IS NOT EXPRESSED IN ADULT DRG NEURONS, THAT NONE OF THE DNA METHYLTRANSFERASES ARE REGULATED WITH INJURY AND THAT INTERFERING WITH THEIR FUNCTION HAS NO EFFECT ON NOCICEPTION. OUR RESULTS THEREFORE CURRENTLY DO NOT SUPPORT A ROLE FOR NEURONAL DNA METHYLTRANSFERASES IN PAIN PROCESSING IN ADULT ANIMALS. 2018 19 4969 35 PATHOLOGICAL NEUROINFLAMMATORY CONVERSION OF REACTIVE ASTROCYTES IS INDUCED BY MICROGLIA AND INVOLVES CHROMATIN REMODELING. FOLLOWING BRAIN INJURY OR IN NEURODEGENERATIVE DISEASES, ASTROCYTES BECOME REACTIVE AND MAY SUFFER PATHOLOGICAL REMODELING, FEATURES OF WHICH ARE THE LOSS OF THEIR HOMEOSTATIC FUNCTIONS AND A PRO-INFLAMMATORY GAIN OF FUNCTION THAT FACILITATES NEURODEGENERATION. PHARMACOLOGICAL INTERVENTION TO MODULATE THIS ASTROGLIAL RESPONSE AND NEUROINFLAMMATION IS AN INTERESTING NEW THERAPEUTIC RESEARCH STRATEGY, BUT IT STILL REQUIRES A DEEPER UNDERSTANDING OF THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF THE PHENOMENON. BASED ON THE KNOWN MICROGLIAL-ASTROGLIAL INTERACTION, THE PROMINENT ROLE OF THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY IN MEDIATING ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION, AND ITS ABILITY TO RECRUIT CHROMATIN-REMODELING ENZYMES, WE FIRST EXPLORED THE MICROGLIAL ROLE IN THE INITIATION OF ASTROGLIAL PRO-INFLAMMATORY CONVERSION AND THEN MONITORED THE PROGRESSION OF EPIGENETIC CHANGES IN THE ASTROCYTIC CHROMATIN. DIFFERENT CONFIGURATIONS OF PRIMARY GLIAL CULTURE WERE USED TO MODULATE MICROGLIA-ASTROCYTE CROSSTALK WHILE INDUCING PRO-INFLAMMATORY GAIN OF FUNCTION BY LIPOPOLYSACCHARIDE (LPS) EXPOSURE. IN VIVO, BRAIN ISCHEMIA BY CORTICAL DEVASCULARIZATION (PIAL DISRUPTION) WAS PERFORMED TO VERIFY THE PRESENCE OF EPIGENETIC MARKS IN REACTIVE ASTROCYTES. OUR RESULTS SHOWED THAT 1) MICROGLIA IS REQUIRED TO INITIATE THE PATHOLOGICAL CONVERSION OF ASTROCYTES BY TRIGGERING THE NF-KAPPAB SIGNALING PATHWAY; 2) THIS INTERACTION IS MEDIATED BY SOLUBLE FACTORS AND INDUCES STABLE ASTROGLIAL PHENOTYPIC CHANGES; 3) THE PATHOLOGICAL CONVERSION PROMOTES CHROMATIN REMODELING WITH STABLE INCREASE IN H3K9K14AC, TEMPORARY INCREASE IN H3K27AC, AND TEMPORARY REDUCTION IN HETEROCHROMATIN MARK H3K9ME3; AND 4) IN VIVO REACTIVE ASTROCYTES SHOW INCREASED H3K27AC MARK IN THE NEUROINFLAMMATORY MILIEU FROM THE ISCHEMIC PENUMBRA. OUR FINDINGS INDICATE THAT ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION IS ASSOCIATED WITH PROFOUND CHANGES IN THE CONFIGURATION OF ASTROCYTIC CHROMATIN, WHICH IN TURN ARE INITIATED BY MICROGLIA-DERIVED CUES. THESE RESULTS OPEN A NEW AVENUE IN THE STUDY OF POTENTIAL PHARMACOLOGICAL INTERVENTIONS THAT MODIFY THE INITIATION AND STABILIZATION OF ASTROGLIAL PATHOLOGICAL REMODELING, WHICH WOULD BE USEFUL IN ACUTE AND CHRONIC CNS INJURY. EPIGENETIC CHANGES REPRESENT A PLAUSIBLE PHARMACOLOGICAL TARGET TO INTERFERE WITH THE STABILIZATION OF THE PATHOLOGICAL ASTROGLIAL PHENOTYPE. 2021 20 5645 35 SEX DEPENDENT ALTERATION OF EPIGENETIC MARKS AFTER CHRONIC MORPHINE TREATMENT IN MICE ORGANS. EPIGENETIC MARKS MAY BE ALSO AFFECTED BY SEVERAL FACTORS, SUCH AS AGE, LIFESTYLE, EARLY LIFE EXPERIENCES AND EXPOSURE TO CHEMICALS OR DRUGS, SUCH AS OPIOIDS. PREVIOUS STUDIES HAVE FOCUSED ON HOW MORPHINE EPIGENETICALLY REGULATES DIFFERENT REGIONS OF THE BRAIN THAT ARE IMPLICATED IN TOLERANCE, DEPENDENCE AND OTHER PSYCHIATRIC DISORDERS MORE RELATED TO THE PHYSIO-PATHOLOGICAL EFFECTS OF OPIOIDS. NEVERTHELESS, A SIGNIFICANT KNOWLEDGE GAP REMAINS REGARDING THE EFFECT OF CHRONIC TREATMENT ON OTHER ORGANS AND BIOLOGICAL SYSTEMS. THEREFORE, THE AIM OF THIS WORK IS TO INCREASE OUR KNOWLEDGE ABOUT THE IMPACT OF CHRONIC MORPHINE EXPOSURE ON DNA METHYLATION AND HISTONE MODIFICATION LEVELS IN EACH OF THE ORGANS OF MALE AND FEMALE MODEL MICE IN VIVO. OUR RESULTS REVEAL, FOR THE FIRST TIME, THAT CHRONIC MORPHINE TREATMENT INDUCED CHANGES IN DNA METHYLATION/HYDROXYMETHYLATION AND HISTONE MODIFICATION IN-VIVO AT THE SYSTEMIC LEVEL, REVEALING A POTENTIAL PHYSIOLOGICAL EFFECT ON THE REGULATION OF GENE EXPRESSION. NOTABLY, MORPHINE-INDUCED EPIGENETIC MODIFICATION OCCURS IN A SEX-DEPENDENT MANNER, REVEALING THE EXISTENCE OF DIFFERENT UNDERLYING MECHANISMS OF EPIGENETIC MODIFICATION IN MALE AND FEMALE MICE. 2021