1 4766 155 NT-4/5 AND LIF, BUT NOT NT-3 AND BDNF, PROMOTE NPY MRNA EXPRESSION IN CORTICAL NEURONS IN THE ABSENCE OF SPONTANEOUS BIOELECTRICAL ACTIVITY. EPIGENETIC FACTORS ARE KNOWN TO INFLUENCE THE DIFFERENTIATION OF NEOCORTICAL NEURONS. THE PRESENT STUDY ANALYSES THE ROLE OF SPONTANEOUS BIOELECTRICAL ACTIVITY (SBA) AND NEUROTROPHIC FACTORS ON THE EXPRESSION OF NEUROPEPTIDE Y (NPY) IN RAT VISUAL CORTICAL NEURONS USING ORGANOTYPIC MONOCULTURES PREPARED FROM NEWBORN ANIMALS AND IN SITU HYBRIDIZATION TO DETECT THE NPY MESSENGER RIBONUCLEIC ACID (MRNA). SPONTANEOUSLY ACTIVE CORTEX CULTURES DISPLAY NPY MRNA EXPRESSION IN ABOUT 7% OF ALL CORTICAL NEURONS FROM 10 DAYS IN VITRO (DIV) ON. BLOCKING THE SBA BY CHRONIC APPLICATION OF 10 MM MG2+ FOR 3-30 DIV REDUCES THE PERCENTAGE OF NPY NEURONS TO ABOUT 2%. ALLOWING AN INITIAL PHASE OF SBA (1-20 DIV) FOLLOWED BY AN SBA BLOCKADE (FOR 21-50 DIV) RESULTS IN 2% LABELLED NEURONS, INDICATING A DRAMATIC REDUCTION OF NPY MRNA EXPRESSION IN THE ABSENCE OF SBA. SURPRISINGLY, THE REVERSE EXPERIMENT (A PERIOD OF SBA BLOCKADE FOR 1-20 DIV FOLLOWED BY A PERIOD OF SBA RECOVERY FOR 21-40 DIV) DOES NOT CAUSE AN UPREGULATION OF NPY MRNA EXPRESSION. HOWEVER, ALLOWING CULTURES TO DIFFERENTIATE AS SPONTANEOUSLY ACTIVE CULTURES, THEN APPLYING A TRANSIENT PERIOD OF SBA BLOCKADE WHICH IS FOLLOWED BY A SECOND PERIOD OF SBA, DOES RESCUE THE NPY MRNA EXPRESSION IN 7% OF THE CORTICAL NEURONS. WE CONCLUDE THAT SBA IS A MAIN TRIGGER FOR NPY MRNA EXPRESSION AND IT IS PARTICULARLY IMPORTANT DURING AN EARLY POSTNATAL PERIOD OF DIFFERENTIATION. WE THEN ANALYSED WHETHER NEUROTROPHIC FACTORS KNOWN TO MODULATE CORTICAL NEUROPEPTIDE EXPRESSION ARE ABLE TO DO SO IN THE ABSENCE OF SBA. SUPPLEMENTING CHRONICALLY BLOCKED CULTURES WITH THE NEUROTROPHINS, BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), NEUROTROPHIN-3 (NT-3), NEUROTROPHIN-4/5 (NT-4/5) AND THE CYTOKINE, LEUKAEMIA INHIBITORY FACTOR (LIF), REVEALS THAT BDNF AND NT-3 ARE UNABLE TO INCREASE THE PERCENTAGE OF NPY NEURONS. IN CONTRAST, LIF AND NT-4/5 INCREASE THE PERCENTAGE OF NPY NEURONS TO 4 AND 6-7%, RESPECTIVELY. MOREOVER, NEURONS TREATED WITH NT-4/5 DISPLAY A VERY HIGH LEVEL OF NPY MRNA EXPRESSION IN SOMATA AND IN THE DENDRITIC TREES. THE DATA SUGGEST A COMPLEX INTERPLAY AND A HIERARCHY OF EPIGENETIC FACTORS IN REGULATING THE NEUROCHEMICAL ARCHITECTURE OF THE DEVELOPING NEOCORTEX.	1998	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
2 2674  38 ETHOSUXIMIDE REDUCES EPILEPTOGENESIS AND BEHAVIORAL COMORBIDITY IN THE GAERS MODEL OF GENETIC GENERALIZED EPILEPSY. PURPOSE: ETHOSUXIMIDE (ESX) IS A DRUG OF CHOICE FOR THE SYMPTOMATIC TREATMENT OF ABSENCE SEIZURES. CHRONIC TREATMENT WITH ESX HAS BEEN REPORTED TO HAVE DISEASE-MODIFYING ANTIEPILEPTOGENIC ACTIVITY IN THE WAG/RIJ RAT MODEL OF GENETIC GENERALIZED EPILEPSY (GGE) WITH ABSENCE SEIZURES. HERE WE EXAMINED WHETHER CHRONIC TREATMENT WITH ESX (1) POSSESSES ANTIEPILEPTOGENIC EFFECTS IN THE GENETIC ABSENCE EPILEPSY RATS FROM STRASBOURG (GAERS) MODEL OF GGE, (2) IS ASSOCIATED WITH A MITIGATION OF BEHAVIORAL COMORBIDITIES, AND (3) INFLUENCES GENE EXPRESSION IN THE SOMATOSENSORY CORTEX REGION WHERE SEIZURES ARE THOUGHT TO ORIGINATE. METHODS: GAERS AND NONEPILEPTIC CONTROL (NEC) RATS WERE CHRONICALLY TREATED WITH ESX (IN DRINKING WATER) OR CONTROL (TAP WATER) FROM 3 TO 22 WEEKS OF AGE. SUBSEQUENTLY, ALL ANIMALS RECEIVED TAP WATER ONLY FOR ANOTHER 12 WEEKS TO ASSESS ENDURING EFFECTS OF TREATMENT. SEIZURE FREQUENCY AND ANXIETY-LIKE BEHAVIORS WERE SERIALLY ASSESSED THROUGHOUT THE EXPERIMENTAL PARADIGM. TREATMENT EFFECTS ON THE EXPRESSION OF KEY COMPONENTS OF THE EPIGENETIC MOLECULAR MACHINERY, THE DNA METHYLTRANSFERASE ENZYMES, WERE ASSESSED USING QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR). KEY FINDINGS: ESX TREATMENT SIGNIFICANTLY REDUCED SEIZURES IN GAERS DURING THE TREATMENT PHASE, AND THIS EFFECT WAS MAINTAINED DURING THE 12-WEEK POSTTREATMENT PHASE (P < 0.05). FURTHERMORE, THE ANXIETY-LIKE BEHAVIORS PRESENT IN GAERS WERE REDUCED BY ESX TREATMENT (P < 0.05). MOLECULAR ANALYSIS REVEALED THAT ESX TREATMENT WAS ASSOCIATED WITH INCREASED EXPRESSION OF DNA METHYLTRANSFERASE ENZYME MESSENGER RNA (MRNA) IN CORTEX. SIGNIFICANCE: CHRONIC ESX TREATMENT HAS DISEASE-MODIFYING EFFECTS IN THE GAERS MODEL OF GGE, WITH ANTIEPILEPTOGENIC EFFECTS AGAINST ABSENCE SEIZURES AND MITIGATION OF BEHAVIORAL COMORBIDITIES. THE CELLULAR MECHANISM FOR THESE EFFECTS MAY INVOLVE EPIGENETIC MODIFICATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3 5838  30 STRIATAL SHATI/NAT8L-BDNF PATHWAYS DETERMINE THE SENSITIVITY TO SOCIAL DEFEAT STRESS IN MICE THROUGH EPIGENETIC REGULATION. THE GLOBAL NUMBER OF PATIENTS WITH DEPRESSION INCREASES IN CORRELATION TO EXPOSURE TO SOCIAL STRESS. CHRONIC STRESS DOES NOT TRIGGER DEPRESSION IN ALL INDIVIDUALS, AS SOME REMAIN RESILIENT. THE UNDERLYING MOLECULAR MECHANISMS THAT CONTRIBUTE TO STRESS SENSITIVITY HAVE BEEN POORLY UNDERSTOOD, ALTHOUGH REVEALING THE REGULATION OF STRESS SENSITIVITY COULD HELP DEVELOP TREATMENTS FOR DEPRESSION. WE PREVIOUSLY FOUND THAT STRIATAL SHATI/NAT8L, AN N-ACETYLTRANSFERASE, WAS INCREASED IN A DEPRESSION MOUSE MODEL. WE INVESTIGATED THE ROLES OF SHATI/NAT8L IN STRESS SENSITIVITY IN MICE AND FOUND THAT SHATI/NAT8L AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS IN THE DORSAL STRIATUM WERE INCREASED IN STRESS-SUSCEPTIBLE MICE BUT NOT IN RESILIENT MICE EXPOSED TO REPEATED SOCIAL DEFEAT STRESS (RSDS). KNOCKDOWN OF SHATI/NAT8L IN THE DORSAL STRIATUM INDUCED RESILIENCE TO RSDS. IN ADDITION, BLOCKADE OF BDNF SIGNALING IN THE DORSAL STRIATUM BY ANA-12, A BDNF-SPECIFIC RECEPTOR TROPOMYOSIN-RECEPTOR-KINASE B (TRKB) INHIBITOR, ALSO INDUCED RESILIENCE TO STRESS. SHATI/NAT8L IS CORRELATED WITH BDNF EXPRESSION AFTER RSDS, AND BDNF IS DOWNSTREAM OF SHATI/NAT8L PATHWAYS IN THE DORSAL STRIATUM; SHATI/NAT8L IS EPIGENETICALLY REGULATED BY BDNF VIA HISTONE ACETYLATION. OUR RESULTS DEMONSTRATE THAT STRIATAL SHATI/NAT8L-BDNF PATHWAYS DETERMINE STRESS SENSITIVITY THROUGH EPIGENETIC REGULATION. THE STRIATAL SHATI/NAT8L-BDNF PATHWAY COULD BE A NOVEL TARGET FOR TREATMENTS OF DEPRESSION AND COULD ESTABLISH A NOVEL THERAPEUTIC STRATEGY FOR DEPRESSION PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
4 1429  25 DIFFERENTIAL EXPRESSION OF MICRORNAS IN THE HIPPOCAMPI OF MALE AND FEMALE RODENTS AFTER CHRONIC ALCOHOL ADMINISTRATION. BACKGROUND: WOMEN ARE MORE VULNERABLE THAN MEN TO THE NEUROTOXICITY AND SEVERE BRAIN DAMAGE CAUSED BY CHRONIC HEAVY ALCOHOL USE. IN ADDITION, BRAIN DAMAGE DUE TO CHRONIC HEAVY ALCOHOL USE MAY BE ASSOCIATED WITH SEX-DEPENDENT EPIGENETIC MODIFICATIONS. THIS STUDY AIMED TO IDENTIFY MICRORNAS (MIRNAS) AND THEIR TARGET GENES THAT ARE DIFFERENTIALLY EXPRESSED IN THE HIPPOCAMPI OF MALE AND FEMALE ANIMAL MODELS IN RESPONSE TO ALCOHOL. METHODS: AFTER CHRONIC ALCOHOL ADMINISTRATION (3~3.5 G/KG/DAY) IN MALE (CONTROL, N = 10; ALCOHOL, N = 12) OR FEMALE (CONTROL, N = 10; ALCOHOL, N = 12) SPRAGUE-DAWLEY RATS FOR 6 WEEKS, WE MEASURED BODY WEIGHTS AND DOUBLECORTIN (DCX; A NEUROGENESIS MARKER) CONCENTRATIONS AND ANALYZED UP- OR DOWNREGULATED MIRNAS USING GENECHIP MIRNA 4.0 ARRAYS. THE DIFFERENTIALLY EXPRESSED MIRNAS AND THEIR PUTATIVE TARGET GENES WERE VALIDATED BY RT-QPCR. RESULTS: ALCOHOL ATTENUATED BODY WEIGHT GAIN ONLY IN THE MALE GROUP. ON THE OTHER HAND, ALCOHOL LED TO INCREASED SERUM AST IN FEMALE RATS AND DECREASED SERUM TOTAL CHOLESTEROL CONCENTRATIONS IN MALE RATS. THE EXPRESSION OF DCX WAS SIGNIFICANTLY REDUCED IN THE HIPPOCAMPI OF MALE ALCOHOL-TREATED RATS. NINE MIRNAS WERE SIGNIFICANTLY UP- OR DOWNREGULATED IN MALE ALCOHOL-TREATED RATS, INCLUDING UPREGULATION OF MIR-125A-3P, LET-7A-5P, AND MIR-3541, AND DOWNREGULATION OF THEIR TARGET GENES (PRDM5, SUV39H1, PTPRZ1, MAPK9, ING4, WT1, NKX3-1, DAB2IP, RNF152, RIPK1, LIN28A, APBB3, NRAS, AND ACVR1C). ON THE OTHER HAND, 7 MIRNAS WERE SIGNIFICANTLY UP- OR DOWNREGULATED IN ALCOHOL-TREATED FEMALE RATS, INCLUDING DOWNREGULATION OF MIR-881-3P AND MIR-504 AND UPREGULATION OF THEIR TARGET GENES (NAA50, CLOCK, CBFB, ARIH1, UBE2G1, AND GNG7). CONCLUSIONS: THESE RESULTS SUGGEST THAT CHRONIC HEAVY ALCOHOL USE PRODUCES SEX-DEPENDENT EFFECTS ON NEUROGENESIS AND MIRNA EXPRESSION IN THE HIPPOCAMPUS AND THAT SEX DIFFERENCES SHOULD BE CONSIDERED WHEN DEVELOPING MIRNA BIOMARKERS TO DIAGNOSE OR TREAT ALCOHOLICS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5 1421  25 DIFFERENTIAL BRAIN ADRA2A AND ADRA2C GENE EXPRESSION AND EPIGENETIC REGULATION IN SCHIZOPHRENIA. EFFECT OF ANTIPSYCHOTIC DRUG TREATMENT. POSTSYNAPTIC ALPHA(2A)-ADRENOCEPTOR DENSITY IS ENHANCED IN THE DORSOLATERAL PREFRONTAL CORTEX (DLPFC) OF ANTIPSYCHOTIC-TREATED SCHIZOPHRENIA SUBJECTS. THIS ALTERATION MIGHT BE DUE TO TRANSCRIPTIONAL ACTIVATION, AND COULD BE REGULATED BY EPIGENETIC MECHANISMS SUCH AS HISTONE POSTTRANSLATIONAL MODIFICATIONS (PTMS). THE AIM OF THIS STUDY WAS TO EVALUATE ADRA2A AND ADRA2C GENE EXPRESSION (CODIFYING FOR ALPHA(2)-ADRENOCEPTOR SUBTYPES), AND PERMISSIVE AND REPRESSIVE HISTONE PTMS AT GENE PROMOTER REGIONS IN THE DLPFC OF SUBJECTS WITH SCHIZOPHRENIA AND MATCHED CONTROLS (N = 24 PAIRS). WE STUDIED THE EFFECT OF ANTIPSYCHOTIC (AP) TREATMENT IN AP-FREE (N = 12) AND AP-TREATED (N = 12) SUBGROUPS OF SCHIZOPHRENIA SUBJECTS AND IN RATS ACUTELY AND CHRONICALLY TREATED WITH TYPICAL AND ATYPICAL ANTIPSYCHOTICS. ADRA2A MRNA EXPRESSION WAS SELECTIVELY UPREGULATED IN AP-TREATED SCHIZOPHRENIA SUBJECTS (+93%) WHEREAS ADRA2C MRNA EXPRESSION WAS UPREGULATED IN ALL SCHIZOPHRENIA SUBJECTS (+53%) REGARDLESS OF ANTIPSYCHOTIC TREATMENT. ACUTE AND CHRONIC CLOZAPINE TREATMENT IN RATS DID NOT ALTER BRAIN CORTEX ADRA2A MRNA EXPRESSION BUT INCREASED ADRA2C MRNA EXPRESSION. BOTH ADRA2A AND ADRA2C PROMOTER REGIONS SHOWED EPIGENETIC MODIFICATION BY HISTONE METHYLATION AND ACETYLATION IN HUMAN DLPFC. THE UPREGULATION OF ADRA2A EXPRESSION IN AP-TREATED SCHIZOPHRENIA SUBJECTS MIGHT BE RELATED TO OBSERVED BIVALENT CHROMATIN AT ADRA2A PROMOTER REGION IN SCHIZOPHRENIA (DEPICTED BY INCREASED PERMISSIVE H3K4ME3 AND REPRESSIVE H3K27ME3) AND COULD BE TRIGGERED BY THE ENHANCED H4K16AC AT ADRA2A PROMOTER. IN CONCLUSION, EPIGENETIC PREDISPOSITION DIFFERENTIALLY MODULATED ADRA2A AND ADRA2C MRNA EXPRESSION IN DLPFC OF SCHIZOPHRENIA SUBJECTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6  368  31 AMYLOID BETA-MEDIATED EPIGENETIC ALTERATION OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 3 CONTROLS CELL SURVIVAL IN ALZHEIMER'S DISEASE. SWEDISH DOUBLE MUTATION (KM670/671NL) OF AMYLOID PRECURSOR PROTEIN (APP) IS REPORTED TO INCREASE TOXIC AMYLOID BETA (ABETA) PRODUCTION VIA ABERRANT CLEAVAGE AT THE BETA-SECRETASE SITE AND THEREBY CAUSE EARLY-ONSET ALZHEIMER'S DISEASE (AD). HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS LEADING TO AD PATHOGENESIS REMAINS LARGELY UNKNOWN. PREVIOUSLY, OUR TRANSCRIPTOME SEQUENCE ANALYSES REVEALED GLOBAL EXPRESSIONAL MODIFICATIONS OF OVER 600 GENES IN APP-SWEDISH MUTANT-EXPRESSING H4 (H4-SW) CELLS COMPARED TO WILD TYPE H4 CELLS. INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 3 (IGFBP3) IS ONE GENE THAT SHOWED SIGNIFICANTLY DECREASED MRNA EXPRESSION IN H4-SW CELLS. IN THIS STUDY, WE INVESTIGATED THE FUNCTIONAL ROLE OF IGFBP3 IN AD PATHOGENESIS AND ELUCIDATED THE MECHANISMS REGULATING ITS EXPRESSION. WE OBSERVED DECREASED IGFBP3 EXPRESSION IN THE H4-SW CELL LINE AS WELL AS THE HIPPOCAMPUS OF AD MODEL TRANSGENIC MICE. TREATMENT WITH EXOGENOUS IGFBP3 PROTEIN INHIBITED ABETA1-42- INDUCED CELL DEATH AND CASPASE-3 ACTIVITY, WHEREAS SIRNA-MEDIATED SUPPRESSION OF IGFBP3 EXPRESSION INDUCED CELL DEATH AND CASPASE-3 CLEAVAGE. IN PRIMARY HIPPOCAMPAL NEURONS, ADMINISTRATION OF IGFBP3 PROTEIN BLOCKED APOPTOTIC CELL DEATH DUE TO ABETA1-42 TOXICITY. THESE DATA IMPLICATE A PROTECTIVE ROLE FOR IGFBP3 AGAINST ABETA1-42-MEDIATED APOPTOSIS. NEXT, WE INVESTIGATED THE REGULATORY MECHANISMS OF IGFBP3 EXPRESSION IN AD PATHOGENESIS. WE OBSERVED ABNORMAL IGFBP3 HYPERMETHYLATION WITHIN THE PROMOTER CPG ISLAND IN H4-SW CELLS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR 5-AZA-2'-DEOXYCYTIDINE RESTORED IGFBP3 EXPRESSION AT BOTH THE MRNA AND PROTEIN LEVELS. CHRONIC EXPOSURE TO ABETA1-42 INDUCED IGFBP3 HYPERMETHYLATION AT CPGS, PARTICULARLY AT LOCI -164 AND -173, AND SUBSEQUENTLY SUPPRESSED IGFBP3 EXPRESSION. THEREFORE, WE DEMONSTRATE THAT EXPRESSION OF ANTI-APOPTOTIC IGFBP3 IS REGULATED BY EPIGENETIC DNA METHYLATION, SUGGESTING A MECHANISM THAT CONTRIBUTES TO AD PATHOGENESIS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7 3130  34 GLAST BUT NOT LEAST--DISTRIBUTION, FUNCTION, GENETICS AND EPIGENETICS OF L-GLUTAMATE TRANSPORT IN BRAIN--FOCUS ON GLAST/EAAT1. SYNAPTICALLY RELEASED L-GLUTAMATE, THE MOST IMPORTANT EXCITATORY NEUROTRANSMITTER IN THE CNS, IS REMOVED FROM EXTRACELLULAR SPACE BY FAST AND EFFICIENT TRANSPORT MEDIATED BY SEVERAL TRANSPORTERS; THE MOST ABUNDANT ONES ARE EAAT1/GLAST AND EAAT2/GLT1. THE REVIEW FIRST SUMMARIZES THEIR LOCATION, FUNCTIONS AND BASIC CHARACTERISTICS. WE THEN LOOK AT GENETICS AND EPIGENETICS OF EAAT1/GLAST AND EAAT2/GLT1 AND PERFORM IN SILICO ANALYSES OF THEIR PROMOTER REGIONS. THERE IS ONE CPG ISLAND IN SLC1A2 (EAAT2/GLT1) GENE AND NONE IN SLC1A3 (EAAT1/GLAST) SUGGESTING THAT DNA METHYLATION IS NOT THE MOST IMPORTANT EPIGENETIC MECHANISM REGULATING EAAT1/GLAST LEVELS IN BRAIN. THERE ARE TARGETS FOR SPECIFIC MIRNA IN SLC1A2 (EAAT2/GLT1) GENE. WE ALSO NOTE THAT WHILE DEFECTS IN EAAT2/GLT1 HAVE BEEN ASSOCIATED WITH VARIOUS PATHOLOGICAL STATES INCLUDING CHRONIC NEURODEGENERATIVE DISEASES, VERY LITTLE IS KNOWN ON POSSIBLE CONTRIBUTIONS OF DEFECTIVE OR DYSFUNCTIONAL EAAT1/GLAST TO ANY SPECIFIC BRAIN DISEASE. FINALLY, WE REVIEW EVIDENCE OF EAAT1/GLAST INVOLVEMENT IN MECHANISMS OF BRAIN RESPONSE TO ALCOHOLISM AND PRESENT SOME PRELIMINARY DATA SHOWING THAT ETHANOL, AT CONCENTRATIONS WHICH MAY BE REACHED FOLLOWING HEAVY DRINKING, CAN HAVE AN EFFECT ON THE DISTRIBUTION OF EAAT1/GLAST IN CULTURED ASTROCYTES; THE EFFECT IS BLOCKED BY BACLOFEN, A GABA-B RECEPTOR AGONIST AND A DRUG POTENTIALLY USEFUL IN THE TREATMENT OF ALCOHOLISM. WE ARGUE THAT MORE RESEARCH EFFORT SHOULD BE FOCUSED ON EAAT1/GLAST, PARTICULARLY IN RELATION TO ALCOHOLISM AND DRUG ADDICTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8 4508  26 MS-11, A MIMETIC OF THE MSIN3-BINDING HELIX IN NRSF, AMELIORATES SOCIAL INTERACTION DEFICITS IN A PRENATAL VALPROIC ACID-INDUCED AUTISM MOUSE MODEL. GROWING EVIDENCE SUGGESTS PIVOTAL ROLES FOR EPIGENETIC MECHANISMS IN BOTH ANIMAL MODELS OF AND INDIVIDUALS WITH AUTISM SPECTRUM DISORDERS (ASD). NEURON-RESTRICTIVE SILENCER FACTOR (NRSF) BINDS TO NEURON-RESTRICTIVE SILENCING ELEMENTS IN NEURONAL GENES AND RECRUITS CO-REPRESSORS, SUCH AS MSIN3, TO EPIGENETICALLY INHIBIT NEURONAL GENE EXPRESSION. BECAUSE DYSREGULATION OF NRSF IS RELATED TO ASD, HERE WE EXAMINED THE EFFECTS OF MS-11, A CHEMICALLY OPTIMIZED MIMETIC OF THE MSIN3-BINDING HELIX IN NRSF, ON THE BEHAVIORAL AND MORPHOLOGICAL ABNORMALITIES FOUND IN A MOUSE MODEL OF VALPROIC ACID (VPA)-INDUCED ASD. CHRONIC TREATMENT WITH MS-11 IMPROVED PRENATAL VPA-INDUCED DEFICITS IN SOCIAL INTERACTION. ADDITIONALLY, WE FOUND THAT NRSF MRNA EXPRESSION WAS GREATER IN THE SOMATOSENSORY CORTEX OF VPA-EXPOSED MICE THAN OF CONTROLS. AGREEING WITH THESE BEHAVIORAL FINDINGS, MICE THAT WERE PRENATALLY EXPOSED TO VPA SHOWED LOWER DENDRITIC SPINE DENSITY IN THE SOMATOSENSORY CORTEX, WHICH WAS REVERSED BY CHRONIC TREATMENT WITH MS-11. THESE FINDINGS SUGGEST THAT MS-11 HAS THE POTENTIAL FOR IMPROVING ASD-RELATED SYMPTOMS THROUGH INHIBITION OF MSIN3-NRSF BINDING.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9 1298  25 DECREASED NUCLEAR RECEPTOR ACTIVITY AND EPIGENETIC MODULATION ASSOCIATES WITH DOWN-REGULATION OF HEPATIC DRUG-METABOLIZING ENZYMES IN CHRONIC KIDNEY DISEASE. PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) REQUIRE MANY MEDICATIONS. CYP2C AND CYP3A DRUG-METABOLIZING ENZYMES PLAY A CRITICAL ROLE IN DETERMINING THE PHARMACOKINETICS OF THE MAJORITY OF PRESCRIBED MEDICATIONS. THESE ENZYMES ARE TRANSCRIPTIONALLY REGULATED BY THE NUCLEAR RECEPTORS PREGNANE X RECEPTOR (PXR) AND HEPATIC NUCLEAR FACTOR 4ALPHA (HNF-4ALPHA). EXPRESSION OF CYP2C AND CYP3A IS DECREASED IN CKD; HOWEVER, THE MECHANISMS BY WHICH THIS OCCURS IS UNKNOWN. WE INDUCED CKD IN RATS BY 5/6 NEPHRECTOMY AND USED CHROMATIN IMMUNOPRECIPITATION (CHIP) TO DETERMINE NUCLEAR RECEPTOR- AND EPIGENETIC ALTERATION-MEDIATED DIFFERENCES IN THE PROMOTER REGION OF THE CYP2C AND CYP3A GENES. RNA POLYMERASE II AND HNF-4ALPHA BINDING WAS DECREASED 76 AND 57% IN THE CYP2C11 PROMOTOR AND 71 AND 77% IN THE CYP3A2 PROMOTER, RESPECTIVELY (P<0.05). CHIP ALSO REVEALED A 57% DECREASE IN PXR BINDING TO THE CYP3A2 PROMOTER IN CKD RATS (P<0.05). THE DECREASE IN PXR AND HNF-4ALPHA BINDING WAS ACCOMPANIED BY DIMINISHED HISTONE 4 ACETYLATION IN THE CYP3A2 PROMOTER (48%) AND HISTONE 3 ACETYLATION IN THE CYP2C11 (77%) AND CYP3A2 (77%) PROMOTER LOCI FOR NUCLEAR RECEPTOR ACTIVATION (P<0.05). THIS STUDY SUGGESTS THAT DECREASED NUCLEAR RECEPTOR BINDING AND HISTONE ACETYLATION MAY CONTRIBUTE TO THE MECHANISM OF DRUG-METABOLIZING ENZYME DOWN-REGULATION AND ALTERED PHARMACOKINETICS IN CKD.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10 6636  40 UNRAVELING A NEW PLAYER IN MULTIPLE SCLEROSIS PATHOGENESIS: THE RNA-BINDING PROTEIN HUR. BACKGROUND: ELAV-LIKE PROTEINS ARE A SMALL FAMILY OF RNA-BINDING PROTEINS THAT ARE FUNDAMENTAL PLAYERS IN POST-TRANSCRIPTIONAL MECHANISMS AND ARE INVOLVED IN THE PATHOGENESIS OF NEUROLOGIC AND PSYCHIATRIC DISORDERS. HUR, THE UBIQUITOUSLY EXPRESSED MEMBER OF THE FAMILY, IS ALSO IMPLICATED IN SUSTAINING INFLAMMATION AND INFLAMMATORY DISEASES, SUPPORTING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. INFLAMMATION PLAYS A CENTRAL ROLE IN MULTIPLE SCLEROSIS (MS), WHICH REPRESENTS THE MOST COMMON CAUSE OF PERMANENT PHYSICAL DISABILITY IN YOUNG ADULTS. MS IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM, WITH A COMPLEX AETIOLOGY INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. NO DATA ARE AVAILABLE ON THE POTENTIAL ENTANGLEMENT OF HUR IN MS PATHOGENESIS IN PATIENTS. IN THE PRESENT WORK, WE AIMED AT EXPLORING HUR PROTEIN LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM MS PATIENTS, COMPARED TO HEALTHY CONTROLS. TO FURTHER ELUCIDATE THE POSSIBLE INVOLVEMENT OF HUR IN MS, WE ALSO INVESTIGATED THE RELATIONSHIP BETWEEN THIS SPECIFIC RNA-BINDING PROTEIN AND HSP70-2 PROTEIN, ALSO CONSIDERING THE HSP70-2 RS1061581 POLYMORPHISM, GIVEN THAT HSP70-2 MRNA HAS BEEN REPORTED AS A HUR TARGET AND THIS SPECIFIC POLYMORPHISM TO BE ASSOCIATED WITH MS RISK. METHODS: ALLELES AND GENOTYPES FOR HSP70-2 RS1061581 POLYMORPHISM WERE ASSESSED, BY USING A POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM, FOLLOWED BY DIGESTION WITH RESTRICTION ENZYME, IN MS PATIENTS AND HEALTHY CONTROLS. PBMCS FROM A SUBGROUP OF PATIENTS AND CONTROLS WERE USED TO EVALUATE HUR AND HSP70-2 PROTEIN CONTENT BY WESTERN BLOT. RESULTS: PBMCS FROM 52 MS PATIENTS HAD A LOWER HUR AND HIGHER HSP70-2 PROTEIN CONTENT COMPARED TO 43 HEALTHY CONTROLS. AN INCREASE OF 100 UNITS OF HUR SIGNIFICANTLY DECREASED THE RISK OF DEVELOPING MS BY 9.8% (OR: 0.902, 95% CI: 0.83-0.98), CONTROLLING FOR HSP70-2 PROTEIN EXPRESSION, HSP70-2 RS1061581 GENOTYPE, AGE AND SEX. MOREOVER, HOLDING HUR LEVELS, AN INCREASE OF 100 UNITS OF HSP70-2 PROTEIN SIGNIFICANTLY INCREASED THE MS RISK BY 18.1% (OR: 1.181, 95% CI: 1.03-1.36) AND THE GENETIC SUSCEPTIBILITY OF DEVELOPING MS FOR HSP70-2 RS1061581 GG CARRIERS IS CONFIRMED. OF INTEREST, MS PATIENTS WITH A MODERATE TO SEVERE FORM OF MS (MSSS >/= 3) SHOWED A TREND TOWARDS A REDUCTION OF HUR PROTEIN LEVELS COMPARED TO PATIENTS WITH MILD DISEASE SEVERITY (MSSS < 3). CONCLUSIONS: HUR PROTEIN LEVELS ARE REDUCED IN MS PATIENTS COMPARED TO HEALTHY SUBJECTS, AND THE PROTEIN AMOUNT MAY CONTINUE TO DECLINE WITH DISEASE PROGRESSION, SUGGESTING A PUTATIVE ROLE OF THIS RNA-BINDING PROTEIN. MOREOVER, OUR RESULTS SUGGEST THAT MS PATHOLOGY MAY HAVE DISRUPTED THE LINK BETWEEN HUR AND ITS TARGET TRANSCRIPT HSP70-2. IT WILL BE IMPORTANT TO FURTHER EXPLORE THE EXACT ROLE OF HUR IN MS, CONSIDERING THE COMPLEX INTERPLAY WITH OTHER RNA-BINDING FACTORS AND TARGET MRNAS.	2020	

11 2758  30 EXPRESSION OF HORMONAL CARCINOGENESIS GENES AND RELATED REGULATORY MICRORNAS IN UTERUS AND OVARIES OF DDT-TREATED FEMALE RATS. THE INSECTICIDE DICHLORODIPHENYLTRICHLOROETHANE (DDT) IS A NONMUTAGENIC XENOBIOTIC COMPOUND ABLE TO EXERT ESTROGEN-LIKE EFFECTS RESULTING IN ACTIVATION OF ESTROGEN RECEPTOR-ALPHA (ERALPHA) FOLLOWED BY CHANGED EXPRESSION OF ITS DOWNSTREAM TARGET GENES. IN ADDITION, STUDIES PERFORMED OVER RECENT YEARS SUGGEST THAT DDT MAY ALSO INFLUENCE EXPRESSION OF MICRORNAS. HOWEVER, AN IMPACT OF DDT ON EXPRESSION OF ER, MICRORNAS, AND RELATED TARGET GENES HAS NOT BEEN FULLY ELUCIDATED. HERE, USING REAL-TIME PCR, WE ASSESSED CHANGES IN EXPRESSION OF KEY GENES INVOLVED IN HORMONAL CARCINOGENESIS AS WELL AS POTENTIALLY RELATED REGULATORY ONCOGENIC/TUMOR SUPPRESSOR MICRORNAS AND THEIR TARGET GENES IN THE UTERUS AND OVARIES OF FEMALE WISTAR RATS DURING SINGLE AND CHRONIC MULTIPLE-DOSE DDT EXPOSURE. WE FOUND THAT APPLYING DDT RESULTS IN ALTERED EXPRESSION OF MICRORNAS-221, -222, -205, -126A, AND -429, THEIR TARGET GENES (PTEN, DICER1), AS WELL AS GENES INVOLVED IN HORMONAL CARCINOGENESIS (ESR1, PGR, CCND1, CYP19A1). NOTABLY, CYP19A1 EXPRESSION SEEMS TO BE ALSO REGULATED BY MICRORNAS-221, -222, AND -205. THE DATA SUGGEST THAT EPIGENETIC EFFECTS INDUCED BY DDT AS A POTENTIAL CARCINOGEN MAY BE BASED ON AT LEAST TWO MECHANISMS: (I) ACTIVATION OF ERALPHA FOLLOWED BY ALTERED EXPRESSION OF THE TARGET GENES ENCODING RECEPTOR PGR AND CCND1 AS WELL AS IMPAIRED EXPRESSION OF CYP19A1, AFFECTING, THEREBY, CELL HORMONE BALANCE; AND (II) CHANGED EXPRESSION OF MICRORNAS RESULTING IN IMPAIRED EXPRESSION OF RELATED TARGET GENES INCLUDING REDUCED LEVEL OF CYP19A1 MRNA.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
12 1622  32 DNA METHYLTRANSFERASES IN MALAR MELASMA AND THEIR MODIFICATION BY SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. BACKGROUND: MALAR MELASMA HAS A CHRONIC AND RECURRENT CHARACTER THAT MAY BE RELATED TO EPIGENETIC CHANGES. OBJECTIVE: TO RECOGNIZE THE EXPRESSION AND DNA METHYLATION OF DNA METHYLTRANSFERASES (DNMTS) IN MALAR MELASMA AND PERILESIONAL SKIN, AS WELL AS THE CHANGES IN DNMTS AFTER THEIR TREATMENT WITH SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. METHODS: THIRTY FEMALE PATIENTS WERE CLINICALLY EVALUATED FOR THE EXPRESSION OF DNMT1 AND DNMT3B USING REAL-TIME PCR AND IMMUNOFLUORESCENCE. THESE INITIAL RESULTS WERE COMPARED TO RESULTS AFTER EIGHT WEEKS OF TREATMENT WITH SUNSCREEN IN COMBINATION WITH NIACINAMIDE, RETINOIC ACID, OR PLACEBO. RESULTS: THE RELATIVE EXPRESSION OF DNMT1 WAS SIGNIFICANTLY ELEVATED IN MELASMA COMPARED WITH UNAFFECTED SKIN IN ALL SUBJECTS, INDICATING DNA HYPERMETHYLATION. AFTER TREATMENT, IT WAS DECREASED IN ALL GROUPS: NIACINAMIDE (7 VERSUS 1; P<0.01), RETINOIC ACID (7 VERSUS 2; P<0.05), AND PLACEBO (7 VERSUS 3; P<0.05), WHICH CORRELATES WITH CLINICAL IMPROVEMENT. DNMT3B WAS NOT OVEREXPRESSED IN LESIONAL SKIN BUT REDUCED IN ALL GROUPS. CONCLUSIONS: WE FOUND DNA HYPERMETHYLATION IN MELASMA LESIONS. ENVIRONMENTAL FACTORS SUCH AS SOLAR RADIATION MAY INDUCE CELLULAR CHANGES THAT TRIGGER HYPERPIGMENTATION THROUGH THE ACTIVATION OF PATHWAYS REGULATED BY EPIGENETIC MODIFICATIONS. HOWEVER, LIMITING OR DECREASING DNA METHYLATION THROUGH SUNSCREEN, NIACINAMIDE, AND RETINOIC ACID TREATMENTS THAT PROVIDE PHOTOPROTECTION AND GENETIC TRANSCRIPTION CAN COUNTERACT THIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13 1330  38 DEPRESSIVE-LIKE BEHAVIORS ARE REGULATED BY NOX1/NADPH OXIDASE BY REDOX MODIFICATION OF NMDA RECEPTOR 1. INVOLVEMENT OF REACTIVE OXYGEN SPECIES (ROS) HAS BEEN SUGGESTED IN THE DEVELOPMENT OF PSYCHIATRIC DISORDERS. NOX1 IS A NONPHAGOCYTIC FORM OF NADPH OXIDASE WHOSE EXPRESSION IN THE NERVOUS SYSTEM IS NEGLIGIBLE COMPARED WITH OTHER NOX ISOFORMS. HOWEVER, NOX1-DERIVED ROS INCREASE INFLAMMATORY PAIN AND TOLERANCE TO OPIOID ANALGESIA. TO CLARIFY THE ROLE OF NOX1 IN THE BRAIN, WE EXAMINED DEPRESSIVE-LIKE BEHAVIORS IN MICE DEFICIENT IN NOX1 (NOX1(-/Y)). DEPRESSIVE-LIKE BEHAVIORS INDUCED BY CHRONIC SOCIAL DEFEAT STRESS OR ADMINISTRATION OF CORTICOSTERONE (CORT) WERE SIGNIFICANTLY AMELIORATED IN NOX1(-/Y) GENERATION OF ROS WAS SIGNIFICANTLY ELEVATED IN THE PREFRONTAL CORTEX (PFC) OF MICE ADMINISTRATED WITH CORT, WHILE NOX1 MRNA WAS UPREGULATED ONLY IN THE VENTRAL TEGMENTAL AREA (VTA) AMONG BRAIN AREAS RESPONSIBLE FOR EMOTIONAL BEHAVIORS. DELIVERY OF MIRNA AGAINST NOX1 TO VTA RESTORED CORT-INDUCED DEPRESSIVE-LIKE BEHAVIORS IN WILD-TYPE (WT) LITTERMATES. ADMINISTRATION OF CORT TO WT, BUT NOT TO NOX1(-/Y), SIGNIFICANTLY REDUCED TRANSCRIPT LEVELS OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), WITH A CONCOMITANT INCREASE IN DNA METHYLATION OF THE PROMOTER REGIONS IN BDNF DELIVERY OF MIRNA AGAINST NOX1 TO VTA RESTORED THE LEVEL OF BDNF MRNA IN WT PFC. REDOX PROTEOME ANALYSES DEMONSTRATED THAT NMDA RECEPTOR 1 (NR1) WAS AMONG THE MOLECULES REDOX REGULATED BY NOX1. IN CULTURED CORTICAL NEURONS, HYDROGEN PEROXIDE SIGNIFICANTLY SUPPRESSED NMDA-INDUCED UPREGULATION OF BDNF TRANSCRIPTS IN NR1-EXPRESSING CELLS BUT NOT IN CELLS HARBORING MUTANT NR1 (C744A). TOGETHER, THESE FINDINGS SUGGEST A KEY ROLE OF NOX1 IN DEPRESSIVE-LIKE BEHAVIORS THROUGH NR1-MEDIATED EPIGENETIC MODIFICATION OF BDNF IN THE MESOPREFRONTAL PROJECTION.SIGNIFICANCE STATEMENT NADPH OXIDASE IS A SOURCE OF REACTIVE OXYGEN SPECIES (ROS) THAT HAVE BEEN IMPLICATED IN THE PATHOGENESIS OF VARIOUS NEUROLOGICAL DISORDERS. WE PRESENTLY SHOWED THE INVOLVEMENT OF A NONPHAGOCYTIC TYPE OF NADPH OXIDASE, NOX1, IN MAJOR DEPRESSIVE DISORDERS, INCLUDING BEHAVIORAL, BIOCHEMICAL, AND ANATOMICAL CHANGES IN MICE. THE OXIDATION OF NR1 BY NOX1-DERIVED ROS WAS DEMONSTRATED IN PREFRONTAL CORTEX (PFC), WHICH MAY BE CAUSALLY LINKED TO THE DOWNREGULATION OF BDNF, PROMOTING DEPRESSIVE-LIKE BEHAVIORS. GIVEN THAT NOX1 IS UPREGULATED ONLY IN VTA BUT NOT IN PFC, MESOCORTICAL PROJECTIONS APPEAR TO PLAY A CRUCIAL ROLE IN NOX1-DEPENDENT DEPRESSIVE-LIKE BEHAVIORS. OUR STUDY IS THE FIRST TO PRESENT THE POTENTIAL MOLECULAR MECHANISM UNDERLYING THE DEVELOPMENT OF MAJOR DEPRESSION THROUGH THE NOX1-INDUCED OXIDATION OF NR1 AND EPIGENETIC MODIFICATION OF BDNF.	2017	
                                                                                                                                                                                                                                                                                               
14 1016  25 CIITA EXPRESSION IS REGULATED BY HISTONE DEACETYLASE ENZYMES AND HAS A ROLE IN ALPHA-SYNUCLEIN PRE-FORMED FIBRIL-INDUCED ANTIGEN PRESENTATION IN MURINE MICROGLIAL CELL LINE. AIM: PARKINSON'S DISEASE (PD) IS A CHRONIC NEURODEGENERATIVE DISORDER RELATED WITH SEVERAL GENETIC AND EPIGENETIC FACTORS. IN THE CONTEXT OF EPIGENETIC FACTORS, HISTONE ACETYLATION IS ONE OF THE MOST ASSOCIATED MECHANISMS WITH PARKINSON'S DISEASE PROGRESSION. THIS STUDY INVESTIGATES THE EFFECTS OF THE INCREASED HISTONE ACETYLATION ON ANTIGEN PRESENTATION IN MICROGLIAL CELLS WHICH WERE INDUCED BY PRE-FORMED FIBRILS OF ALPHA-SYNUCLEIN (PFF ALPHA-SYNUCLEIN). METHODS: PARKINSON'S DISEASE MODEL WAS CREATED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION TO THE BV-2 MICROGLIAL CELLS. BV-2 CELLS WERE CO-TREATED WITH CUDC-907 AND TMP-195 TO INCREASE HISTONE ACETYLATION IN THE PRESENCE OF ALPHA-SYNUCLEIN. ANTIGEN REPRESENTATION WAS EVALUATED BY DETERMINING EXPRESSION LEVELS OF MAJOR HISTOCOMPATIBILITY COMPLEX-II (MHC-II) AND CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX (CIITA). RESULTS: OUR RESULTS SHOWED THAT PFF ALPHA-SYNUCLEIN SIGNIFICANTLY INCREASED MHC-II EXPRESSION, AND THAT EFFECT WAS MOST SEVERE AT 6 H OF ADMINISTRATION OF ALPHA-SYNUCLEIN. INCREASING HISTONE ACETYLATION VIA CUDC-907 AND TMP-195 ENHANCED MHC-II LEVELS EXPRESSION, WHICH WAS MORE SEVERE IN CUDC-907. ADDITIONALLY, CIITA EXPRESSION LEVELS WERE SIGNIFICANTLY INCREASED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION AND INTENSIFIED WITH THE CO-TREATMENT OF CUDC-907 AND TMP-195. FURTHERMORE, PFF ALPHA-SYNUCLEIN CAUSED A TIME-DEPENDENT INCREASE IN THE IFN-GAMMA (IFN-?) AND INTERLEUKIN-16(IL-16) LEVELS, AND THAT INCREASE WAS POTENTIATED WITH CUDC-907 AND TMP-195. CONCLUSION: CHANGES IN MHC-II AND CIITA EXPRESSION INDICATE THAT HISTONE ACETYLATION INCREASES THE ANTIGEN PRESENTATION PROPERTIES OF MICROGLIAL CELLS AFTER PFF ALPHA-SYNUCLEIN OR HISTONE DEACETYLASE INHIBITOR (HDACI) ADMINISTRATION. OUR RESULTS SHOW THAT MICROGLIAL ANTIGEN PRESENTATION MIGHT HAVE AN ESSENTIAL ROLE IN THE PATHOLOGY OF PARKINSON'S DISEASE, AND ALPHA-SYNUCLEIN LIKELY TO PLAY A PRIMARY ROLE IN THIS MECHANISM.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15  685  32 BRAIN-DERIVED NEUROTROPHIC FACTOR INVOLVED EPIGENETIC REPRESSION OF UGT2B7 IN COLORECTAL CARCINOMA: A MECHANISM TO ALTER MORPHINE GLUCURONIDATION IN TUMOR. URIDINE DIPHOSPHATE-GLUCURONOSYLTRANSFERASE (UGT) 2B7, AS ONE OF SIGNIFICANT DRUG ENZYMES, IS RESPONSIBLE ON THE GLUCURONIDATION OF ABUNDANT ENDOBIOTICS OR XENOBIOTICS. WE HERE REPORT THAT IT IS MARKEDLY REPRESSED IN THE TUMOR TISSUES OF COLORECTAL CARCINOMA (CRC) PATIENTS. ACCORDINGLY, MORPHINE IN CRC CELLS WILL STIMULATE THE EXPRESSION OF ITS MAIN METABOLIC ENZYME, UGT2B7 DURING TOLERANCE GENERATION BY ACTIVATING THE POSITIVE SIGNALS IN HISTONE 3, ESPECIALLY FOR TRIMETHYLATED LYSINE 27 (H3K4ME3) AND ACETYLATED LYSINE 4 (H3K27AC). FURTHER STUDY REVEALS THAT BRAIN-DERIVED NEUTROPHILIC FACTOR (BDNF), A SECRETORY NEUROTROPHIN, ENRICHED IN CRC CAN INTERACT AND INHIBIT UGT2B7 BY PRIMARILY BLOCKING THE POSITIVE SIGNALS OF H3K4ME3 AS WELL AS ACTIVATING H3K27AC ON THE PROMOTER REGION OF UGT2B7. MEANWHILE, BDNF REPRESSION ATTRIBUTES TO THE SENSITIZATIONS OF MAIN CORE FACTORS IN POLY-COMB REPRESSIVE COMPLEX (PRC) 1 RATHER THAN PRC2 AS THE REASON OF THE DEPRESSION OF SUZ12 IN THE LATER COMPLEX. BESIDES THAT, THE PRODUCTIONS OF TWO MAIN MORPHINE GLUCURONIDES ARE BOTH INCREASED IN THE BDNF DEFICIENT OR TSA AND BIX-01294 TREATED MORPHINE TOLERANCE-LIKE HCT-116 CELLS. ON THE SAME CONDITION, ACTIVE METABOLITE, MORPHINE-6-GLUCURONIDE (M6G) WAS ACCUMULATED MORE THAN INACTIVE M3G. OUR FINDINGS IMPLY THAT ENZYMATIC ACTIVITY ENHANCEMENT AND SUBSTRATE REGIOSELECTIVE CATALYSIS ALTERATION OF UGT2B7 MAY RELEASE MORPHINE TOLERANCE UNDER THE CURE OF TUMOR-INDUCED PAIN.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16 3657  32 INDUCTION AND RECOVERY OF CPG SITE SPECIFIC METHYLATION CHANGES IN HUMAN BRONCHIAL CELLS AFTER LONG-TERM EXPOSURE TO CARBON NANOTUBES AND ASBESTOS. INTRODUCTION: INHALATION OF ASBESTOS INDUCES LUNG CANCER VIA DIFFERENT CELLULAR MECHANISMS. TOGETHER WITH THE INCREASED PRODUCTION OF CARBON NANOTUBES (CNTS) GROWS THE CONCERN ABOUT ADVERSE EFFECTS ON THE LUNGS GIVEN THE SIMILARITIES WITH ASBESTOS. WHILE IT HAS BEEN ESTABLISHED THAT CNT AND ASBESTOS INDUCE EPIGENETIC ALTERATIONS, IT IS CURRENTLY NOT KNOWN WHETHER ALTERATIONS AT EPIGENETIC LEVEL REMAIN STABLE AFTER WITHDRAWAL OF THE EXPOSURE. IDENTIFICATION OF DNA METHYLATION CHANGES AFTER A LOW DOSE OF CNT AND ASBESTOS EXPOSURE AND RECOVERY CAN BE USEFUL TO DETERMINE THE FIBRE/PARTICLE TOXICITY AND ADVERSE OUTCOME. METHODS: HUMAN BRONCHIAL EPITHELIAL CELLS (16HBE) WERE TREATED WITH A LOW AND NON-CYTOTOXIC DOSE (0.25 MICROG/ML) OF MULTI-WALLED CARBON NANOTUBES (MWCNTS-NM400) OR SINGLE-WALLED CARBON NANOTUBES (SWCNTS-SRM2483) AND 0.05 MICROG/ML AMOSITE (BROWN) ASBESTOS FOR THE COURSE OF FOUR WEEKS (SUB-CHRONIC EXPOSURE). AFTER THIS TREATMENT, THE CELLS WERE FURTHER INCUBATED (WITHOUT PARTICLE/FIBRE) FOR TWO WEEKS, ALLOWING RECOVERY FROM THE EXPOSURE (RECOVERY PERIOD). NUCLEAR DEPOSITIONS OF THE CNTS WERE ASSESSED USING FEMTOSECOND PULSED LASER MICROSCOPY IN A LABEL-FREE MANNER. DNA METHYLATION ALTERATIONS WERE ANALYSED USING MICROARRAYS THAT ASSESS MORE THAN 850 THOUSAND CPG SITES IN THE WHOLE GENOME. RESULTS: AT NON-CYTOTOXIC DOSES, CNTS WERE NOTED TO BE INCORPORATED WITH IN THE NUCLEUS AFTER A FOUR WEEKS PERIOD. EXPOSURE TO MWCNTS INDUCED A SINGLE HYPOMETHYLATION AT A CPG SITE AND GENE PROMOTER REGION. NO CHANGE IN DNA METHYLATION WAS OBSERVED AFTER THE RECOVERY PERIOD FOR MWCNTS. EXPOSURE TO SWCNTS OR AMOSITE INDUCED HYPERMETHYLATION AT CPG SITES AFTER SUB-CHRONIC EXPOSURE WHICH MAY INVOLVE IN 'TRANSCRIPTION FACTOR ACTIVITY' AND 'SEQUENCE-SPECIFIC DNA BINDING' GENE ONTOLOGIES. AFTER THE RECOVERY PERIOD, HYPERMETHYLATION AND HYPOMETHYLATION WERE NOTED FOR BOTH SWCNTS AND AMOSITE. HIPPOCALCINLIKE 1 (HPCAL1), PROTEASE SERINE 3 (PRSS3), KALLIKREIN-RELATED PEPTIDASE 3 (KLK3), KRUPPEL LIKE FACTOR 3 (KLF3) GENES WERE HYPERMETHYLATED AT DIFFERENT TIME POINTS IN EITHER SWCNT-EXPOSED OR AMOSITE-EXPOSED CELLS. CONCLUSION: THESE RESULTS SUGGEST THAT THE SPECIFIC SWCNT (SRM2483) AND AMOSITE FIBRES STUDIED INDUCE HYPO- OR HYPERMETHYLATION ON CPG SITES IN DNA AFTER VERY LOW-DOSE EXPOSURE AND RECOVERY PERIOD. THIS EFFECT WAS NOT SEEN FOR THE STUDIED MWCNT (NM400).	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17 2666  30 ESTABLISHMENT OF AN INTERMITTENT COLD STRESS MODEL USING TUPAIA BELANGERI AND EVALUATION OF COMPOUND C737 TARGETING NEURON-RESTRICTIVE SILENCER FACTOR. PREVIOUS STUDIES HAVE SHOWN THAT INTERMITTENT COLD STRESS (ICS) INDUCES DEPRESSION-LIKE BEHAVIORS IN MAMMALS. TUPAIA BELANGERI (THE TREE SHREW) IS THE ONLY EXPERIMENTAL ANIMAL OTHER THAN THE CHIMPANZEE THAT HAS BEEN SHOWN TO BE SUSCEPTIBLE TO INFECTION BY HEPATITIS B AND C VIRUSES. MOREOVER, FULL GENOME SEQUENCE ANALYSIS HAS REVEALED STRONG HOMOLOGY BETWEEN HOST PROTEINS IN TUPAIA AND IN HUMANS AND OTHER PRIMATES. TUPAIA NEUROMODULATOR RECEPTOR PROTEINS ARE ALSO KNOWN TO HAVE A HIGH DEGREE OF HOMOLOGY WITH THEIR CORRESPONDING PRIMATE PROTEINS. BASED ON THESE SIMILARITIES, WE HYPOTHESIZED THAT INDUCTION OF ICS IN TUPAIA WOULD PROVIDE A USEFUL ANIMAL MODEL OF STRESS RESPONSES. WE EXPOSED YOUNG ADULT TUPAIA TO ICS AND OBSERVED DECREASES IN BODY TEMPERATURE AND BODY WEIGHT IN BOTH FEMALE AND MALE TUPAIA, SUGGESTING THAT TUPAIA ARE AN APPROPRIATE ANIMAL MODEL FOR ICS STUDIES. WE FURTHER EXAMINED THE EFFICACY OF A NEW SMALL-MOLECULE COMPOUND, C737, AGAINST THE EFFECTS OF ICS. C737 MIMICS THE HELICAL STRUCTURE OF NEURON-RESTRICTIVE SILENCER FACTOR (NRSF/REST), WHICH REGULATES A WIDE RANGE OF TARGET GENES INVOLVED IN NEURONAL FUNCTION AND PAIN MODULATION. TREATMENT WITH C737 SIGNIFICANTLY REDUCED STRESS-INDUCED WEIGHT LOSS IN FEMALE TUPAIA; THESE EFFECTS WERE STRONGER THAN THOSE ELICITED BY THE ANTIDEPRESSANT AGOMELATINE. THESE RESULTS SUGGEST THAT TUPAIA REPRESENTS A USEFUL NON-RODENT ICS MODEL. OUR DATA ALSO PROVIDE NEW INSIGHTS INTO THE FUNCTION OF NRSF/REST IN STRESS-INDUCED DEPRESSION AND OTHER DISORDERS WITH EPIGENETIC INFLUENCES OR THOSE WITH HIGH PREVALENCE IN WOMEN.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18 2080  26 EPIGENETIC DNA METHYLATION OF EBI3 MODULATES HUMAN INTERLEUKIN-35 FORMATION VIA NFKB SIGNALING: A PROMISING THERAPEUTIC OPTION IN ULCERATIVE COLITIS. ULCERATIVE COLITIS (UC), A SEVERE CHRONIC DISEASE WITH UNCLEAR ETIOLOGY THAT IS ASSOCIATED WITH INCREASED RISK FOR COLORECTAL CANCER, IS ACCOMPANIED BY DYSREGULATION OF CYTOKINES. EPSTEIN-BARR VIRUS-INDUCED GENE 3 (EBI3) ENCODES A SUBUNIT IN THE UNIQUE HETERODIMERIC IL-12 CYTOKINE FAMILY OF EITHER PRO- OR ANTI-INFLAMMATORY FUNCTION. AFTER HAVING RECENTLY DEMONSTRATED THAT UPREGULATION OF EBI3 BY HISTONE ACETYLATION ALLEVIATES DISEASE SYMPTOMS IN A DEXTRAN SULFATE SODIUM (DSS)-TREATED MOUSE MODEL OF CHRONIC COLITIS, WE NOW AIMED TO EXAMINE A POSSIBLE FURTHER EPIGENETIC REGULATION OF EBI3 BY DNA METHYLATION UNDER INFLAMMATORY CONDITIONS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR (DNMTI) DECITABINE (DAC) AND TNFALPHA LED TO SYNERGISTIC UPREGULATION OF EBI3 IN HUMAN COLON EPITHELIAL CELLS (HCEC). USE OF DIFFERENT SIGNALING PATHWAY INHIBITORS INDICATED NFKAPPAB SIGNALING WAS NECESSARY AND PROPORTIONAL TO THE SYNERGISTIC EBI3 INDUCTION. MALDI-TOF/MS AND HPLC-ESI-MS/MS ANALYSIS OF DAC/TNFALPHA-TREATED HCEC IDENTIFIED IL-12P35 AS THE MOST PROBABLE BINDING PARTNER TO FORM A FUNCTIONAL PROTEIN. EBI3/IL-12P35 HETERODIMERS (IL-35) INDUCE THEIR OWN GENE UPREGULATION, SOMETHING THAT WAS INDEED OBSERVED IN HCEC CULTURED WITH MEDIA FROM PREVIOUSLY DAC/TNFALPHA-TREATED HCEC. THESE RESULTS SUGGEST THAT UNDER INFLAMMATORY AND DEMETHYLATING CONDITIONS THE UPREGULATION OF EBI3 RESULTS IN THE FORMATION OF ANTI-INFLAMMATORY IL-35, WHICH MIGHT BE CONSIDERED AS A THERAPEUTIC TARGET IN COLITIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
19 1843  26 EFFECTS OF TELOMERASE INHIBITOR ON EPIGENETIC CHROMATIN MODIFICATION ENZYMES IN MALIGNANCIES. TELOMERASE HAS A CRITICAL ROLE IN CELL PROLIFERATION, TUMOR MAINTAINING, AND THERAPY RESISTANCE, WHICH ACT BY MODIFYING MANY SIGNALING PATHWAYS. 2-[(E)-3-NAPHTALEN-2-YL-BUT-2-ENOYLAMINO]-BENZOIC ACID (BIBR1532) IS ONE OF THE MOST STUDIED TELOMERASE INHIBITORS, AND IT TARGETS TELOMERASE COMPONENTS TERC AND TERT. IN THIS NOVEL STUDY, WE AIMED TO INVESTIGATE THE EPIGENETIC EFFECTS OF BIBR1532 ON BOTH HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS. K-562 HUMAN CHRONIC MYELOID LEUKEMIA CELL LINE AND U87MG GLIOBLASTOMA CELL LINE WERE COMPARED WITH CONTROL GROUPS WITHOUT BIBR1532 TREATMENT. CYTOTOXIC EFFECTS OF BIBR1532 WERE DETERMINED BY USING WST-1 ASSAY. APOPTOTIC EFFECTS OF BIBR1532 WERE DETECTED BY USING ANNEXIN V METHOD. TO ASSESS EXPRESSION CHANGES IN THE HUMAN EPIGENETIC CHROMATIN MODIFICATION ENZYME GENES, TOTAL RNA WAS ISOLATED FROM K-562 AND U87MG CELLS TREATED WITH BIBR1532 AND UNTREATED CONTROL CELLS. BIBR1532 INDUCED 2.41-FOLD APOPTOTIC CELL DEATH IN U87MG CELL LINES COMPARED WITH CONTROL GROUPS. APOPTOSIS WAS SLIGHTLY INDUCED IN K-562 CELLS WITH BIBR1532 TREATMENT COMPARED WITH CONTROL CELLS. WE OBSERVED THAT BIBR1532 ALSO REGULATES SIMILAR GENES IN BOTH CELL LINES, AND IT IS USEFUL ON EPIGENETIC MECHANISMS. AS A RESULT, TELOMERASE INHIBITOR BIBR1532 HAS A SIGNIFICANT EFFECT ON BOTH HEMATOLOGICAL MALIGNANCIES AND SOLID TUMORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  582  24 BEHAVIORAL AND PHYSIOLOGICAL EFFECTS OF ACUTE AND CHRONIC KAVA EXPOSURE IN ADULT ZEBRAFISH. KAVA KAVA (PIPER METHYSTICUM) IS A MEDICINAL PLANT CONTAINING KAVALACTONES THAT EXERT POTENT SEDATIVE, ANALGESIC AND ANTI-STRESS ACTION. HOWEVER, THEIR PHARMACOLOGICAL EFFECTS AND MOLECULAR TARGETS REMAIN POORLY UNDERSTOOD. THE ZEBRAFISH (DANIO RERIO) HAS RECENTLY EMERGED AS A POWERFUL NEW MODEL ORGANISM FOR NEUROSCIENCE RESEARCH AND DRUG DISCOVERY. HERE, WE EVALUATE THE EFFECTS OF ACUTE AND CHRONIC EXPOSURE TO KAVA AND KAVALACTONES ON ADULT ZEBRAFISH ANXIETY, AGGRESSION AND SOCIALITY, AS WELL AS ON THEIR NEUROCHEMICAL, NEUROENDOCRINE AND GENOMIC RESPONSES. SUPPORTING EVOLUTIONARILY CONSERVED MOLECULAR TARGETS, ACUTE KAVA AND KAVALACTONES EVOKED DOSE-DEPENDENT BEHAVIORAL INHIBITION, UPREGULATED BRAIN EXPRESSION OF EARLY PROTOONCOGENES C-FOS AND C-JUN, ELEVATED BRAIN MONOAMINES AND LOWERED WHOLE-BODY CORTISOL. CHRONIC 7-DAY KAVA EXPOSURE EVOKED SIMILAR BEHAVIORAL EFFECTS, DID NOT ALTER CORTISOL LEVELS, AND FAILED TO EVOKE WITHDRAWAL-LIKE STATES UPON DISCONTINUATION. HOWEVER, CHRONIC KAVA UPREGULATED SEVERAL MICROGLIAL (INOS, EGR-2, CD11B), ASTROCYTAL (C3, C4B, S100A), EPIGENETIC (NCOA-1) AND PRO-INFLAMMATORY (IL-1BETA, IL-6, TNFA) BIOMARKER GENES, DOWNREGULATED CD206 AND IL-4, AND DID NOT AFFECT MAJOR APOPTOTIC GENES IN THE BRAIN. COLLECTIVELY, THIS STUDY SUPPORTS ROBUST, EVOLUTIONARILY CONSERVED BEHAVIORAL AND PHYSIOLOGICAL EFFECTS OF KAVA AND KAVALACTONES IN ZEBRAFISH, IMPLICATES BRAIN MONOAMINES IN THEIR ACUTE EFFECTS, AND PROVIDES NOVEL IMPORTANT INSIGHTS INTO POTENTIAL ROLE OF NEUROGLIAL AND EPIGENETIC MECHANISMS IN LONG-TERM KAVA USE.	2020