1  6098 105 THE EFFECTS OF VALPROIC ACID ON SKIN HEALING: EXPERIMENTAL STUDY IN RATS. PURPOSE: TO RECOGNIZE THE EFFECTS OF VALPROIC ACID (VPA), AN EPIGENETIC DRUG, ON THE SKIN HEALING PROCESS. METHODS: SIXTY MALE WISTAR RATS WERE DIVIDED INTO TWO GROUPS: THE EXPERIMENT TREATED WITH VPA (100 MG/KG/DAY); AND THE CONTROL, WITH 0.9% SODIUM CHLORIDE BY GAVAGE. SKIN HEALING WAS STUDIED IN THREE MOMENTS (THE THIRD, THE SEVENTH, AND THE 14TH DAY), EVALUATING THE PARAMETERS: INFLAMMATORY REACTION AND ITS INTENSITY (ANTI-LCA), ANGIOGENESIS (ANTI-CD34), COLLAGEN I AND III (ANTI-COLLAGEN I, ANTI-COLLAGEN III AND PICROSIRIUS-RED F3BA) AND MYOFIBROBLASTS (ANTI-ALPHA-AMS). RESULTS: THE INFLAMMATORY REACTION WAS ACUTE OR SUB-ACUTE IN BOTH GROUPS ON THE THIRD DAY. ON THE SEVENTH AND THE 14TH DAY, CHRONIC PREDOMINATED IN THE CONTROL (P=0.006), AND SUB-ACUTE IN THE EXPERIMENT (P=0.020). THERE WAS A GREATER NUMBER OF LEUKOCYTES IN THE GROUP TREATED ONLY ON THE THIRD DAY (P=0.036). THE NUMBER OF VESSELS WAS LOWER IN THE TREATED GROUP AT THE THREE TIMES (P3=0.002, P7<0.001, AND P14=0.027). MYOFIBROBLASTS WERE RARE IN THE THIRD DAY AND MODERATE QUANTITY IN THE REMAINING PERIODS. COLLAGEN I DENSITY WAS HIGHER IN THE CONTROL AT THE THREE TIMES (P<0.001) AND COLLAGEN III IN THE TREATED GROUP (P<0.001). CONCLUSIONS: VPA LED TO A MORE INTENSE INFLAMMATORY REACTION, DECREASED ANGIOGENESIS AND COLLAGEN DEPOSITION, ESPECIALLY TYPE I COLLAGEN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  6456  17 THYMOSIN BETA4 PREVENTS OXIDATIVE STRESS, INFLAMMATION, AND FIBROSIS IN ETHANOL- AND LPS-INDUCED LIVER INJURY IN MICE. THYMOSIN BETA 4 (TBETA4), AN ACTIN-SEQUESTERING PROTEIN, IS INVOLVED IN TISSUE DEVELOPMENT AND REGENERATION. IT PREVENTS INFLAMMATION AND FIBROSIS IN SEVERAL TISSUES. WE INVESTIGATED THE ROLE OF TBETA4 IN CHRONIC ETHANOL- AND ACUTE LIPOPOLYSACCHARIDE- (LPS-) INDUCED MOUSE LIVER INJURY. C57BL/6 MICE WERE FED 5% ETHANOL IN LIQUID DIET FOR 4 WEEKS PLUS BINGE ETHANOL (5 G/KG, GAVAGE) WITH OR WITHOUT LPS (2 MG/KG, INTRAPERITONEAL) FOR 6 HOURS. TBETA4 (1 MG/KG, INTRAPERITONEAL) WAS ADMINISTERED FOR 1 WEEK. WE DEMONSTRATED THAT TBETA4 PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN LIVER INJURY MARKERS AS WELL AS CHANGES IN LIVER PATHOLOGY. IT ALSO PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN OXIDATIVE STRESS BY DECREASING ROS AND LIPID PEROXIDATION AND INCREASING THE ANTIOXIDANTS, REDUCED GLUTATHIONE AND MANGANESE-DEPENDENT SUPEROXIDE DISMUTASE. IT ALSO PREVENTED THE ACTIVATION OF NUCLEAR FACTOR KAPPA B BY BLOCKING THE PHOSPHORYLATION OF THE INHIBITORY PROTEIN, IKAPPAB, THEREBY PREVENTED PROINFLAMMATORY CYTOKINE PRODUCTION. MOREOVER, TBETA4 PREVENTED FIBROGENESIS BY SUPPRESSING THE EPIGENETIC REPRESSOR, METHYL-CPG-BINDING PROTEIN 2, THAT COORDINATELY REVERSED THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND DOWNREGULATED FIBROGENIC GENES, PLATELET-DERIVED GROWTH FACTOR-BETA RECEPTOR, ALPHA-SMOOTH MUSCLE ACTIN, COLLAGEN 1, AND FIBRONECTIN, RESULTING IN REDUCED FIBROSIS. OUR DATA SUGGEST THAT TBETA4 HAS ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTIFIBROTIC POTENTIAL DURING ALCOHOLIC LIVER INJURY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3   893  27 CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL IMPAIR SYNAPTIC GABA(A) RECEPTOR-MEDIATED NEUROTRANSMISSION IN DEEP-LAYER PREFRONTAL CORTEX. BACKGROUND: THE PREFRONTAL CORTEX (PFC) ACTS AS AN INTEGRATIVE HUB FOR THE PROCESSING OF CORTICAL AND SUBCORTICAL INPUT INTO MEANINGFUL EFFERENT SIGNALING, PERMITTING COMPLEX ASSOCIATIVE BEHAVIORS. PFC DYSFUNCTION IS CONSISTENTLY OBSERVED WITH ETHANOL (ETOH) DEPENDENCE AND IS A CORE COMPONENT OF THE PATHOLOGY OF ALCOHOL USE DISORDERS IN CURRENT MODELS OF ADDICTION. WHILE INTRACORTICAL GAMMA-AMINOBUTRYRIC ACID (GABA)ERGIC NEUROTRANSMISSION IS UNDERSTOOD TO BE ESSENTIAL FOR MAINTAINING COORDINATED NETWORK ACTIVITY WITHIN THE CORTEX, RELATIVELY LITTLE IS KNOWN REGARDING FUNCTIONAL GABAERGIC ADAPTATIONS IN PFC DURING ETOH DEPENDENCE. METHODS: IN THE PRESENT STUDY, MALE AND FEMALE (> POSTNATAL DAY 60) SPRAGUE-DAWLEY RATS WERE ADMINISTERED ETOH (5.0 G/KG; INTRAGASTRIC GAVAGE) FOR 14 TO 15 CONSECUTIVE DAYS. TWENTY-FOUR HOURS AFTER THE FINAL ADMINISTRATION, ANIMALS WERE SACRIFICED AND BRAINS EXTRACTED FOR ELECTROPHYSIOLOGICAL RECORDINGS OF ISOLATED GABA(A) RECEPTOR-MEDIATED CURRENTS OR ANALYSIS OF GABA(A) RECEPTOR SUBUNIT PROTEIN EXPRESSION IN DEEP-LAYER PFC NEURONS. RESULTS: CHRONIC ETOH EXPOSURE SIGNIFICANTLY ATTENUATED ACTIVITY-DEPENDENT SPONTANEOUS GABA(A) RECEPTOR-MEDIATED INHIBITORY POSTSYNAPTIC CURRENT (IPSC) FREQUENCY WITH NO EFFECT ON AMPLITUDE. FURTHERMORE, ANALYSIS OF IPSC DECAY KINETICS REVEALED A SIGNIFICANT ENHANCEMENT OF IPSC DECAY TIME THAT WAS ASSOCIATED WITH DECREMENTS IN EXPRESSION OF THE ALPHA1 GABA(A) RECEPTOR SUBUNIT, INDICATIVE OF FURTHER IMPAIRED PHASIC INHIBITION. THESE PHENOMENA OCCURRED IRRESPECTIVE OF NEURON PROJECTION DESTINATION AND SEX. BASED ON PREVIOUS OBSERVATIONS BY OUR LABORATORY OF AN EPIGENETIC MECHANISM FOR ETOH-INDUCED CHANGES IN CORTICAL GABA(A) RECEPTOR SUBUNIT EXPRESSION, THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A WAS ADMINISTERED TO WATER- AND ETOH-EXPOSED ANIMALS, AND PREVENTED ETOH-INDUCED CHANGES IN SPONTANEOUS IPSC FREQUENCY, IPSC DECAY KINETICS, AND GABA(A) RECEPTOR SUBUNIT EXPRESSION. CONCLUSIONS: TAKEN TOGETHER, THESE RESULTS DEMONSTRATE THAT CHRONIC ETOH EXPOSURE IMPAIRS SYNAPTIC INHIBITORY NEUROTRANSMISSION IN DEEP-LAYER PYRAMIDAL NEURONS OF THE MEDIAL PFC IN BOTH MALE AND FEMALE RATS. THESE MALADAPTATIONS OCCUR IN NEURONS PROJECTING TO NUMEROUS REGIONS IMPLICATED IN THE SEQUELAE OF ETOH DEPENDENCE, OFFERING A MECHANISTIC LINK BETWEEN THE MANIFESTATION OF PFC DYSFUNCTION AND NEGATIVE AFFECTIVE STATES OBSERVED WITH EXTENDED CONSUMPTION.	2019	

4  1997  25 EPIGENETIC AND INFLAMMATORY EVENTS IN EXPERIMENTAL PERIODONTITIS FOLLOWING SYSTEMIC MICROBIAL CHALLENGE. AIM: THE PURPOSE OF THIS STUDY WAS TO DETERMINE INFLAMMATORY AND EPIGENETIC FEATURES FOLLOWING INDUCTION OF ORAL AND GUT DYSBIOSIS IN EXPERIMENTAL PERIODONTITIS IN ORDER TO EXAMINE THE INTERPLAY BETWEEN ORAL AND SYSTEMIC INFECTION. MATERIALS AND METHODS: PERIODONTITIS WAS INDUCED IN 6- TO 8-WEEK-OLD C57BL/6 MICE BY (A) LIGATURE PLACEMENT (LIG GROUP) (ORAL CHALLENGE); (B) P. GINGIVALIS GAVAGE (PG GROUP) (SYSTEMIC CHALLENGE); AND (C) THE COMBINATION OF THE TWO MODELS ORAL AND SYSTEMIC CHALLENGE (PG + LIG). THE DURATION OF THE EXPERIMENT WAS 60 DAYS, AND THE ANIMALS WERE THEN SACRIFICED FOR ANALYSES. ALVEOLAR BONE LOSS WAS ASSESSED, AND A MULTIPLEX IMMUNOASSAY WAS PERFORMED. MAXILLAE AND GUT TISSUES WERE IMMUNOSTAINED FOR DNMT3B (DE NOVO METHYLATION MARKER), B AND T LYMPHOCYTE ATTENUATOR (BTLA) AND IL-18R1 (INFLAMMATION MARKERS). RESULTS: PG AND PG + LIG GROUPS EXHIBITED HIGHER BONE LOSS WHEN COMPARED TO SHAM. BAFF, VEGF, RANKL, RANTES AND IP-10 WERE SIGNIFICANTLY HIGHER WITH PG GAVAGE. LIKEWISE, DNMT3B WAS OVEREXPRESSED IN BOTH GUT AND MAXILLA AFTER THE PG ADMINISTRATION. THE SAME PATTERN WAS OBSERVED FOR BTLA AND IL-18R1 IN GUT TISSUES. CONCLUSIONS: THE SYSTEMIC MICROBIAL CHALLENGE EITHER ALONE OR IN COMBINATION WITH LOCAL CHALLENGE LEADS TO DISTINCT PATTERNS OF INFLAMMATORY AND EPIGENETIC FEATURES WHEN COMPARED TO SIMPLY LOCALLY INDUCED EXPERIMENTAL PERIODONTITIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5  4819  22 OCCURRENCE OF TOXICITY AND CELL PROLIFERATION AFTER A SINGLE GAVAGE ADMINISTRATION OF CHLOROFORM TO MALE F344 RATS. CHLOROFORM, AN INDUSTRIAL SOLVENT AND ONE OF THE MOST COMMON ENVIRONMENTAL CONTAMINANTS WHICH PRODUCES CARCINOGENIC EFFECTS IN THE LIVER AND KIDNEY OF RODENTS, IS NOT GENOTOXIC IN MOST TRADITIONAL BACTERIAL AND MAMMALIAN TEST SYSTEMS. ITS CARCINOGENIC POTENTIAL APPEARS ATTRIBUTABLE TO THE SUSTAINED CELL TURNOVER (REGENERATIVE HYPERPLASIA) WHICH RESULTS FROM CHRONIC CHLOROFORM TOXICITY. IN THIS PRESENT STUDY, CELL PROLIFERATION (REPLICATIVE DNA SYNTHESIS, RDS) AND HISTOPATHOLOGICAL CHANGES IN HEPATOCYTES AND RENAL TUBULAR EPITHELIAL CELLS WERE ASSESSED IN MALE F344 RATS FOLLOWING A SINGLE GAVAGE CHLOROFORM EXPOSURE (50, 150 OR 500 MG/KG). IN ADDITION, BIOCHEMICAL PARAMETERS (BUN, GOT, LDH AND NAG) WERE EXAMINED USING PLASMA AND URINE SAMPLES. CELL PROLIFERATION AND HISTOPATHOLOGICAL CHANGES (E.G. HYPERTROPHY, NECROSIS, VACUOLATION) WERE ONLY SEEN AT THE DOSE OF 500 MG/KG IN THE LIVER AND KIDNEY. AT THE SAME DOSE, ALL BIOCHEMICAL MARKERS WERE INCREASED AT THE 24 TO 48 HR TIME POINTS. THESE RESULTS OBTAINED ARE THUS IN LINE WITH EARLIER FINDINGS POINTING TO EPIGENETIC CARCINOGENICITY.	1998	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6  2120  24 EPIGENETIC HISTONE MODIFICATIONS IN A CLINICALLY RELEVANT RAT MODEL OF CHRONIC ETHANOL-BINGE-MEDIATED LIVER INJURY. PURPOSE: ETHANOL BINGE AUGMENTS LIVER INJURY AFTER CHRONIC ETHANOL CONSUMPTION IN HUMANS, BUT THE MECHANISM BEHIND THE ENHANCED LIVER INJURY BY ETHANOL BINGE IS NOT KNOWN. IN THIS STUDY WE USED A CLINICALLY RELEVANT RAT MODEL IN WHICH LIVER INJURY IS AMPLIFIED BY BINGE AFTER CHRONIC ETHANOL TREATMENT AND INVESTIGATED THE IMPORTANCE OF HISTONE MODIFICATIONS. METHODS: EIGHT-WEEK-OLD SPRAGUE-DAWLEY RATS WERE FED ETHANOL IN A LIQUID DIET FOR 4 WEEKS. CONTROL RATS WERE FED AN ISOCALORIC LIQUID DIET. THIS WAS FOLLOWED BY THREE BINGE ADMINISTRATIONS OF ETHANOL (INTRAGASTRIC 5 G/KG BODY WEIGHT, 12 H APART). IN THE CONTROL, ETHANOL WAS REPLACED BY WATER. FOUR HOURS AFTER THE LAST BINGE ADMINISTRATION, LIVER SAMPLES WERE ANALYZED FOR HISTONE MODIFICATIONS AND PARAMETERS OF LIVER INJURY. RESULTS: CHRONIC ETHANOL ADMINISTRATION ALONE CAUSED AN INCREASE IN HISTONE H3 SER10 AND SER28 (H3S10 OR S28) PHOSPHORYLATION, AND BINGE ETHANOL REDUCED THEIR LEVELS. LEVELS OF DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10) INCREASED AFTER ACUTE BINGE ETHANOL AND REMAINED SAME AFTER CHRONIC ETHANOL BINGE. IN CONTRAST, HISTONE H3 LYSINE-9 ACETYLATION (H3ACK9) WAS NOT INCREASED AFTER CHRONIC ETHANOL BUT INCREASED SIGNIFICANTLY AFTER ACUTE BINGE AND CHRONIC ETHANOL BINGE. INCREASE IN HISTONE ACETYLATION WAS ACCOMPANIED BY INCREASED PHOSPHO-ERK1/2 IN THE NUCLEAR EXTRACTS. INCREASED ACETYLATION AFTER CHRONIC ETHANOL BINGE WAS ALSO ACCOMPANIED BY INCREASED PROTEIN LEVELS OF GCN5 HISTONE ACETYL TRANSFERASE AND A MODEST INCREASE IN HDAC3 IN THE NUCLEUS. HISTONE LYSINE-9 DIMETHYLATION WAS SIGNIFICANTLY INCREASED AFTER CHRONIC ETHANOL BINGE. CHRONIC ETHANOL BINGE ALSO RESULTED IN A DECREASE IN THE SAM:SAH RATIO WITH A RELATIVE DECREASE OF SAM LEVELS AND A CORRESPONDING INCREASE IN SAH LEVELS. CONCLUSIONS: ETHANOL BINGE AFTER CHRONIC ETHANOL ALTERED THE PROFILE OF SITE-SPECIFIC HISTONE MODIFICATIONS AND MAY UNDERLIE THE MECHANISM OF AUGMENTED LIVER INJURY BY CHRONIC-ETHANOL-BINGE-TREATED RATS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7  3331  29 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	
                                                                                                                                                                                                                                                                     
8  6918  27 [WNT3A SIGNALING PATHWAY PLAYS A ROLE IN NEUROPATHIC PAIN THROUGH EPIGENETIC MODIFICATION OF JMJD6]. TO EXPLORE WHETHER WNT3A EXERTS A ROLE IN NEUROPATHIC PAIN THROUGH JUMONJI C DOMAIN 6 (JMJD6)-ASSOCIATED EPIGENETIC MODIFICATION. METHODS: SD RATS WERE DIVIDED INTO 4 GROUPS: A SHAM GROUP, A CHRONIC CONSTRICTION INJURY (CCI) GROUP, A CCI+NEGATIVE LENTIVIRAL EXPRESSION VECTOR (LV-NC) GROUP AND A CCI+LENTIVIRAL OVEREXPRESSION VECTOR (LV-JMJD6) GROUP. THE SCIATIC NERVE CCI MODEL OF SD RAT AND JMJD6 LENTIVIRAL EXPRESSION VECTOR WERE CONSTRUCTED. ON THE THIRD DAY AFTER CCI, THE INTRATHECAL CATHETER WAS PREPARED, AND 20 MUL OF NORMAL SALINE AND LENTIVIRUS-CONTAINING REAGENT (VIRUS TITER 1X108 TU/ML) WERE ADMINISTERED. THE RATS' PAW WITHDRAWAL MECHANICAL THRESHOLD (PWMT) AND PAW WITHDRAWAL THERMAL LATENCY (PWTL) WERE MONITORED, AND WESTERN BLOTTING WAS USED TO DETECT THE EXPRESSION OF WNT3A AND NR2B PROTEIN IN THE SPINAL CORD. CO-IMMUNOPRECIPITATION WAS APPLIED TO DETECT THE INTERACTION BETWEEN JMJD6 AND WNT3A. RESULTS: COMPARED WITH THE SHAM GROUP, THE PWMT OF THE RATS IN EACH GROUP AFTER CCI WAS SIGNIFICANTLY DECREASED AND THE PWTL WAS SIGNIFICANTLY SHORTENED (P<0.05). COMPARED WITH THE CCI GROUP AND THE CCI+LV-NC GROUP, PWMT IN THE CCI+LV-JMJD6 GROUP WAS INCREASED SIGNIFICANTLY ON THE 10TH DAY AND THE 14TH DAY AFTER CCI, AND THE PWTL WAS SIGNIFICANTLY PROLONGED ON THE 14TH DAY AFTER CCI (P<0.05). ON THE 14TH DAY AFTER CCI, THE EXPRESSION LEVELS OF WNT3A AND NR2B IN THE CCI GROUP AND THE CCI+LV-NC GROUP WERE SIGNIFICANTLY HIGHER THAN THOSE IN THE SHAM GROUP. AFTER INTRATHECAL INJECTION OF LENTIVIRAL VECTOR, WNT3A AND NR2B PROTEIN EXPRESSION LEVELS IN THE CCI+LV-JMJD6 GROUP WERE LOWER COMPARED WITH THE CCI+LV-NC GROUP (P<0.05). THE RESULTS OF CO-IMMUNOPRECIPITATION SHOWED NO DIRECT INTERACTION BETWEEN WNT3A AND JMJD6. CONCLUSION: WNT3A IS INVOLVED IN MEDIATING NEUROPATHIC PAIN, AND ITS EFFECT MAY BE RELATED TO THE EPIGENETIC MODIFICATION OF JMJD6, WHICH IS LIKELY REGULATED THROUGH INDIRECT INTERACTION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  3785  25 INTERGENERATIONAL EFFECTS OF PRE-PREGNANCY CHRONIC LIPOPOLYSACCHARIDE FROM PORPHYROMONAS GINGIVALIS ON THE LEARNING, MEMORY AND SEIZURE SUSCEPTIBILITY OF OFFSPRING. OBJECTIVE: THE AIM OF THIS STUDY WAS TO INVESTIGATE THE EFFECTS OF PRE-PREGNANCY CHRONIC EXPOSURE TO PORPHYROMONAS GINGIVALIS LPS (PG LPS) ON THE LEARNING, MEMORY, AND SEIZURE SUSCEPTIBILITY OF THE OFFSPRING. DESIGN: TO ACHIEVE PERIODONTITIS, PG LPS (5 MUG/KG) WAS INJECTED INTO THE GINGIVAL OF FIVE FEMALE RATS EVERY 48 H FOR THREE WEEKS. FIVE CONTROL FEMALE RATS RECEIVED SALINE (0.9 %) AND FIVE FEMALE WERE KEPT INTACT. THE CONCENTRATIONS OF TNF-ALPHA AND IL-6 WERE MEASURED IN THE BLOOD SAMPLES. ONE WEEK AFTER THE FINAL INJECTION, FEMALES WERE MATED WITH INTACT MALES. FOLLOWING BIRTH AND WEANING, TWO MALE AND TWO FEMALE OFFSPRING WERE RANDOMLY SELECTED FROM EACH MOTHER, AND NEW GROUPS OF MALE AND FEMALE OFFSPRING WERE DEFINED FOR BEHAVIORAL ASSESSMENTS. MORRIS WATER MAZE WAS USED TO EVALUATE SPATIAL MEMORY, SHUTTLE BOX WAS USED TO INVESTIGATE AVOIDANCE MEMORY AND A PENTYLENETETRAZOLE-INDUCED SEIZURE WAS USED TO EVALUATE SEIZURE SUSCEPTIBILITY IN THE OFFSPRING. RESULTS: SPATIAL LEARNING AND AVOIDANCE MEMORY SIGNIFICANTLY DECREASED IN BOTH MALE AND FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE RATS, COMPARED TO THE CONTROL OFFSPRING. LATENCY TO REACH SEIZURE STAGES 1 AND 2 SIGNIFICANTLY INCREASED IN THE MALE OFFSPRING, BUT NOT THE FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE, COMPARED TO THE CONTROL OFFSPRING. HOWEVER, NO SIGNIFICANT DIFFERENCE WAS FOUND IN LATENCY TO REACH STAGES 3-5. CONCLUSION: PRE-PREGNANCY EXPOSURE TO PG LPS COULD AFFECT SOME BEHAVIORAL FUNCTIONS IN BOTH MALE AND FEMALE OFFSPRING INTERGENERATIONALLY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10  3164  26 GREEN TEA PREVENTS NAFLD BY MODULATION OF MIR-34A AND MIR-194 EXPRESSION IN A HIGH-FAT DIET MOUSE MODEL. BACKGROUND/AIMS: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS CONSIDERED THE HEPATIC MANIFESTATION OF METABOLIC SYNDROME. IT IS CURRENTLY THE MOST COMMON CHRONIC LIVER DISEASE WITH COMPLEX PATHOGENESIS AND CHALLENGING TREATMENT. HERE, WE INVESTIGATED THE HEPATOPROTECTIVE ROLE OF GREEN TEA (GT) AND DETERMINED THE INVOLVEMENT OF MIRNAS AND ITS MECHANISM OF ACTION. METHODS: MALE C57BL/6 MICE WERE FED WITH A HIGH-FAT DIET FOR 4 WEEKS. AFTER THIS PERIOD, THE ANIMALS RECEIVED GAVAGE WITH GT (500 MG/KG BODY WEIGHT) OVER 12 WEEKS (5 DAYS/WEEK). HEPG2 CELL LINES WERE TRANSFECTED WITH MIR-34A OR MIR-194 MIMETICS AND INHIBITORS TO VALIDATE THE IN VIVO RESULTS OR WERE TREATED WITH TNF-ALPHA TO EVALUATE MIRNA REGULATION. RESULTS: GT SUPPLEMENTATION PROTECTS AGAINST NAFLD DEVELOPMENT BY ALTERING LIPID METABOLISM, INCREASING GENE EXPRESSION INVOLVED IN TRIGLYCERIDES AND FATTY ACID CATABOLISM, AND DECREASING UPTAKE AND LIPID ACCUMULATION. THIS PHENOTYPE WAS ACCOMPANIED BY MIR-34A DOWNREGULATION AND AN INCREASE IN THEIR MRNA TARGETS SIRT1, PPARALPHA, AND INSIG2. GT UPREGULATED HEPATIC MIR-194 BY INHIBITING TNF-ALPHA ACTION LEADING TO A DECREASE IN MIR-194 TARGET GENES HMGCS/APOA5. CONCLUSION: OUR STUDY IDENTIFIED FOR THE FIRST TIME THAT THE BENEFICIAL EFFECTS OF GT IN THE LIVER CAN BE DUE TO THE MODULATION OF MIRNAS, OPENING NEW PERSPECTIVES FOR THE TREATMENT OF NAFLD FOCUSING ON EPIGENETIC REGULATION OF MIR-34A AND MIR-194 AS GREEN TEA TARGETS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  1980  20 EPIGENETIC ALTERATIONS IN CYTOCHROME P450 OXIDOREDUCTASE (POR) IN SPERM OF RATS EXPOSED TO TETRAHYDROCANNABINOL (THC). AS MARIJUANA LEGALIZATION IS INCREASING, RESEARCH REGARDING POSSIBLE LONG-TERM RISKS FOR USERS AND THEIR OFFSPRING IS NEEDED. LITTLE DATA EXISTS ON EFFECTS OF PATERNAL TETRAHYDROCANNABINOL (THC) EXPOSURE PRIOR TO REPRODUCTION. THIS STUDY DETERMINED IF CHRONIC THC EXPOSURE ALTERS SPERM DNA METHYLATION (DNAM) AND IF SUCH EFFECTS ARE INTERGENERATIONALLY TRANSMITTED. ADULT MALE RATS UNDERWENT ORAL GAVAGE WITH THC OR VEHICLE CONTROL. DIFFERENTIALLY METHYLATED (DM) LOCI IN MOTILE SPERM WERE IDENTIFIED USING REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS). ANOTHER COHORT WAS INJECTED WITH VEHICLE OR THC, AND SPERM DNAM WAS ANALYZED. FINALLY, THC-EXPOSED AND CONTROL ADULT MALE RATS WERE MATED WITH THC-NAIVE FEMALES. DNAM LEVELS OF TARGET GENES IN BRAIN TISSUES OF THE OFFSPRING WERE DETERMINED BY PYROSEQUENCING. RRBS IDENTIFIED 2,940 DM CPGS MAPPING TO 627 GENES. SIGNIFICANT HYPERMETHYLATION WAS CONFIRMED (P < 0.05) FOLLOWING ORAL THC ADMINISTRATION FOR CYTOCHROME P450 OXIDOREDUCTASE (POR), INVOLVED IN TOXIN PROCESSING AND DISORDERS OF SEXUAL DEVELOPMENT. POR HYPERMETHYLATION WAS NOT OBSERVED AFTER THC INJECTION OR IN THE SUBSEQUENT GENERATION. THESE RESULTS SUPPORT THAT THC ALTERS DNAM IN SPERM AND THAT ROUTE OF EXPOSURE CAN HAVE DIFFERENTIAL EFFECTS. ALTHOUGH WE DID NOT OBSERVE EVIDENCE OF INTERGENERATIONAL TRANSMISSION OF THE DNAM CHANGE, LARGER STUDIES ARE REQUIRED TO DEFINITIVELY EXCLUDE THIS POSSIBILITY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12  3346  18 HISTONE DEACETYLASES MEDIATE GABA(A) RECEPTOR EXPRESSION, PHYSIOLOGY, AND BEHAVIORAL MALADAPTATIONS IN RAT MODELS OF ALCOHOL DEPENDENCE. ALCOHOL USE DISORDERS ARE CHRONIC DEBILITATING DISEASES CHARACTERIZED BY SEVERE WITHDRAWAL SYMPTOMS THAT CONTRIBUTE TO MORBIDITY AND RELAPSE. GABA(A) RECEPTOR (GABA(A)R) ADAPTATIONS HAVE LONG BEEN IMPLICATED IN THE CHRONIC EFFECTS OF ALCOHOL AND CONTRIBUTE TO MANY WITHDRAWAL SYMPTOMS ASSOCIATED WITH ALCOHOL DEPENDENCE. IN RODENTS, GABA(A)R HYPOFUNCTION RESULTS FROM DECREASES IN GABRA1 EXPRESSION, ALTHOUGH THE UNDERLYING MECHANISM CONTROLLING GABRA1 EXPRESSION AFTER CHRONIC ETHANOL EXPOSURE IS STILL UNKNOWN. WE FOUND THAT CHRONIC ETHANOL EXPOSURE USING EITHER ETHANOL GAVAGE OR TWO-BOTTLE CHOICE VOLUNTARY ACCESS PARADIGMS DECREASED GABRA1 EXPRESSION AND INCREASED HDAC2 AND HDAC3 EXPRESSION. ADMINISTRATION OF THE HDAC INHIBITOR TRICHOSTATIN A (TSA) AFTER CHRONIC ETHANOL EXPOSURE PREVENTS THE DECREASE IN GABRA1 EXPRESSION AND FUNCTION AS WELL AS THE INCREASE IN HDAC2 AND HDAC3 EXPRESSION IN BOTH THE CORTEX AND THE MEDIAL PREFRONTAL CORTEX (MPFC). CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL, BUT NOT ACUTE ETHANOL EXPOSURE OR ACUTE WITHDRAWAL, CAUSE A SELECTIVE UPREGULATION OF HDAC2 AND HDAC3 ASSOCIATED WITH THE GABRA1 PROMOTER THAT ACCOMPANIES A DECREASE IN H3 ACETYLATION OF THE GABRA1 PROMOTER AND THE REDUCTION IN GABA(A)R ALPHA1 SUBUNIT EXPRESSION. TSA ADMINISTRATION PREVENTED EACH OF THESE MOLECULAR EVENTS AS WELL AS BEHAVIORAL MANIFESTATIONS OF ETHANOL DEPENDENCE, INCLUDING TOLERANCE TO ZOLPIDEM-INDUCED LOSS OF RIGHTING REFLEX, REDUCED OPEN-ARM TIME IN THE ELEVATED PLUS MAZE, REDUCED CENTER-TIME AND LOCOMOTOR ACTIVITY IN THE OPEN-FIELD ASSAY, AND TSA REDUCED VOLUNTARY ETHANOL CONSUMPTION. THE RESULTS SHOW HOW CHRONIC ETHANOL EXPOSURE REGULATES THE HIGHLY PROMINENT GABA(A)R ALPHA1 SUBUNIT BY AN EPIGENETIC MECHANISM THAT REPRESENTS A POTENTIAL TREATMENT MODALITY FOR ALCOHOL DEPENDENCE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13  4945  14 PATERNAL PRECONCEPTION EVERY-OTHER-DAY ETHANOL DRINKING ALTERS BEHAVIOR AND ETHANOL CONSUMPTION IN OFFSPRING. ALCOHOL USE DISORDER IS A DEVASTATING DISEASE WITH A COMPLEX ETIOLOGY. RECENT PRECLINICAL STUDIES HAVE REVEALED THAT PATERNAL PRECONCEPTION CHRONIC INTERMITTENT ETHANOL (ETOH) EXPOSURE VIA VAPORIZED ETOH ALTERED DRINKING BEHAVIORS AND SENSITIVITY TO ETOH SELECTIVELY IN MALE OFFSPRING. IN THE CURRENT STUDY, WE USED A VOLUNTARY ORAL ROUTE OF PATERNAL PRECONCEPTION ETOH EXPOSURE, I.E., INTERMITTENT EVERY-OTHER-DAY TWO-BOTTLE CHOICE DRINKING, AND TESTED OFFSPRING FOR BEHAVIORAL ALTERATIONS. FIFTEEN ETOH DRINKING SIRES AND 10 CONTROL SIRES WERE MATED TO ETOH NAIVE FEMALES TO PRODUCE ETOH-SIRED AND CONTROL-SIRED OFFSPRING. THESE OFFSPRING WERE TESTED USING THE ELEVATED PLUS MAZE, OPEN FIELD, DRINKING IN THE DARK, AND UNLIMITED ACCESS TWO-BOTTLE CHOICE ASSAYS. WE FOUND THAT PATERNAL PRECONCEPTION EVERY-OTHER-DAY TWO-BOTTLE CHOICE DRINKING RESULTED IN REDUCED ETOH CONSUMPTION SELECTIVELY IN MALE OFFSPRING IN THE DRINKING IN THE DARK ASSAY COMPARED TO CONTROL-SIRED OFFSPRING. NO DIFFERENCES WERE DETECTED IN EITHER SEX IN THE UNLIMITED ACCESS TWO-BOTTLE CHOICE AND ELEVATED PLUS MAZE ASSAYS. OPEN FIELD ANALYSIS REVEALED COMPLEX CHANGES IN BASAL BEHAVIOR AND ETOH-INDUCED BEHAVIORS THAT WERE SEX SPECIFIC. WE CONCLUDED THAT PATERNAL PRECONCEPTION VOLUNTARY ETOH CONSUMPTION HAS PERSISTENT EFFECTS THAT IMPACT THE NEXT GENERATION. THIS STUDY ADDS TO A GROWING APPRECIATION THAT ONE'S BEHAVIORAL RESPONSE TO ETOH AND ETOH DRINKING BEHAVIOR ARE IMPACTED BY ETOH EXPOSURE OF THE PRIOR GENERATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  3619  21 IN VIVO ACUTE ON CHRONIC ETHANOL EFFECTS IN LIVER: A MOUSE MODEL EXHIBITING EXACERBATED INJURY, ALTERED METABOLIC AND EPIGENETIC RESPONSES. CHRONIC ALCOHOLICS WHO ALSO BINGE DRINK (I.E., ACUTE ON CHRONIC) ARE PRONE TO AN EXACERBATED LIVER INJURY BUT ITS MECHANISM IS NOT UNDERSTOOD. WE THEREFORE INVESTIGATED THE IN VIVO EFFECTS OF CHRONIC AND BINGE ETHANOL INGESTION AND COMPARED TO CHRONIC ETHANOL FOLLOWED BY THREE REPEAT BINGE ETHANOL ON THE LIVER OF MALE C57/BL6 MICE FED ETHANOL IN LIQUID DIET (4%) FOR FOUR WEEKS FOLLOWED BY BINGE ETHANOL (INTRAGASTRIC ADMINISTRATION, 3.5 G/KG BODY WEIGHT, THREE DOSES, 12H APART). CHRONIC FOLLOWED BY BINGE ETHANOL EXACERBATED FAT ACCUMULATION, NECROSIS, DECREASE IN HEPATIC SAM AND SAM:SAH RATIO, INCREASE IN ADENOSINE LEVELS, AND ELEVATED CYP2E1 LEVELS. HISTONE H3 LYSINE ACETYLATION (H3ACK9), DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10), AND PHOSPHORYLATED H2AX INCREASED AFTER BINGE WHEREAS PHOSPHORYLATION OF HISTONE H3 SER 10 (H3S10) AND H3 SER 28 (H3S28) INCREASED AFTER CHRONIC ETHANOL-BINGE. HISTONE H3 LYSINE 4 AND 9 DIMETHYLATION INCREASED WITH A MARKED DIMETHYLATION IN H3K9 IN CHRONIC ETHANOL BINGE GROUP. TRIMETHYLATED HISTONE H3 LEVELS DID NOT CHANGE. NUCLEAR LEVELS OF HISTONE ACETYL TRANSFERASE GCN5 AND HISTONE DEACETYLASE HDAC3 WERE ELEVATED WHEREAS PHOSPHO-CREB DECREASED IN A DISTINCTIVE MANNER. TAKEN TOGETHER, ACUTE ON CHRONIC ETHANOL INGESTION CAUSED AMPLIFICATION OF LIVER INJURY AND ELICITED CHARACTERISTIC PROFILES OF HISTONE MODIFICATIONS, METABOLIC ALTERATIONS, AND CHANGES IN NUCLEAR PROTEIN LEVELS. THESE FINDINGS DEMONSTRATE THAT CHRONIC ETHANOL EXPOSURE RENDERS LIVER MORE SUSCEPTIBLE TO REPEAT ACUTE/BINGE ETHANOL INDUCED ACCELERATION OF ALCOHOLIC LIVER DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
15  5480  24 RESVERATROL REVERSES MORPHINE-INDUCED NEUROINFLAMMATION IN MORPHINE-TOLERANT RATS BY REVERSAL HDAC1 EXPRESSION. BACKGROUND/PURPOSE: WE PREVIOUSLY SHOWED THAT SUBSEQUENT INTRATHECAL (I.T.) INJECTION OF RESVERATROL (30 MUG) SIGNIFICANTLY REVERSES MORPHINE-EVOKED NEUROINFLAMMATION IN MORPHINE-TOLERANT RATS. THE PRESENT STUDY EXAMINED THE UNDERLYING MECHANISM. METHODS: MALE WISTAR RATS WERE IMPLANTED WITH TWO I.T. CATHETERS, ONE OF WHICH WAS CONNECTED TO A MINIOSMOTIC PUMP AND USED FOR MORPHINE (15 MUG/H) OR SALINE INFUSION FOR 120 HOURS. TO EXAMINE THE EFFECTS ON SPINAL CORD EXPRESSION OF HISTONE DEACETYLASE 1 (HDAC1), THE INFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), AND TNF RECEPTOR (TNFR) 1 AND TNFR2 DURING TOLERANCE INDUCTION, A TAIL-FLICK TEST WAS PERFORMED PRIOR TO INFUSION AND AFTER 24 HOURS, 48 HOURS, 72 HOURS, 96 HOURS, AND 120 HOURS OF INFUSION. RESULTS: RESVERATROL TREATMENT PRIOR TO MORPHINE CHALLENGE RESTORED THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN MORPHINE-TOLERANT RATS AND REVERSED THE MORPHINE INFUSION-INDUCED INCREASE IN HDAC1, TNF-ALPHA, AND TNFR1 EXPRESSION. MOREOVER, CHRONIC MORPHINE INFUSION INCREASED TNFR1-SPECIFIC EXPRESSION IN NEURON IN MORPHINE-TOLERANT RAT SPINAL CORDS, AND THIS EFFECT WAS ALMOST COMPLETELY INHIBITED BY RESVERATROL TREATMENT PRIOR TO MORPHINE CHALLENGE. CONCLUSION: RESVERATROL RESTORES THE ANTINOCICEPTIVE EFFECT OF MORPHINE BY REVERSING MORPHINE INFUSION-INDUCED SPINAL CORD NEUROINFLAMMATION AND INCREASE IN TNFR1 EXPRESSION. THE REVERSAL OF THE MORPHINE-INDUCED INCREASE IN TNFR1 EXPRESSION BY RESVERATROL IS PARTIALLY DUE TO REVERSAL OF THE MORPHINE INFUSION-INDUCED INCREASE IN HDAC1 EXPRESSION. RESVERATROL PRETREATMENT CAN BE USED AS AN ADJUVANT IN CLINICAL PAIN MANAGEMENT FOR PATIENTS WHO NEED LONG-TERM MORPHINE TREATMENT OR WITH NEUROPATHIC PAIN.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16   614  23 BINGE ALCOHOL-INDUCED MICROVESICULAR LIVER STEATOSIS AND INJURY ARE ASSOCIATED WITH DOWN-REGULATION OF HEPATIC HDAC 1, 7, 9, 10, 11 AND UP-REGULATION OF HDAC 3. BACKGROUND: BINGE, AS WELL AS CHRONIC, ALCOHOL CONSUMPTION AFFECTS GLOBAL HISTONE ACETYLATION LEADING TO CHANGES IN GENE EXPRESSION. IT IS BECOMING INCREASINGLY EVIDENT THAT THESE HISTONE-ASSOCIATED EPIGENETIC MODIFICATIONS PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF ALCOHOL-MEDIATED HEPATIC INJURY. METHODS: C57BL/6 MICE WERE GAVAGED 3 TIMES (12-HOUR INTERVALS) WITH ETHANOL (ETOH; 4.5 G/KG). HEPATIC HISTONE DEACETYLASE (HDAC) MRNAS WERE ASSESSED BY QRT-PCR. TOTAL HDAC ACTIVITY WAS ESTIMATED BY A COLORIMETRIC HDAC ACTIVITY/INHIBITION ASSAY. HISTONE ACETYLATION LEVELS WERE EVALUATED BY WESTERN BLOT. LIVER STEATOSIS AND INJURY WERE EVALUATED BY HISTOPATHOLOGY, PLASMA AMINOTRANSFERASE (ALT) ACTIVITY, AND LIVER TRIGLYCERIDE ACCUMULATION. EXPRESSION OF FATTY ACID SYNTHASE (FAS) AND CARNITINE PALMITOYL TRANSFERASE 1A (CPT1A) WAS ALSO EXAMINED. HDAC 9 ASSOCIATION WITH FAS PROMOTER WAS ANALYZED. RESULTS: BINGE ALCOHOL EXPOSURE RESULTED IN ALTERATIONS OF HEPATIC HDAC MRNA LEVELS. DOWN-REGULATION OF HDAC CLASS I (HDAC 1), CLASS II (HDAC 7, 9, 10), AND CLASS IV (HDAC 11) AND UP-REGULATION OF HDAC CLASS I (HDAC 3) GENE EXPRESSION WERE OBSERVED. CORRESPONDENT TO THE DECREASE IN HDAC ACTIVITY, AN INCREASE IN HEPATIC HISTONE ACETYLATION WAS OBSERVED. THESE MOLECULAR EVENTS WERE ASSOCIATED WITH MICROVESICULAR HEPATIC STEATOSIS AND INJURY CHARACTERIZED BY INCREASED HEPATIC TRIGLYCERIDES (48.02 +/- 3.83 VS. 19.90 +/- 3.48 MG/G LIVER, P < 0.05) AND ELEVATED PLASMA ALT ACTIVITY (51.98 +/- 6.91 VS. 20.8 +/- 0.62 U/L, P < 0.05). HEPATIC STEATOSIS WAS ASSOCIATED WITH AN INCREASE IN FAS AND A DECREASE IN CPT1A MRNA AND PROTEIN EXPRESSION. FAS PROMOTER ANALYSIS REVEALED THAT BINGE ETOH TREATMENT DECREASED HDAC 9 OCCUPANCY AT THE FAS PROMOTER RESULTING IN ITS TRANSCRIPTIONAL ACTIVATION. CONCLUSIONS: DEREGULATION OF HEPATIC HDAC EXPRESSION LIKELY PLAYS A MAJOR ROLE IN THE BINGE ALCOHOL-INDUCED HEPATIC STEATOSIS AND LIVER INJURY BY AFFECTING LIPOGENESIS AND FATTY ACID BETA-OXIDATION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                         
17   894  23 CHRONIC ETHANOL FEEDING ALTERS HEPATOCYTE MEMORY WHICH IS NOT ALTERED BY ACUTE FEEDING. BACKGROUND: GENE EXPRESSION CHANGES IN THE LIVER AFTER ACUTE BINGE DRINKING MAY DIFFER FROM THE CHANGES SEEN IN CHRONIC ETHANOL FEEDING IN THE RAT. THE CHANGES IN GENE EXPRESSION AFTER CHRONIC ETHANOL FEEDING MAY SENSITIZE THE LIVER TO ALCOHOL-INDUCED LIVER DAMAGE, WHICH IS NOT SEEN AFTER ACUTE BINGE DRINKING. METHODS: TO TEST THIS HYPOTHESIS, GENE MICROARRAY ANALYSIS WAS PERFORMED ON THE LIVERS OF RATS (N = 3) FED AN ACUTE BINGE DOSE OF ETHANOL (6 G/KG BODY WT) AND KILLED AT 3 AND 12 HOURS AFTER ETHANOL BY GAVAGE. THE GENE MICROARRAYS WERE COMPARED WITH THOSE MADE ON THE LIVER OF RATS FROM A PREVIOUS STUDY, IN WHICH THE RATS WERE FED ETHANOL BY INTRAGASTRIC TUBE FOR 1 MONTH (36% OF CALORIES DERIVED FROM ETHANOL). RESULTS: MICROARRAY ANALYSIS DATA VARIED BETWEEN THE ACUTE AND CHRONIC MODELS IN SEVERAL IMPORTANT RESPECTS. GROWTH FACTORS INCREASED MAINLY IN THE CHRONIC ALCOHOL FED RAT. CHANGES IN ENZYMES INVOLVED IN OXIDATIVE STRESS WERE NOTED ONLY WITH CHRONIC ETHANOL FEEDING. GENE EXPRESSION OF FAT METABOLISM WAS INCREASED ONLY WITH CHRONIC ETHANOL FEEDING. MOST IMPORTANTLY, EPIGENETIC RELATED ENZYMES AND ACETYLATION AND METHYLATION OF HISTONES CHANGED ONLY AFTER CHRONIC ETHANOL FEEDING. CONCLUSIONS: THE RESULTS SUPPORT THE CONCEPT THAT CHRONIC ETHANOL INGESTION INDUCES ALTERED GENE EXPRESSION AS A RESULT OF CHANGES IN EPIGENETIC MECHANISMS, WHERE ACETYLATION AND METHYLATION OF HISTONES WERE ALTERED.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18  3483  22 IDENTIFICATION OF CERNA NETWORK TO EXPLAIN THE MECHANISM OF COGNITIVE DYSFUNCTIONS INDUCED BY PS NPS IN MICE. PLASTICS BREAKING DOWN OF LARGER PLASTICS INTO SMALLER ONES (MICROPLASTICS AND NANOPLASTIC) AS POTENTIAL THREATS TO THE ECOSYSTEM. PREVIOUS STUDIES DEMONSTRATE THAT THE CENTRAL NERVOUS SYSTEM (CNS) IS A VULNERABLE TARGET OF NANOPLASTICS. HOWEVER, THE POTENTIALLY EPIGENETIC BIOMARKERS OF NANOPLASTIC NEUROTOXICITY IN RODENT MODELS ARE STILL UNKNOWN. THE PRESENT RESEARCH AIMED TO DETERMINE THE ROLE OF COMPETING ENDOGENOUS RNA (CERNA) IN THE PROCESS OF POLYSTYRENE NANOPLASTICS (PS NPS) EXPOSURE-INDUCED NERVE INJURY. THE STUDY WAS DESIGNED TO INVESTIGATE WHETHER 25 NM PS NPS COULD CAUSE LEARNING DYSFUNCTION AND TO ELUCIDATE THE UNDERLYING MECHANISMS IN MICE. A TOTAL OF 40 MICE WERE DIVIDED INTO 4 GROUPS AND WERE EXPOSED TO PS NPS (0, 10, 25, 50 MG/KG). CHRONIC TOXICITY WAS INTRODUCED IN MICE BY ADMINISTRATION OF ORAL GAVAGE FOR 6 MONTHS. THE EVALUATION INCLUDED ASSESSMENT OF THEIR BEHAVIOR, PATHOLOGICAL INVESTIGATION AND DETERMINATION OF THE LEVELS OF REACTIVE OXYGEN SPECIES (ROS) AND DNA DAMAGE. RNA-SEQ WAS PERFORMED TO DETECT THE EXPRESSION LEVELS OF CIRCRNAS, MIRNAS AND MRNAS IN PFC SAMPLES OF MICE TREATED WITH 0 AND 50 MG/KG PS NPS. THE RESULTS INDICATED THAT EXPOSURE OF MICE TO PS NPS CAUSED A DOSE-DEPENDENT COGNITIVE DECLINE. ROS LEVELS AND DNA DAMAGE WERE INCREASED IN THE PFC FOLLOWING EXPOSURE OF THE MICE TO PS NPS. A TOTAL OF 987 MRNAS, 29 MIRNAS AND 67 CIRCRNAS DEMONSTRATED SIGNIFICANT DIFFERENCES BETWEEN THE 0 AND 50 MG/KG PS NPS GROUPS. FUNCTIONAL ENRICHMENT ANALYSES INDICATED THAT PS NPS MAY INDUCE MAJOR INJURY IN THE SYNAPTIC FUNCTION. A TOTAL OF 96 MRNAS, WHICH WERE ASSOCIATED WITH SYNAPTIC DYSFUNCTION WERE IDENTIFIED. A COMPETING ENDOGENOUS RNA (CERNA) NETWORK CONTAINING 27 CIRCRNAS, 19 MIRNAS AND 35 SYNAPTIC DYSFUNCTION-RELATED MRNAS WAS CONSTRUCTED. THE PRESENT STUDY PROVIDED INSIGHT INTO THE MOLECULAR EVENTS ASSOCIATED WITH NANOPLASTIC TOXICITY AND INDUCTION OF COGNITIVE DYSFUNCTION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19  2907  24 GENE EXPRESSION MODIFICATIONS IN THE LIVER CAUSED BY BINGE DRINKING AND S-ADENOSYLMETHIONINE FEEDING. THE ROLE OF EPIGENETIC CHANGES. CHRONIC ETHANOL INGESTION, ACHIEVED BY FEEDING ETHANOL AT A CONSTANT RATE USING INTRAGASTRIC TUBE FEEDING, ALTERS THE EXPRESSION OF GENES IN THE LIVER. THIS IS DONE BY EPIGENETIC MECHANISMS, WHICH DEPEND ON THE BLOOD ALCOHOL LEVELS AT THE TIME OF KILLING. HOWEVER, ACUTE BOLUS FEEDING OF ETHANOL CHANGES GENE EXPRESSION WITHOUT LASTING EPIGENETIC CHANGES. THIS OCCURS WITH HISTONE 3 METHYLATION AND ACETYLATION MODIFICATIONS. THE GENE EXPRESSION RESPONSE TO AN ACUTE BOLUS OF ETHANOL MIGHT BE MODIFIED BY FEEDING S-ADENOSYLMETHIONINE (SAME), A METHYL DONOR. IN THE PRESENT STUDY, RATS WERE GIVEN A BOLUS OF ETHANOL (6 G/KG BODY WEIGHT (BW), SAME (1 G/KG BW), ETHANOL + SAME, OR ISOCALORIC GLUCOSE. THE GROUP OF RATS (N = 3) WERE KILLED AT 3 AND 12 H POST BOLUS, AND GENE MICROARRAY ANALYSIS WAS PERFORMED ON THEIR LIVER CELLS. SAME REDUCED THE 3 H BLOOD ETHANOL LEVELS AND INCREASED THE ALT LEVELS AT 3 H. VENN DIAGRAMS SHOWED THAT ALCOHOL CHANGED THE EXPRESSION OF 646 GENES AT 3 H POST BOLUS AND 586 GENES AT 12 H. SAME CHANGED THE EXPRESSION OF 1,012 GENES WHEN FED WITH ETHANOL 3 H POST ETHANOL BOLUS AND 554 GENES AT 12 H POST ETHANOL BOLUS. SAME ALONE CHANGED THE EXPRESSION OF 1,751 GENES AT 3 H AND 1,398 AT 12 H. THERE WERE MORE CHANGES IN GENE EXPRESSION AT 3 H THAN AT 12 H POST ETHANOL WHEN ETHANOL ALONE WAS COMPARED TO THE DEXTROSE CONTROL. THE SAME WAS TRUE WHEN SAME WAS COMPARED TO SAME + ETHANOL. ETHANOL UP REGULATED GENE EXPRESSION IN MOST FUNCTIONAL PATHWAYS AT 3 H. HOWEVER, WHEN SAME WAS FED WITH ETHANOL AT 3 H, MOST PATHWAYS WERE DOWN REGULATED. AT 12 H, HOWEVER, WHEN ETHANOL WAS FED, THE PATHWAYS WERE HALF UP REGULATED AND HALF DOWN REGULATED. THE SAME WAS TRUE WHEN SAME + ETHANOL WAS FED. THE EXPRESSION OF EPIGENETICALLY IMPORTANT GENES, SUCH AS BHMT AND FOXN3, WAS UP REGULATED 3 H POST ALCOHOL BOLUS. AT 3 H, SAME DOWN REGULATED THE EXPRESSION OF GENES, SUCH AS BHMT, MAT2A, JUN, TNFRS9, AHCY 1, TGFBR1 AND 2, AND PCAF. AT 12 H, THE INSULIN SIGNALING PATHWAYS WERE HALF DOWN REGULATED BY ETHANOL, WHICH WAS PARTLY PREVENTED BY SAME. THE MAPK PATHWAY WAS UP REGULATED BY ETHANOL, BUT SAME DID NOT PREVENT THIS. IN CONCLUSION, PROFOUND CHANGES IN GENE EXPRESSION EVOLVED BETWEEN 3 H AND 12 POST ETHANOL BOLUS. SAME DOWN REGULATED THESE CHANGES IN GENE EXPRESSION AT 3 H, AND LESS SO AT 12 H.	2010	
                                                                                                        
20  1800  23 EFFECT OF HISTONE DEACETYLASE INHIBITOR ON ETHANOL WITHDRAWAL-INDUCED HYPERALGESIA IN RATS. BACKGROUND: INCREASED PAIN SENSITIVITY IS OBSERVED FOLLOWING ALCOHOL WITHDRAWAL, AND ATTEMPTS TO ALLEVIATE THIS HYPERALGESIA CAN CONTRIBUTE TO THE CYCLE OF ADDICTION. THE AIM OF THIS STUDY WAS TO DETERMINE IF ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA WAS OBSERVED IN A CHRONIC ETHANOL EXPOSURE MODEL AND IF THIS PAIN WAS AFFECTED BY HISTONE DEACETYLASE INHIBITORS, THUS REVEALING AN EPIGENETIC MECHANISM. METHODS: ADULT MALE SPRAGUE DAWLEY RATS RECEIVED LIEBER-DECARLI LIQUID CONTROL OR ETHANOL (9% V/V) DIET FOR 15 DAYS. MECHANICAL SENSITIVITY WAS MEASURED WITH VON FREY HAIR STIMULATION OF THE HINDPAW DURING ETHANOL ADMINISTRATION AND 24- AND 72-HOUR WITHDRAWAL. RESULTS: ETHANOL WITHDRAWAL PRODUCED SEVERE AND SUSTAINED MECHANICAL HYPERALGESIA, AN EFFECT NOT OBSERVED IN THE CONTROL OR ETHANOL-MAINTAINED GROUPS. FURTHERMORE, THIS HYPERALGESIA WAS ATTENUATED BY THE HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID TREATMENT. CONCLUSIONS: HEIGHTENED PAIN SENSITIVITY WAS OBSERVED FOLLOWING WITHDRAWAL FROM CHRONIC ETHANOL EXPOSURE, AND HISTONE DEACETYLASE INHIBITORS COULD BE NOVEL TREATMENTS FOR THIS ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA.	2019