1  2473 101 EPIGENETIC TREATMENTS OF ADULT RATS PROMOTE RECOVERY FROM VISUAL ACUITY DEFICITS INDUCED BY LONG-TERM MONOCULAR DEPRIVATION. IN MAMMALS THE DEVELOPMENT OF THE VISUAL SYSTEM MAY BE ALTERED DURING A SENSITIVE PERIOD BY MODIFYING THE VISUAL INPUT TO ONE OR BOTH EYES. THESE PLASTIC PROCESSES ARE REDUCED AFTER THE END OF THE SENSITIVE PERIOD. IT HAS BEEN PROPOSED THAT REDUCED LEVELS OF PLASTICITY ARE AT THE BASIS OF THE LACK OF RECOVERY FROM EARLY VISUAL DEPRIVATION OBSERVED IN ADULT ANIMALS. A DEVELOPMENTAL DOWNREGULATION OF EXPERIENCE-DEPENDENT REGULATION OF HISTONE ACETYLATION HAS RECENTLY BEEN FOUND TO BE INVOLVED IN CLOSING THE SENSITIVE PERIOD. THEREFORE, WE TESTED WHETHER PHARMACOLOGICAL EPIGENETIC TREATMENTS INCREASING HISTONE ACETYLATION COULD BE USED TO REVERSE VISUAL ACUITY DEFICITS INDUCED BY LONG-TERM MONOCULAR DEPRIVATION INITIATED DURING THE SENSITIVE PERIOD. WE FOUND THAT CHRONIC INTRAPERITONEAL ADMINISTRATION OF VALPROIC ACID OR SODIUM BUTYRATE (TWO DIFFERENT HISTONE DEACETYLASES INHIBITORS) TO LONG-TERM MONOCULARLY DEPRIVED ADULT RATS COUPLED WITH REVERSE LID-SUTURING CAUSED A COMPLETE RECOVERY OF VISUAL ACUITY, TESTED ELECTROPHYSIOLOGICALLY AND BEHAVIORALLY. THUS, MANIPULATIONS OF THE EPIGENETIC MACHINERY CAN BE USED TO PROMOTE FUNCTIONAL RECOVERY FROM EARLY ALTERATIONS OF SENSORY INPUT IN THE ADULT CORTEX.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  4588  33 NANOPARTICLE EXPOSURES FROM NANO-ENABLED TONER-BASED PRINTING EQUIPMENT AND HUMAN HEALTH: STATE OF SCIENCE AND FUTURE RESEARCH NEEDS. TONER FORMULATIONS USED BY LASER PRINTERS (LP) AND PHOTOCOPIERS (PC), COLLECTIVELY CALLED "TONER-BASED PRINTING EQUIPMENT" (TPE), ARE NANO-ENABLED PRODUCTS (NEP) BECAUSE THEY CONTAIN SEVERAL ENGINEERED NANOMATERIALS (ENM) THAT IMPROVE TONER PERFORMANCE. IT HAS BEEN SHOWN THAT DURING CONSUMER USE (PRINTING), THESE ENM ARE RELEASED IN THE AIR, TOGETHER WITH OTHER SEMI-VOLATILE ORGANIC NANOPARTICLES, AND NEWLY FORMED GASEOUS CO-POLLUTANTS SUCH AS VOLATILE ORGANIC COMPOUNDS (VOC). THE AIM OF THIS REVIEW IS TO DETAIL AND ANALYZE PHYSICO-CHEMICAL AND MORPHOLOGICAL (PCM), AS WELL AS THE TOXICOLOGICAL PROPERTIES OF PARTICULATE MATTER (PM) EMISSIONS FROM TPE. THE REVIEW COVERS EVOLUTION OF SCIENCE SINCE THE EARLY 2000, WHEN THIS PRINTING TECHNOLOGY FIRST BECAME A SUBJECT OF PUBLIC INTEREST, AS WELL AS THE LAGGING REGULATORY FRAMEWORK AROUND IT. IMPORTANT STUDIES THAT HAVE SIGNIFICANTLY CHANGED OUR UNDERSTANDING OF THESE EXPOSURES ARE ALSO HIGHLIGHTED. THE REVIEW CONTINUES WITH A CRITICAL APPRAISAL OF THE MOST UP-TO-DATE CELLULAR, ANIMAL AND HUMAN TOXICOLOGICAL EVIDENCE ON THE POTENTIAL ADVERSE HUMAN HEALTH EFFECTS OF PM EMITTED FROM TPE. WE HIGHLIGHT SEVERAL LIMITATIONS OF EXISTING STUDIES, INCLUDING (I) USE OF HIGH AND OFTEN UNREALISTIC DOSES IN VITRO OR IN VIVO; (II) UNREALISTICALLY HIGH-DOSE RATES IN INTRATRACHEAL INSTILLATION STUDIES; (III) IMPROPER USE OF TONERS AS SURROGATE FOR EMITTED NANOPARTICLES; (IV) LACK OF OR INADEQUATE PCM CHARACTERIZATION OF EXPOSURES; AND (V) LACK OF DOSIMETRY CONSIDERATIONS IN IN VITRO STUDIES. PRESENTLY, THERE IS COMPELLING EVIDENCE THAT THE PM(0.1) FROM TPE ARE BIOLOGICALLY ACTIVE AND CAPABLE OF INDUCING OXIDATIVE STRESS IN VITRO AND IN VIVO, RESPIRATORY TRACT INFLAMMATION IN VIVO (IN RATS) AND IN HUMANS, SEVERAL ENDPOINTS OF CELLULAR INJURY IN MONOCULTURES AND CO-CULTURES, INCLUDING MODERATE EPIGENETIC MODIFICATIONS IN VITRO. IN HUMANS, LIMITED EPIDEMIOLOGICAL STUDIES REPORT TYPICALLY 2-3 TIMES HIGHER PREVALENCE OF CHRONIC COUGH, WHEEZING, NASAL BLOCKAGE, EXCESSIVE SPUTUM PRODUCTION, BREATHING DIFFICULTIES, AND SHORTNESS OF BREATH, IN COPIER OPERATORS RELATIVE TO CONTROLS. SUCH SYMPTOMS CAN BE EXACERBATED DURING CHRONIC EXPOSURES, AND IN INDIVIDUALS SUSCEPTIBLE TO INHALED POLLUTANTS. THUS RESPIRATORY, IMMUNOLOGICAL, CARDIOVASCULAR, AND OTHER DISORDERS MAY BE DEVELOPED FOLLOWING SUCH EXPOSURES; HOWEVER, FURTHER TOXICOLOGICAL AND LARGER SCALE MOLECULAR EPIDEMIOLOGICAL STUDIES MUST BE DONE TO FULLY UNDERSTAND THE MECHANISM OF ACTION OF THESE TPE EMITTED NANOPARTICLES. MAJOR RESEARCH GAPS HAVE ALSO BEEN IDENTIFIED. AMONG THEM, A METHODICAL RISK ASSESSMENT BASED ON "REAL WORLD" EXPOSURES RATHER THAN ON THE TONER PARTICLES ALONE NEEDS TO BE PERFORMED TO PROVIDE THE MUCH-NEEDED DATA TO ESTABLISH REGULATORY GUIDELINES PROTECTIVE OF INDIVIDUALS EXPOSED TO TPE EMISSIONS AT BOTH THE OCCUPATIONAL AND CONSUMER LEVEL. INDUSTRY-WIDE MOLECULAR EPIDEMIOLOGY AS WELL AS MECHANISTIC ANIMAL AND HUMAN STUDIES ARE ALSO URGENTLY NEEDED.	2017	

3  5854  22 SUBSTANCE P AND NEPRILYSIN IN CHRONIC PANCREATITIS. BACKGROUND/AIMS: WE AIMED TO ANALYZE SUBSTANCE P (SP) AND NEPRILYSIN (NEP), THE MEMBRANE METALLOPEPTIDASE THAT DEGRADES SP, IN CHRONIC PANCREATITIS (CP). METHODS: SP AND NEP MRNA LEVELS WERE ANALYZED BY QRT-PCR IN TISSUE SAMPLES FROM 30 PATIENTS WITH CP AND 8 ORGAN DONORS. IN ADDITION, SP SERUM LEVELS WERE DETERMINED BEFORE AND AFTER SURGERY IN THE SAME PATIENTS, BY MEANS OF A COMPETITIVE ELISA ASSAY. GENETIC AND EPIGENETIC ANALYSES OF THE NEP GENE WERE ALSO PERFORMED. RESULTS: SP MRNA EXPRESSION LEVELS WERE HIGHER IN CP TISSUES COMPARED TO CONTROLS (P = 0.0152), WHILE NEP MRNA SHOWED NO SIGNIFICANT DIFFERENCES BETWEEN CP AND HEALTHY SUBJECTS (P = 0.2102). IN CP PATIENTS, SP SERUM LEVELS CORRELATED WITH THOSE IN TISSUE, AND AFTER SURGICAL RESECTION SP SERUM LEVELS WERE REDUCED COMPARED TO THE PREOPERATIVE VALUES. FAILURE OF NEP TO OVEREXPRESS IN CP TISSUES WAS ASSOCIATED WITH SIGNIFICANT MIR-128A OVEREXPRESSION (P = 0.02), RATHER THAN WITH MUTATIONS IN THE NEP CODING REGION OR THE PRESENCE OF HYPERMETHYLATION SITES IN THE NEP PROMOTER REGION. CONCLUSION: TISSUE AND SERUM LEVELS OF SP WERE INCREASED IN CP, WHILE NEP LEVELS REMAINED UNALTERED. IN AN SP/NEP-MEDIATED PATHWAY, IT WOULD APPEAR THAT NEP FAILS TO PROVIDE ADEQUATE SURVEILLANCE OF SP LEVELS. FAILURE OF NEP TO OVEREXPRESS COULD BE ASSOCIATED WITH MIRNA REGULATION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4  3712  15 INHALED POLLUTANTS: THE MOLECULAR SCENE BEHIND RESPIRATORY AND SYSTEMIC DISEASES ASSOCIATED WITH ULTRAFINE PARTICULATE MATTER. AIR POLLUTION OF ANTHROPOGENIC ORIGIN IS LARGELY FROM THE COMBUSTION OF BIOMASS (E.G., WOOD), FOSSIL FUELS (E.G., CARS AND TRUCKS), INCINERATORS, LANDFILLS, AGRICULTURAL ACTIVITIES AND TOBACCO SMOKE. AIR POLLUTION IS A COMPLEX MIXTURE THAT VARIES IN SPACE AND TIME, AND CONTAINS HUNDREDS OF COMPOUNDS INCLUDING VOLATILE ORGANIC COMPOUNDS (E.G., BENZENE), METALS, SULPHUR AND NITROGEN OXIDES, OZONE AND PARTICULATE MATTER (PM). PM(0.1) (ULTRAFINE PARTICLES (UFP)), THOSE PARTICLES WITH A DIAMETER LESS THAN 100 NM (INCLUDES NANOPARTICLES (NP)) ARE CONSIDERED ESPECIALLY DANGEROUS TO HUMAN HEALTH AND MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF NUMEROUS RESPIRATORY AND CARDIOVASCULAR DISEASES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND ATHEROSCLEROSIS. SOME OF THE PATHOGENIC MECHANISMS THROUGH WHICH PM(0.1) MAY CONTRIBUTE TO CHRONIC DISEASE IS THEIR ABILITY TO INDUCE INFLAMMATION, OXIDATIVE STRESS AND CELL DEATH BY MOLECULAR MECHANISMS THAT INCLUDE TRANSCRIPTION FACTORS SUCH AS NUCLEAR FACTOR KAPPAB (NF-KAPPAB) AND NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE 2 (NRF2). EPIGENETIC MECHANISMS INCLUDING NON-CODING RNA (NCRNA) MAY ALSO CONTRIBUTE TOWARDS THE DEVELOPMENT OF CHRONIC DISEASE ASSOCIATED WITH EXPOSURE TO PM(0.1). THIS PAPER HIGHLIGHTS EMERGING MOLECULAR CONCEPTS ASSOCIATED WITH INHALATIONAL EXPOSURE TO PM(0.1) AND THEIR ABILITY TO CONTRIBUTE TO CHRONIC RESPIRATORY AND SYSTEMIC DISEASE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  1827  41 EFFECTS OF HISTONE DEACETYLASE INHIBITORS ON THE DEVELOPMENT OF EPILEPSY AND PSYCHIATRIC COMORBIDITY IN WAG/RIJ RATS. EPIGENETIC MECHANISMS, SUCH AS ALTERATIONS IN HISTONE ACETYLATION BASED ON HISTONE DEACETYLASES (HDACS) ACTIVITY, HAVE BEEN LINKED NOT ONLY TO NORMAL BRAIN FUNCTION BUT ALSO TO SEVERAL BRAIN DISORDERS INCLUDING EPILEPSY AND THE EPILEPTOGENIC PROCESS. IN WAG/RIJ RATS, A GENETIC MODEL OF ABSENCE EPILEPSY, EPILEPTOGENESIS AND MILD-DEPRESSION COMORBIDITY, WE INVESTIGATED THE EFFECTS OF TWO HDAC INHIBITORS (HDACI), NAMELY SODIUM BUTYRATE (NAB), VALPROIC ACID (VPA) AND THEIR CO-ADMINISTRATION, ON THE DEVELOPMENT OF ABSENCE SEIZURES AND RELATED PSYCHIATRIC/NEUROLOGIC COMORBIDITIES FOLLOWING TWO DIFFERENT EXPERIMENTAL PARADIGMS. TREATMENT EFFECTS HAVE BEEN EVALUATED BY EEG RECORDINGS (EEG) AND BEHAVIOURAL TESTS AT DIFFERENT TIME POINTS. PROLONGED AND DAILY VPA AND NAB TREATMENT, STARTED BEFORE ABSENCE SEIZURE ONSET (P30), SIGNIFICANTLY REDUCED THE DEVELOPMENT OF ABSENCE EPILEPSY SHOWING ANTIEPILEPTOGENIC EFFECTS. THESE EFFECTS WERE ENHANCED BY NAB/VPA CO-ADMINISTRATION. FURTHERMORE, EARLY-CHRONIC HDACI TREATMENT IMPROVED DEPRESSIVE-LIKE BEHAVIOUR AND COGNITIVE PERFORMANCE 1 MONTH AFTER TREATMENT WITHDRAWAL. WAG/RIJ RATS OF 7 MONTHS OF AGE SHOWED REDUCED ACETYLATED LEVELS OF HISTONE H3 AND H4, ANALYSED BY WESTERN BLOTTING OF HOMOGENIZED BRAIN, IN COMPARISON TO WAG/RIJ BEFORE SEIZURE ONSET (P30). THE BRAIN HISTONE ACETYLATION INCREASED SIGNIFICANTLY DURING TREATMENT WITH NAB OR VPA ALONE AND MORE MARKEDLY DURING CO-ADMINISTRATION. WE ALSO OBSERVED DECREASED EXPRESSION OF BOTH HDAC1 AND 3 FOLLOWING HDACI TREATMENT COMPARED TO CONTROL GROUP. OUR RESULTS SUGGEST THAT HISTONE MODIFICATIONS MAY HAVE A CRUCIAL ROLE IN THE DEVELOPMENT OF EPILEPSY AND EARLY TREATMENT WITH HDACI MIGHT BE A POSSIBLE STRATEGY FOR PREVENTING EPILEPTOGENESIS ALSO AFFECTING BEHAVIOURAL COMORBIDITIES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6  4913  31 PAIN MODULATION IN WAG/RIJ EPILEPTIC RATS (A GENETIC MODEL OF ABSENCE EPILEPSY): EFFECTS OF BIOLOGICAL AND PHARMACOLOGICAL HISTONE DEACETYLASE INHIBITORS. EPIGENETIC MECHANISMS ARE INVOLVED IN EPILEPSY AND CHRONIC PAIN DEVELOPMENT. ABOUT THAT, WE STUDIED THE EFFECTS OF THE NATURAL HISTONE DEACETYLASE (HDAC) INHIBITOR SODIUM BUTYRATE (BUT) IN COMPARISON WITH VALPROIC ACID (VPA) IN A VALIDATED GENETIC MODEL OF GENERALIZED ABSENCE EPILEPSY AND EPILEPTOGENESIS. WAG/RIJ RATS WERE TREATED WITH BUT (30 MG/KG), VPA (300 MG/KG), AND THEIR COMBINATION (BUT + VPA) DAILY PER OS FOR 6 MONTHS. RATS WERE SUBJECTED AT RANDALL-SELITTO, VON FREY, HOT PLATE, AND TAIL FLICK TESTS AFTER 1, 3, AND 6 MONTHS OF TREATMENT TO EVALUATE HYPERSENSITIVITY TO NOXIOUS AND NON-NOXIUOUS STIMULI. MOREOVER, PPAR-GAMMA (G3335 1 MG/KG), GABA-B (CGP35348 80 MG/KG), AND OPIOID (NALOXONE 1 MG/KG) RECEPTOR ANTAGONISTS WERE ADMINISTRATED TO INVESTIGATE THE POSSIBLE MECHANISMS INVOLVED IN ANALGESIC ACTIVITY. THE EXPRESSION OF NFKB, GLUTATHIONE REDUCTASE, AND PROTEIN OXIDATION (CARBONYLATION) WAS ALSO EVALUATED BY WESTERN BLOT ANALYSIS. WAG/RIJ RATS SHOWED AN ALTERED PAIN THRESHOLD THROUGHOUT THE STUDY (P < 0.001). BUT AND BUT + VPA TREATMENT REDUCED HYPERSENSITIVITY (P < 0.01). VPA WAS SIGNIFICANTLY EFFECTIVE ONLY AFTER 1 MONTH (P < 0.01). ALL THE THREE RECEPTORS ARE INVOLVED IN BUT + VPA EFFECTS (P < 0.001). BUT AND BUT + VPA DECREASED THE EXPRESSION OF NFKB AND ENHANCED GLUTATHIONE REDUCTASE (P < 0.01); PROTEIN OXIDATION (CARBONYLATION) WAS REDUCED (P < 0.01). NO EFFECT WAS REPORTED WITH VPA. IN CONCLUSION BUT, ALONE OR IN COADMINISTRATION WITH VPA, IS A VALUABLE CANDIDATE FOR MANAGING THE EPILEPSY-RELATED PERSISTENT PAIN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
7  4944  18 PATERNAL PRECONCEPTION ETHANOL EXPOSURE BLUNTS HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY AND STRESS-INDUCED EXCESSIVE FLUID INTAKE IN MALE MICE. A GROWING NUMBER OF ENVIRONMENTAL INSULTS HAVE BEEN SHOWN TO INDUCE EPIGENETIC EFFECTS THAT PERSIST ACROSS GENERATIONS. FOR INSTANCE, PATERNAL PRECONCEPTION EXPOSURES TO ETHANOL OR STRESS HAVE INDEPENDENTLY BEEN SHOWN TO EXERT SUCH INTERGENERATIONAL EFFECTS. SINCE ETHANOL EXPOSURE IS A PHYSIOLOGICAL STRESSOR THAT ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WE HYPOTHESIZED THAT PATERNAL ETHANOL EXPOSURE WOULD IMPACT STRESS RESPONSIVITY OF OFFSPRING. ADULT MALE MICE WERE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL OR CONTROL CONDITIONS FOR 5 WEEKS BEFORE BEING MATED WITH ETHANOL-NAIVE FEMALES TO PRODUCE ETHANOL (E)- AND CONTROL (C)-SIRED OFFSPRING. ADULT MALE AND FEMALE OFFSPRING WERE TESTED FOR PLASMA CORTICOSTERONE (CORT) LEVELS FOLLOWING ACUTE RESTRAINT STRESS AND THE MALE OFFSPRING WERE FURTHER EXAMINED FOR STRESS-EVOKED 2-BOTTLE CHOICE ETHANOL-DRINKING. PATERNAL ETHANOL EXPOSURE BLUNTED PLASMA CORT LEVELS FOLLOWING ACUTE RESTRAINT STRESS SELECTIVELY IN MALE OFFSPRING; FEMALES WERE UNAFFECTED. IN A STRESS-EVOKED ETHANOL-DRINKING ASSAY, THERE WAS NO EFFECT OF STRESS ON ETHANOL CONSUMPTION. HOWEVER, C-SIRED MALES EXHIBITED INCREASED TOTAL FLUID INTAKE (POLYDIPSIA) IN RESPONSE TO STRESS WHILE E-SIRED MALES WERE RESISTANT TO THIS STRESS-INDUCED PHENOTYPE. TAKEN TOGETHER, THESE DATA SUGGEST THAT PATERNAL ETHANOL EXPOSURE IMPARTS STRESS HYPORESPONSIVITY TO MALE OFFSPRING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8  1761  29 EARLY STRESS EVOKES AGE-DEPENDENT BIPHASIC CHANGES IN HIPPOCAMPAL NEUROGENESIS, BDNF EXPRESSION, AND COGNITION. BACKGROUND: ADULT-ONSET STRESSORS EXERT OPPOSING EFFECTS ON HIPPOCAMPAL NEUROGENESIS AND COGNITION, WITH ENHANCEMENT OBSERVED FOLLOWING MILD STRESS AND DYSFUNCTION FOLLOWING SEVERE CHRONIC STRESS. WHILE EARLY LIFE STRESS EVOKES PERSISTENT CHANGES IN ANXIETY, IT IS UNKNOWN WHETHER EARLY STRESS DIFFERENTIALLY REGULATES HIPPOCAMPAL NEUROGENESIS, TROPHIC FACTOR EXPRESSION, AND COGNITION ACROSS THE LIFE SPAN. METHODS: HIPPOCAMPAL-DEPENDENT COGNITIVE BEHAVIOR, NEUROGENESIS, AND EPIGENETIC REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION WAS EXAMINED AT DISTINCT TIME POINTS ACROSS THE LIFE SPAN IN RATS SUBJECTED TO THE EARLY STRESS OF MATERNAL SEPARATION (ES) AND CONTROL GROUPS. WE ALSO EXAMINED THE INFLUENCE OF CHRONIC ANTIDEPRESSANT TREATMENT ON THE NEUROGENIC, NEUROTROPHIC, AND COGNITIVE CHANGES IN MIDDLE-AGED ES ANIMALS. RESULTS: ANIMALS SUBJECTED TO EARLY STRESS OF MATERNAL SEPARATION EXAMINED DURING POSTNATAL LIFE AND YOUNG ADULTHOOD EXHIBITED ENHANCED HIPPOCAMPAL NEUROGENESIS, DECREASED REPRESSIVE HISTONE METHYLATION AT THE BDNF IV PROMOTER ALONG WITH ENHANCED BDNF LEVELS, AND IMPROVED PERFORMANCE ON THE STRESS-ASSOCIATED MORRIS WATER MAZE. STRIKINGLY, OPPOSING CHANGES IN HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC REGULATION OF BDNF IV EXPRESSION, CONCOMITANT WITH IMPAIRMENTS ON HIPPOCAMPAL-DEPENDENT COGNITIVE TASKS, WERE OBSERVED IN MIDDLE-AGED ES ANIMALS. CHRONIC ANTIDEPRESSANT TREATMENT WITH AMITRIPTYLINE ATTENUATED THE MALADAPTIVE NEUROGENIC, EPIGENETIC, TRANSCRIPTIONAL, AND COGNITIVE EFFECTS IN MIDDLE-AGED ES ANIMALS. CONCLUSIONS: OUR STUDY PROVIDES NOVEL INSIGHTS INTO THE SHORT- AND LONG-TERM CONSEQUENCES OF ES, DEMONSTRATING BOTH BIPHASIC AND UNIQUE, AGE-DEPENDENT CHANGES AT THE MOLECULAR, EPIGENETIC, NEUROGENIC, AND BEHAVIORAL LEVELS. THESE RESULTS INDICATE THAT EARLY STRESS MAY TRANSIENTLY ENDOW ANIMALS WITH A POTENTIAL ADAPTIVE ADVANTAGE IN STRESSFUL ENVIRONMENTS BUT ACROSS A LIFE SPAN IS ASSOCIATED WITH LONG-TERM DELETERIOUS EFFECTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9  5752  30 SOCIAL ISOLATION AND SOCIAL SUPPORT AT ADULTHOOD AFFECT EPIGENETIC MECHANISMS, BRAIN-DERIVED NEUROTROPHIC FACTOR LEVELS AND BEHAVIOR OF CHRONICALLY STRESSED RATS. EPIGENETIC MODULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROVIDES ONE POSSIBLE EXPLANATION FOR THE DYSFUNCTIONS INDUCED BY STRESS, SUCH AS PSYCHIATRIC DISORDERS AND COGNITIVE DECLINE. INTERESTINGLY, SOCIAL SUPPORT CAN BE PROTECTIVE AGAINST SOME OF THESE EFFECTS, BUT THE MECHANISMS OF SOCIAL BUFFERING ARE POORLY UNDERSTOOD. CONVERSELY, EARLY ISOLATION EXACERBATES THE RESPONSES TO STRESSORS, ALTHOUGH ITS EFFECTS IN ADULTHOOD REMAIN UNCLEAR. THIS STUDY INVESTIGATED THE EFFECTS OF SOCIAL ISOLATION AND SOCIAL BUFFERING ON HIPPOCAMPAL EPIGENETIC MECHANISMS, BDNF LEVELS AND BEHAVIORAL RESPONSES OF CHRONICALLY STRESSED YOUNG ADULT RATS. MALE WISTAR RATS (3 MONTHS) WERE ASSIGNED TO ACCOMPANIED (PAIRED) OR ISOLATED HOUSING. AFTER ONE-MONTH HALF OF EACH GROUP WAS SUBMITTED TO A CHRONIC UNPREDICTABLE STRESS (CUS) PROTOCOL FOR 18 DAYS. AMONG ACCOMPANIED ANIMALS, ONLY ONE WAS EXPOSED TO STRESS. BEHAVIORAL ANALYSIS ENCOMPASSED THE OPEN FIELD, PLUS MAZE AND INHIBITORY AVOIDANCE TASKS. HIPPOCAMPAL H3K9 AND H4K12 ACETYLATION, HDAC5 EXPRESSION AND BDNF LEVELS WERE EVALUATED. ISOLATED HOUSING INCREASED HDAC5 EXPRESSION, DECREASED H3K9 AND H4K12 ACETYLATION, REDUCED BDNF LEVELS, AND IMPAIRED LONG-TERM MEMORY. STRESS AFFECTED WEIGHT GAIN, INDUCED ANXIETY-LIKE BEHAVIOR AND DECREASED ACK9H3 LEVELS. INTERACTIONS BETWEEN HOUSING CONDITIONS AND SOCIAL STRESS WERE SEEN ONLY FOR HDAC5 EXPRESSION, WHICH SHOWED A FURTHER INCREASE IN THE ISOLATED + CUS GROUP BUT REMAINED CONSTANT IN ACCOMPANIED ANIMALS. IN CONCLUSION, SOCIAL ISOLATION AT ADULTHOOD INDUCED EPIGENETIC ALTERATIONS AND EXACERBATED THE EFFECTS OF CHRONIC STRESS ON HDAC5. NOTWITHSTANDING, SOCIAL SUPPORT COUNTERACTED THE ADVERSE EFFECTS OF STRESS ON HDAC5 EXPRESSION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  5760  27 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
11  1003  25 CHRONIC TREATMENT WITH FLUOXETINE INDUCES SEX-DEPENDENT ANALGESIC EFFECTS AND MODULATES HDAC2 AND MGLU2 EXPRESSION IN FEMALE MICE. GENDER AND SEX DIFFERENCES IN PAIN RECOGNITION AND DRUG RESPONSES HAVE BEEN REPORTED IN CLINICAL TRIALS AND EXPERIMENTAL MODELS OF PAIN. AMONG ANTIDEPRESSANTS, CONTRADICTORY RESULTS HAVE BEEN OBSERVED IN PATIENTS TREATED WITH SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS). THIS STUDY EVALUATED SEX DIFFERENCES IN RESPONSE TO THE SSRI FLUOXETINE AFTER CHRONIC ADMINISTRATION IN THE MOUSE FORMALIN TEST. ADULT MALE AND FEMALE CD1 MICE WERE INTRAPERITONEALLY INJECTED WITH FLUOXETINE (10 MG/KG) FOR 21 DAYS AND SUBJECTED TO PAIN ASSESSMENT. FLUOXETINE TREATMENT REDUCED THE SECOND PHASE OF THE FORMALIN TEST ONLY IN FEMALE MICE WITHOUT PRODUCING BEHAVIORAL CHANGES IN MALES. WE ALSO OBSERVED THAT FLUOXETINE WAS ABLE TO SPECIFICALLY INCREASE THE EXPRESSION OF METABOTROPIC GLUTAMATE RECEPTOR TYPE-2 (MGLU2) IN FEMALES. ALSO A REDUCED EXPRESSION OF THE EPIGENETIC MODIFYING ENZYME, HISTONE DEACETYLASE 2 (HDAC2), IN DORSAL ROOT GANGLIA (DRG) AND DORSAL HORN (DH) TOGETHER WITH AN INCREASE HISTONE 3 ACETYLATION (H3) LEVEL WAS OBSERVED IN FEMALES BUT NOT IN MALES. WITH THIS STUDY WE PROVIDE EVIDENCE THAT FLUOXETINE INDUCES SEX SPECIFIC CHANGES IN HDAC2 AND MGLU2 EXPRESSION IN THE DH OF THE SPINAL CORD AND IN DRGS AND SUGGESTS A MOLECULAR EXPLANATION FOR THE ANALGESIC EFFECTS IN FEMALE MICE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12   881  27 CHRONIC CLOZAPINE TREATMENT RESTRAINS VIA HDAC2 THE PERFORMANCE OF MGLU2 RECEPTOR AGONISM IN A RODENT MODEL OF ANTIPSYCHOTIC ACTIVITY. PRECLINICAL FINDINGS IN RODENT MODELS POINTED TOWARD ACTIVATION OF METABOTROPIC GLUTAMATE 2/3 (MGLU2/3) RECEPTORS AS A NEW PHARMACOLOGICAL APPROACH TO TREAT PSYCHOSIS. HOWEVER, MORE RECENT STUDIES FAILED TO SHOW CLINICAL EFFICACY OF MGLU2/3 RECEPTOR AGONISM IN SCHIZOPHRENIA PATIENTS. WE PREVIOUSLY PROPOSED THAT LONG-TERM ANTIPSYCHOTIC MEDICATION RESTRICTED THE THERAPEUTIC EFFECTS OF THESE GLUTAMATERGIC AGENTS. HOWEVER, LITTLE IS KNOWN ABOUT THE MOLECULAR MECHANISM UNDERLYING THE POTENTIAL REPERCUSSION OF PREVIOUS ANTIPSYCHOTIC EXPOSURE ON THE THERAPEUTIC PERFORMANCE OF MGLU2/3 RECEPTOR AGONISTS. HERE WE SHOW THAT THIS MALADAPTIVE EFFECT OF ANTIPSYCHOTIC TREATMENT IS MEDIATED MOSTLY VIA HISTONE DEACETYLASE 2 (HDAC2). CHRONIC TREATMENT WITH THE ANTIPSYCHOTIC CLOZAPINE LED TO A DECREASE IN MOUSE FRONTAL CORTEX MGLU2 MRNA, AN EFFECT THAT REQUIRED EXPRESSION OF BOTH HDAC2 AND THE SEROTONIN 5-HT(2A) RECEPTOR. THIS TRANSCRIPTIONAL ALTERATION OCCURRED IN ASSOCIATION WITH HDAC2-DEPENDENT REPRESSIVE HISTONE MODIFICATIONS AT THE MGLU2 PROMOTER. WE FOUND THAT CHRONIC CLOZAPINE TREATMENT DECREASED VIA HDAC2 THE CAPABILITIES OF THE MGLU2/3 RECEPTOR AGONIST LY379268 TO ACTIVATE G-PROTEINS IN THE FRONTAL CORTEX OF MICE. CHRONIC CLOZAPINE TREATMENT BLUNTED THE ANTIPSYCHOTIC-RELATED BEHAVIORAL EFFECTS OF LY379268, AN EFFECT THAT WAS NOT OBSERVED IN HDAC2 KNOCKOUT MICE. MORE IMPORTANTLY, CO-ADMINISTRATION OF THE CLASS I AND II HDAC INHIBITOR SAHA (VORINOSTAT) PRESERVED THE ANTIPSYCHOTIC PROFILE OF LY379268 AND FRONTAL CORTEX MGLU2/3 RECEPTOR DENSITY IN WILD-TYPE MICE. THESE FINDINGS RAISE CONCERNS ON THE DESIGN OF PREVIOUS CLINICAL STUDIES WITH MGLU2/3 AGONISTS, PROVIDING THE RATIONALE FOR THE DEVELOPMENT OF HDAC2 INHIBITORS AS A NEW EPIGENETIC-BASED APPROACH TO IMPROVE THE CURRENTLY LIMITED RESPONSE TO TREATMENT WITH GLUTAMATERGIC ANTIPSYCHOTICS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
13  4766  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  5651  27 SEX DIFFERENCES IN THE EPIGENETIC REGULATION OF CHRONIC VISCERAL PAIN FOLLOWING UNPREDICTABLE EARLY LIFE STRESS. BACKGROUND: WE PREVIOUSLY REPORTED THAT EARLY LIFE STRESS (ELS) DYSREGULATED GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING HORMONE (CRH) EXPRESSION IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). EPIGENETIC MODIFICATIONS SERVE AS MEMORIES OF ADVERSE EVENTS THAT OCCURRED DURING EARLY LIFE. THEREFORE, WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS ALTER GR AND CRH EXPRESSION IN THE CEA AND UNDERLIE CHRONIC VISCERAL PAIN AFTER ELS. METHODS: NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR WESTERN BLOT OR CHIP-QPCR TO STUDY HISTONE MODIFICATIONS AT THE GR AND CRH PROMOTERS. FEMALE ADULT RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS FOR MICROINJECTIONS OF GARCINOL (HAT INHIBITOR) INTO THE CEA. AFTER 7 DAYS OF MICROINJECTIONS, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR CHIP-QPCR ASSAYS. RESULTS: UNPREDICTABLE ELS INCREASED VISCERAL SENSITIVITY IN ADULT FEMALE RATS, BUT NOT IN MALE COUNTERPARTS. ELS INCREASED HISTONE 3 LYSINE 9 (H3K9) ACETYLATION IN THE CEA AND H3K9 ACETYLATION LEVELS AT THE GR PROMOTER IN THE CEA OF ADULT FEMALE RATS. AFTER UNPREDICTABLE ELS, H3K9 ACETYLATION WAS INCREASED AND GR BINDING WAS DECREASED AT THE CRH PROMOTER. ADMINISTRATION OF GARCINOL IN THE CEA OF ADULT FEMALES, THAT UNDERWENT UNPREDICTABLE ELS, NORMALIZED H3K9 ACETYLATION AND RESTORED GR BINDING AT THE CRH PROMOTER. CONCLUSION: DYSREGULATED HISTONE ACETYLATION AND GR BINDING AT THE CRH PROMOTER IN THE CEA ARE AN IMPORTANT MECHANISM FOR "MEMORIZING" ELS EVENTS MEDIATING VISCERAL PAIN IN ADULTHOOD.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15   537  20 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
16  2827  28 FLUOXETINE INCREASES HIPPOCAMPAL NEUROGENESIS AND INDUCES EPIGENETIC FACTORS BUT DOES NOT IMPROVE FUNCTIONAL RECOVERY AFTER TRAUMATIC BRAIN INJURY. THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR FLUOXETINE INDUCES HIPPOCAMPAL NEUROGENESIS, STIMULATES MATURATION AND SYNAPTIC PLASTICITY OF ADULT HIPPOCAMPAL NEURONS, AND REDUCES MOTOR/SENSORY AND MEMORY IMPAIRMENTS IN SEVERAL CNS DISORDERS. IN THE SETTING OF TRAUMATIC BRAIN INJURY (TBI), ITS EFFECTS ON NEUROPLASTICITY AND FUNCTION HAVE YET TO BE THOROUGHLY INVESTIGATED. HERE WE EXAMINED THE EFFICACY OF FLUOXETINE AFTER A MODERATE TO SEVERE TBI, PRODUCED BY A CONTROLLED CORTICAL IMPACT. THREE DAYS AFTER TBI OR SHAM SURGERY, MICE WERE TREATED WITH FLUOXETINE (10 MG/KG/D) OR VEHICLE FOR 4 WEEKS. TO EVALUATE THE EFFECTS OF FLUOXETINE ON NEUROPLASTICITY, HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC MODIFICATION WERE STUDIED. STEREOLOGIC ANALYSIS OF THE DENTATE GYRUS REVEALED A SIGNIFICANT INCREASE IN DOUBLECORTIN-POSITIVE CELLS IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE RELATIVE TO CONTROLS, A FINDING CONSISTENT WITH ENHANCED HIPPOCAMPAL NEUROGENESIS. EPIGENETIC MODIFICATIONS, INCLUDING AN INCREASE IN HISTONE 3 ACETYLATION AND INDUCTION OF METHYL-CPG-BINDING PROTEIN, A TRANSCRIPTION FACTOR INVOLVED IN DNA METHYLATION, WERE LIKEWISE SEEN BY IMMUNOHISTOCHEMISTRY AND QUANTITATIVE WESTERN IMMUNOBLOTS, RESPECTIVELY, IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE. TO DETERMINE IF FLUOXETINE IMPROVES NEUROLOGICAL OUTCOMES AFTER TBI, GAIT FUNCTION AND SPATIAL LEARNING AND MEMORY WERE ASSESSED BY THE CATWALK-ASSISTED GAIT TEST AND BARNES MAZE TEST, RESPECTIVELY. NO DIFFERENCES IN THESE PARAMETERS WERE SEEN BETWEEN FLUOXETINE- AND VEHICLE-TREATED ANIMALS. THUS WHILE FLUOXETINE ENHANCED NEUROPLASTICITY IN THE HIPPOCAMPUS AFTER TBI, ITS CHRONIC ADMINISTRATION DID NOT RESTORE LOCOMOTOR FUNCTION OR AMELIORATE MEMORY DEFICITS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17  1818  30 EFFECTS OF CHRONIC METHAMPHETAMINE EXPOSURE ON REWARDING BEHAVIOR AND NEURODEGENERATION MARKERS IN ADULT MICE. RECREATIONAL AND MEDICAL USE OF STIMULANTS AMONG YOUNG ADULTS HAVE GAINED POPULARITY IN THE UNITED STATES OVER THE LAST DECADE AND THEIR USE MAY INCREASE VULNERABILITY TO BRAIN BIOCHEMICAL CHANGES AND ADDICTIVE BEHAVIORS. THE LONG-TERM EFFECTS OF CHRONIC STIMULANT EXPOSURE IN LATER ADULTHOOD HAVE NOT BEEN FULLY ELUCIDATED.OUR STUDY INVESTIGATED WHETHER CHRONIC EXPOSURE TO METHAMPHETAMINE (METH), AT A DOSE DESIGNED TO EMULATE HUMAN THERAPEUTIC DOSING FOR ADHD, WOULD PROMOTE BIOCHEMICAL ALTERATIONS AND AFFECT SENSITIVITY TO THE REWARDING EFFECTS OF SUBSEQUENT METH DOSING.GROUPS OF 3.5-MONTH-OLD MALE AND FEMALE C57BL/6J MICE WERE ADMINISTERED NON-CONTINGENT INTRAPERITONEAL INJECTIONS OF EITHER SALINE OR METH (1.4 MG/KG) TWICE A DAY FOR 1 MONTH (5 DAYS/WEEK). METH (0.5 MG/KG)-INDUCED CONDITIONED PLACE PREFERENCE (CPP) WAS TESTED IN MICE TO DETERMINE THE EFFECTS OF PREVIOUS METH EXPOSURE ON REWARD-RELATED BEHAVIOR. MICE WERE RANDOMLY ASSIGNED TO EXPERIMENT I (MALES AND FEMALES) OR EXPERIMENT II (FEMALES ONLY) IN WHICH CPP TESTING WAS RESPECTIVELY PERFORMED EITHER 0.5 OR 5 MONTHS AFTER THE END OF METH INJECTIONS, AT ~5 OR 10 MONTHS OLD RESPECTIVELY. THE MIDBRAIN AND STRIATUM, REGIONS INVOLVED IN REWARD CIRCUIT, WERE ASSESSED FOR MARKERS ASSOCIATED WITH NEUROTOXICITY, DOPAMINERGIC FUNCTION, NEUROINFLAMMATION AND EPIGENETIC CHANGES AFTER BEHAVIORAL TESTING.PREVIOUS EXPOSURE TO CHRONIC METH DID NOT HAVE SIGNIFICANT SHORT-TERM EFFECTS ON CPP RESPONSE BUT LED TO A DECREASED CPP RESPONSE IN 10-MONTH-OLD FEMALES. PREVIOUS EXPOSURE TO METH INDUCED SOME SHORT-TERM CHANGES TO BIOCHEMICAL MARKERS MEASURED IN A BRAIN REGION AND SEX-DEPENDENT MANNER, WHILE LONG-TERM CHANGES WERE ONLY OBSERVED WITH GFAP AND KDM5C.IN CONCLUSION, OUR DATA SUGGEST SEX- AND POST-EXPOSURE DURATION-DEPENDENT OUTCOMES AND WARRANT FURTHER EXPLORATION OF THE LONG-TERM NEUROBEHAVIORAL CONSEQUENCES OF PSYCHOSTIMULANT USE IN BOTH SEXES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  1238  21 CURCUMIN BLOCKS CHRONIC MORPHINE ANALGESIC TOLERANCE AND BRAIN-DERIVED NEUROTROPHIC FACTOR UPREGULATION. THIS STUDY WAS CARRIED OUT BASED ON THE ASSUMPTION THAT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MAY COUNTERBALANCE THE ACTION OF MORPHINE IN THE BRAIN. MORPHINE ANALGESIC TOLERANCE AFTER DAILY ADMINISTRATIONS FOR SIX DAYS WAS BLOCKED BY INTRACEREBROVENTRICULAR INJECTION OF ANTI-BDNF IGG ON DAY 5, BUT NOT BY ADMINISTRATIONS ON DAYS 1-4. CHRONIC MORPHINE TREATMENT SIGNIFICANTLY INCREASED THE EXPRESSION OF EXON I AND IV BDNF TRANSCRIPTS, INDICATING DIFFERENTIAL REGULATION OF BDNF GENE EXPRESSION. DAILY ADMINISTRATION OF THE CREB-BINDING PROTEIN INHIBITOR CURCUMIN ABOLISHED THE UPREGULATION OF BDNF TRANSCRIPTION AND MORPHINE ANALGESIC TOLERANCE. THESE RESULTS SUGGEST THAT CURCUMIN MIGHT BE A PROMISING ADJUVANT TO REDUCE MORPHINE ANALGESIC TOLERANCE, AND THAT EPIGENETIC CONTROL COULD BE A NEW STRATEGY USEFUL FOR THE CONTROL OF THIS PROBLEM.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
19   219  25 ACUTE IMMOBILIZATION STRESS FOLLOWING CONTEXTUAL FEAR CONDITIONING REDUCES FEAR MEMORY: TIMING IS ESSENTIAL. BACKGROUND: HISTONE ACETYLATION IS REGULATED IN RESPONSE TO STRESS AND PLAYS AN IMPORTANT ROLE IN LEARNING AND MEMORY. CHRONIC STRESS IS KNOWN TO DETERIORATE COGNITION, WHEREAS ACUTE STRESS FACILITATES MEMORY FORMATION. HOWEVER, WHETHER ACUTE STRESS FACILITATES MEMORY FORMATION WHEN IT IS APPLIED AFTER FEAR STIMULATION IS NOT YET KNOWN. THEREFORE, THIS STUDY AIMED TO INVESTIGATE THE EFFECT OF ACUTE STRESS APPLIED AFTER FEAR TRAINING ON MEMORY FORMATION, MRNA EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), EPIGENETIC REGULATION OF BDNF EXPRESSION, AND CORTICOSTERONE LEVEL IN MICE IN VIVO. METHODS: MICE WERE SUBJECTED TO ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 OR 90 MIN AFTER CONTEXTUAL FEAR CONDITIONING TRAINING, AND ACETYLATION OF HISTONE 3 AT LYSINE 14 (H3K14) AND LEVEL OF CORTICOSTERONE WERE MEASURED USING WESTERN BLOT ANALYSIS AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. A FREEZING BEHAVIOR TEST WAS PERFORMED 24 H AFTER TRAINING, AND MRNA EXPRESSION OF BDNF WAS MEASURED USING REAL-TIME POLYMERASE CHAIN REACTIONS. DIFFERENT GROUPS OF MICE WERE USED FOR EACH TEST. RESULTS: FREEZING BEHAVIOR SIGNIFICANTLY DECREASED WITH THE DOWN-REGULATION OF BDNF MRNA EXPRESSION CAUSED BY ACUTE IMMOBILIZATION STRESS AT 60 MIN AFTER FEAR CONDITIONING TRAINING OWING TO THE REDUCTION OF H3K14 ACETYLATION. HOWEVER, BDNF MRNA EXPRESSION AND H3K14 ACETYLATION WERE NOT REDUCED IN ANIMALS SUBJECTED TO IMMOBILIZATION STRESS AT 90 MIN AFTER THE TRAINING. FURTHER, THE CORTICOSTERONE LEVEL WAS SIGNIFICANTLY HIGH IN MICE SUBJECTED TO IMMOBILIZATION STRESS AT 60 MIN AFTER THE TRAINING. CONCLUSION: ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 MIN AFTER FEAR CONDITIONING TRAINING IMPAIRED MEMORY FORMATION AND REDUCED BDNF MRNA EXPRESSION AND H3K14 ACETYLATION IN THE HIPPOCAMPUS OF MICE OWING TO THE HIGH LEVEL OF CORTICOSTERONE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  3331  34 HISTONE DEACETYLASE INHIBITOR SUBERANILOHYDROXAMIC ACID TREATMENT REVERSES HYPOSENSITIVITY TO GAMMA-AMINOBUTYRIC ACID IN THE VENTRAL TEGMENTAL AREA DURING ETHANOL WITHDRAWAL. BACKGROUND: THE VENTRAL TEGMENTAL AREA (VTA) IS IMPORTANT FOR ALCOHOL-RELATED REWARD AND REINFORCEMENT. MOUSE VTA NEURONS ARE HYPOSENSITIVE TO GAMMA-AMINOBUTYRIC ACID (GABA) DURING ETHANOL (ETOH) WITHDRAWAL, AND GABA RESPONSIVENESS IS NORMALIZED BY IN VITRO TREATMENT WITH HISTONE DEACETYLASE INHIBITORS (HDACI). THE PRESENT STUDY EXAMINED THE EFFECT OF A SYSTEMICALLY ADMINISTERED HDACI, SUBERANILOHYDROXAMIC ACID (SAHA) ON GABA SENSITIVITY, AND RELATED MOLECULAR CHANGES IN VTA NEURONS DURING WITHDRAWAL AFTER CHRONIC ETOH INTAKE IN RATS. METHODS: SPRAGUE DAWLEY MALE ADULT RATS WERE FED WITH LIEBER-DECARLI DIET (9% ETOH OR CONTROL DIET) FOR 16 DAYS. EXPERIMENTAL GROUPS INCLUDED CONTROL DIET-FED AND ETOH DIET-FED (0- OR 24-HOUR WITHDRAWAL) RATS TREATED WITH EITHER SAHA OR VEHICLE INJECTION. SINGLE-UNIT RECORDINGS WERE USED TO MEASURE THE RESPONSE OF VTA NEURONS TO GABA. IMMUNOHISTOCHEMISTRY WAS PERFORMED TO EXAMINE LEVELS OF HDAC2, ACETYLATED HISTONE H3 LYSINE 9 (ACH3K9), AND GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS IN THE VTA; QUANTITATIVE POLYMERASE CHAIN REACTION WAS PERFORMED TO EXAMINE THE MRNA LEVELS OF HDAC2 AND GABA(A) RECEPTOR SUBUNITS. RESULTS: VTA NEURONS FROM THE WITHDRAWAL GROUP EXHIBITED GABA HYPOSENSITIVITY. IN VIVO SAHA TREATMENT 2 HOURS BEFORE SACRIFICE NORMALIZED THE SENSITIVITY OF VTA NEURONS TO GABA. ETOH WITHDRAWAL WAS ASSOCIATED WITH INCREASED HDAC2 AND DECREASED ACH3K9 PROTEIN LEVELS; SAHA TREATMENT NORMALIZED ACH3K9 LEVELS. INTERESTINGLY, NO SIGNIFICANT CHANGE WAS OBSERVED IN THE MRNA LEVELS OF HDAC2. THE MRNA LEVELS, BUT NOT PROTEIN LEVELS, OF GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS WERE INCREASED DURING WITHDRAWAL. CONCLUSIONS: WITHDRAWAL FROM CHRONIC ETOH EXPOSURE RESULTS IN A DECREASE IN GABA-MEDIATED INHIBITION, AND THIS GABA HYPOSENSITIVITY IS NORMALIZED BY IN VIVO SAHA TREATMENT. DISRUPTION OF SIGNALING IN THE VTA PRODUCED BY ALTERATION OF GABA NEUROTRANSMISSION COULD BE 1 NEUROADAPTIVE PHYSIOLOGICAL PROCESS LEADING TO CRAVING AND RELAPSE. THESE RESULTS SUGGEST THAT HDACI PHARMACOTHERAPY WITH AGENTS LIKE SAHA MIGHT BE AN EFFECTIVE TREATMENT FOR ALCOHOLISM.	2018