1   449 117 APOCYNIN PREVENTS ANXIETY-LIKE BEHAVIOR AND HISTONE DEACETYLASES OVEREXPRESSION INDUCED BY SUB-CHRONIC STRESS IN MICE. ANXIETY DISORDERS ARE COMMON MENTAL HEALTH DISEASES AFFECTING UP TO 7% OF PEOPLE AROUND THE WORLD. STRESS IS CONSIDERED ONE OF THE MAJOR ENVIRONMENTAL RISK FACTORS TO PROMOTE ANXIETY DISORDERS THROUGH MECHANISMS INVOLVING EPIGENETIC CHANGES. MOREOVER, ALTERATION IN REDOX BALANCE AND INCREASED REACTIVE OXYGEN SPECIES (ROS) PRODUCTION HAVE BEEN DETECTED IN ANXIETY PATIENTS AND IN STRESSED-ANIMAL MODELS OF ANXIETY. HERE WE TESTED IF THE ADMINISTRATION OF APOCYNIN, A NATURAL ORIGIN ANTIOXIDANT, MAY PREVENT THE ANXIETY-LIKE PHENOTYPE AND REDUCTION OF HISTONE ACETYLATION INDUCED BY A SUBCHRONIC FORCED SWIMMING STRESS (FSS) PARADIGM. WE FOUND THAT APOCYNIN PREVENTED THE ENHANCED LATENCY TIME IN THE NOVELTY-SUPPRESSED FEEDING TEST, AND THE PRODUCTION OF MALONDIALDEHYDE INDUCED BY FSS. MOREOVER, APOCYNIN WAS ABLE TO BLOCK THE UPREGULATION OF P47PHOX, A KEY SUBUNIT OF THE NADPH OXIDASE COMPLEX. FINALLY, APOCYNIN PREVENTED THE RISE OF HIPPOCAMPAL HDAC1, HDAC4 AND HDAC5, AND THE REDUCTION OF HISTONE-3 ACETYLATION LEVELS PROMOTED BY FSS EXPOSURE. IN CONCLUSION, OUR RESULTS PROVIDE EVIDENCE THAT APOCYNIN REDUCES THE DELETERIOUS EFFECT OF STRESS AND SUGGESTS THAT OXIDATIVE STRESS MAY REGULATE EPIGENETIC MECHANISMS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2  5132  29 POTENTIAL EFFECT OF LUTEOLIN, EPIAFZELECHIN, AND ALBIGENIN ON RATS UNDER CADMIUM-INDUCED INFLAMMATORY INSULT: IN SILICO AND IN VIVO APPROACH. INTRODUCTION: CADMIUM(CD) AN INDUSTRIAL POISON PRESENT ABUNDANTLY IN THE ENVIRONMENT, CAUSES HUMAN TOXICITY BY AN INFLAMMATORY PROCESS. CHRONIC EXPOSURE OF CADMIUM CAN CAUSE A NUMBER OF MOLECULAR LESIONS THAT COULD BE RELEVANT TO ONCOGENESIS, THROUGH INDIRECT OR EPIGENETIC MECHANISMS, POTENTIALLY INCLUDING ABNORMAL ACTIVATION OF ONCOGENES AND SUPPRESSION OF APOPTOSIS BY DEPLETION OF ANTIOXIDANTS. AS INDUCTION OF CYCLOOXYGENASE (COX)-2 IS LINKED TO INFLAMMATORY PROCESSES, USE OF LUTEOLIN, EPIAFZELECHIN, AND ALBIGENIN ALONE OR IN DIFFERENT COMBINATIONS MAY BE USED AS ANTI-INFLAMMATORY THERAPEUTIC AGENTS. METHODS: WE, HEREIN, PERFORMED IN SILICO EXPERIMENTS TO CHECK THE BINDING AFFINITY OF PHYTOCHEMICALS AND THEIR THERAPEUTIC EFFECT AGAINST COX-2 IN CADMIUM ADMINISTERED RATS. WISTAR ALBINO RATS WERE GIVEN PHYTOCHEMICALS IN DIFFERENT COMBINATIONS TO CHECK THEIR ANTI-INFLAMMATORY ACTIVITIES AGAINST CADMIUM INTOXICATION. THE LEVEL OF ALANINE AMINOTRANSFERASES (ALT), 4-HYDROXYNONENAL (4HNE), 8-HYDROXY-2-DEOXYGUANOSINE (8-OHDG), TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), ISOPROSTANES (ISOP-2ALPHA), COX-2, AND MALONDIALDEHYDE (MDA) WERE ESTIMATED WITH THEIR RESPECTIVE ELISA AND SPECTROPHOTOMETRIC METHODS. RESULTS: THE GENERATED RESULTS SHOW THAT PHYTOCOMPOUNDS POSSESSED GOOD BINDING ENERGY POTENTIAL AGAINST COX-2, AND COMMON INTERACTIVE BEHAVIOR WAS OBSERVED IN ALL DOCKING STUDIES. MOREOVER, THE LEVEL OF ALT, 4HNE, 8-OHDG, TNF-ALPHA, ISOP-2ALPHA, MALONDIALDEHYDE, AND COX-2 WERE SIGNIFICANTLY INCREASED IN RATS WITH INDUCED TOXICITY COMPARED TO THE CONTROL GROUP, WHEREAS IN COMBINATIONAL THERAPY OF PHYTOCOMPOUNDS, THE LEVELS WERE SIGNIFICANTLY DECREASED IN THE GROUP. DISCUSSION: TAKEN TOGETHER, LUTEOLIN, EPIAFZELECHIN, AND ALBIGENIN CAN BE USED AS ANTI-INFLAMMATORY THERAPEUTIC AGENTS FOR FUTURE NOVEL DRUG DESIGN, AND THUS IT MAY HAVE THERAPEUTIC IMPORTANCE AGAINST CADMIUM TOXICITY.	2023	
                                                                                                                          
3  3378  28 HIV INDUCED NITRIC OXIDE AND LIPID PEROXIDATION, INFLUENCES NEONATAL BIRTHWEIGHT IN A SOUTH AFRICAN POPULATION. HIV HAS BEEN IMPLICATED IN ADVERSE BIRTH OUTCOMES, DUE TO INCREASED OXIDATIVE STRESS AND INFLAMMATION. IN ADDITION, HIV HAS BEEN REPORTED TO INCREASE NITRIC OXIDE LEVELS. THEREFORE THE COMBINED EXPOSURES TO HIV AND TRAFFIC-RELATED AIR POLLUTION, WITHIN SOUTH DURBAN, SOUTH AFRICA (SA), MAY LEAD TO ADVERSE BIRTH OUTCOMES. HOWEVER, THE EXACT MECHANISM IS STILL UNKNOWN; THIS STUDY AIMED TO IDENTIFY A POTENTIAL MECHANISM. FIRST, THE INFLUENCE OF HIV ON OXIDATIVE AND NITROSATIVE STRESS MARKERS IN PREGNANT WOMEN WAS ASSESSED. SECONDLY, THE EFFECT OF THESE STRESS MAKERS AND EXPOSURE TO OXIDES OF NITROGEN (NOX) ON NEONATAL BIRTHWEIGHT (BW) WAS EVALUATED. FINALLY, THE EFFECT HIV AND TRAFFIC-RELATED POLLUTION EXPOSURE HAS ON THE OXIDATIVE AND ENDOPLASMIC PROFILE AND EPIGENETIC REGULATION OF NRF2-KEAP1 PATHWAY BY MIR-144 AND MIR-28 IN PREGNANT WOMEN WAS DETERMINED. WOMEN, IN THEIR THIRD TRIMESTER WITH SINGLETON PREGNANCIES, WHO WERE HIV+ AND HIV-, WERE RECRUITED FROM DURBAN, SA. BIOMARKER LEVELS OF SERUM NITRITES/NITRATES (NO) AND MALONDIALDEHYDE (MDA) WERE ANALYSED AND MRNA EXPRESSION LEVELS OF OXIDATIVE AND ENDOPLASMIC STRESS RESPONSE GENES WERE ASSESSED. LAND REGRESSION MODELLING WAS PERFORMED TO DETERMINE NOX EXPOSURE LEVELS. HIV EXPOSURE DURING PREGNANCY WAS ASSOCIATED WITH INCREASED NO LEVELS. NO WAS SHOWN TO REDUCE NEONATAL BW. NO AND MDA WAS FOUND TO RECIPROCALLY INCREASE EACH OTHER, WITH HIV DIFFERENTIALLY INFLUENCING MDA'S EFFECT ON BW. HIV DOWN-REGULATED MIR-144 WHICH WAS NEGATIVELY ASSOCIATED WITH NRF2, SUGGESTING A POTENTIAL MECHANISM FOR HIV ASSOCIATED CHRONIC OXIDATIVE STRESS. THIS STUDY PROPOSES THAT NO PLAYS A KEY ROLE IN NEONATAL BW REDUCTION IN RESPONSE TO HIV AND TRAFFIC-RELATED AIR POLLUTION.	2018	
                                                                                                                                                                                                                                                                                                                                   
4   294  28 AGING INCREASES VULNERABILITY TO STRESS-INDUCED DEPRESSION VIA UPREGULATION OF NADPH OXIDASE IN MICE. BRAIN AGING PROCEEDS WITH CELLULAR AND MOLECULAR CHANGES IN THE LIMBIC SYSTEM. AGING-DEPENDENT CHANGES MIGHT AFFECT EMOTION AND STRESS COPING, YET THE UNDERLYING MECHANISMS REMAIN UNCLEAR. HERE, WE SHOW AGED (18-MONTH-OLD) MICE EXHIBIT UPREGULATION OF NADPH OXIDASE AND OXIDATIVE STRESS IN THE HIPPOCAMPUS, WHICH MIRRORS THE CHANGES IN YOUNG (2-MONTH-OLD) MICE SUBJECTED TO CHRONIC STRESS. AGED MICE THAT LACK P47PHOX, A KEY SUBUNIT OF NADPH OXIDASE, DO NOT SHOW INCREASED OXIDATIVE STRESS. AGED MICE EXHIBIT DEPRESSION-LIKE BEHAVIOR FOLLOWING WEAK STRESS THAT DOES NOT PRODUCE DEPRESSIVE BEHAVIOR IN YOUNG MICE. AGED MICE HAVE REDUCED EXPRESSION OF THE EPIGENETIC FACTOR SUV39H1 AND ITS UPSTREAM REGULATOR P-AMPK, AND INCREASED EXPRESSION OF PPP2CA IN THE HIPPOCAMPUS-CHANGES THAT OCCUR IN YOUNG MICE EXPOSED TO CHRONIC STRESS. SUV39H1 MEDIATES STRESS- AND AGING-INDUCED SUSTAINED UPREGULATION OF P47PHOX AND OXIDATIVE STRESS. THESE RESULTS SUGGEST THAT AGING INCREASES SUSCEPTIBILITY TO STRESS BY UPREGULATING NADPH OXIDASE IN THE HIPPOCAMPUS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  3318  30 HISTONE ACETYLATION AND EXPRESSION OF MONO-AMINERGIC TRANSMITTERS SYNTHETASES INVOLVED IN CUS-INDUCED DEPRESSIVE RATS. HISTONE ACETYLATION HAS BEEN LINKED TO DEPRESSION, THE ETIOLOGY OF WHICH INVOLVES MANY FACTORS SUCH AS GENETICS, ENVIRONMENTS, AND EPIGENETICS. THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE WHETHER IT WAS ASSOCIATED WITH EPIGENETIC HISTONE MODIFICATION AND GENE EXPRESSION OF ENZYMES RESPONSIBLE FOR THE BIOSYNTHESIS OF NOREPINEPHRINE AND SEROTONIN IN RAT DEPRESSION MODEL INDUCED BY CHRONIC UNPREDICTABLE STRESS (CUS). EIGHT-WEEK-OLD MALE SPRAGUE-DAWLEY RATS WERE EXPOSED TO CUS OVER 28 DAYS. IT WAS SHOWN THAT THE CUS-INDUCED RATS DISPLAYED REMARKED ANXIETY- AND DEPRESSION-LIKE BEHAVIOR WITH WEAKENED LOCOMOTOR ACTIVITY IN OPEN FIELD TEST AND PROLONGED IMMOBILITY IN FORCED SWIMMING TEST. WESTERN BLOT REVEALED THAT CUS LED TO SIGNIFICANT DECREASE IN ACETYLATION OF H3 AT LYSINE 9 (K9) AND H4 AT LYSINE 12 (K12) WITH OBVIOUSLY INCREASING HISTONE DEACETYLASES 5 (HDAC5) EXPRESSION IN HIPPOCAMPUS OF CUS-INDUCED RATS. MEANWHILE, THERE WAS AN OBVIOUSLY DECREASED EXPRESSION OF TYROSINE HYDROXYLASE (TH) AND TRYPTOPHAN HYDROXYLASE (TPH) BOTH AT PROTEIN AND MRNA LEVELS. ADMINISTRATION OF SODIUM VALPROATE (VPA), A HISTONE DEACETYLASE 5 (HDAC5) INHIBITOR, NOT ONLY SIGNIFICANTLY RELIEVED THE ANXIETY- AND DEPRESSION-LIKE BEHAVIORS OF CUS-INDUCED RATS BUT ALSO CLEARLY BLUNTED DECREASE OF H3(K9) AND H4(K12) ACETYLATION AND EXPRESSION OF TH AND TPH, AND PREVENTED INCREASE OF HDAC5 EXPRESSION. THE RESULTS INDICATE THAT THERE EXISTS POSSIBLE INTERRELATION BETWEEN TH AND TPH GENE EXPRESSION AND EPIGENETIC HISTONE ACETYLATION IN CUS-INDUCED DEPRESSIVE RATS, WHICH AT LEAST PARTLY CONTRIBUTES TO THE ETIOLOGY OF DEPRESSION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                         
6  1792  25 EFFECT OF CHRONIC WESTERN DIETS ON NON-ALCOHOLIC FATTY LIVER OF MALE MICE MODIFYING THE PPAR-GAMMA PATHWAY VIA MIR-27B-5P REGULATION. WESTERN DIETS CONTRIBUTE TO METABOLIC DISEASES. HOWEVER, THE EFFECTS OF VARIOUS DIETS AND EPIGENETIC MECHANISMS ARE MOSTLY UNKNOWN. HERE, SIX WEEK-OLD C57BL/6J MALE AND FEMALE MICE WERE FED WITH A LOW-FAT DIET (LFD), HIGH-FAT DIET (HFD), AND HIGH-FAT HIGH-FRUCTOSE DIET (HFD-HF) FOR 20 WEEKS. WE DETERMINED THAT HFD-HF OR HFD MICE EXPERIENCED SIGNIFICANT METABOLIC DYSREGULATION COMPARED TO THE LFD. HFD-HF AND HFD-FED MALE MICE SHOWED SIGNIFICANTLY INCREASED BODY WEIGHT, LIVER SIZE, AND FASTING GLUCOSE LEVELS WITH DOWNREGULATED PPARGAMMA, SCD1, AND FAS PROTEIN EXPRESSION. IN CONTRAST, FEMALE MICE WERE LESS AFFECTED BY HFD AND HFD-HF. AS MIR-27B CONTAINS A SEED SEQUENCE IN PPARGAMMA, IT WAS DISCOVERED THAT THESE CHANGES ARE ACCOMPANIED BY MALE-SPECIFIC UPREGULATION OF MIR-27B-5P, WHICH IS EVEN MORE PRONOUNCED IN THE HFD-HF GROUP (P < 0.01 VS. LFD) COMPARED TO THE HFD GROUP (P < 0.05 VS. LFD). OTHER MIR-27 SUBTYPES WERE INCREASED BUT NOT SIGNIFICANTLY. HFD-HF SHOWED INSIGNIFICANT CHANGES IN FIBROSIS MARKERS WHEN COMPARED TO LFD. INTERESTINGLY, FAT BALLOONING IN HEPATOCYTES WAS INCREASED IN HFD-FED MICE COMPARED TO HFD-HF FED MICE, HOWEVER, THE HFD-HF LIVER SHOWED AN INCREASE IN THE NUMBER OF SMALL CELLS. HERE, WE CONCLUDED THAT CHRONIC WESTERN DIET-COMPOSITION ADMINISTERED FOR 20 WEEKS MAY SURPASS THE NON-ALCOHOLIC FATTY LIVER (NAFL) STAGE BUT MAY BE AT AN INTERMEDIATE STAGE BETWEEN FATTY LIVER AND FIBROSIS VIA MIR-27B-5P-INDUCED PPARGAMMA DOWNREGULATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7  1783  26 EFFECT OF AGOMELATINE ON MEMORY DEFICITS AND HIPPOCAMPAL GENE EXPRESSION INDUCED BY CHRONIC SOCIAL DEFEAT STRESS IN MICE. CHRONIC STRESS IS KNOWN TO INDUCE NOT ONLY ANXIETY AND DEPRESSIVE-LIKE PHENOTYPES IN MICE BUT ALSO COGNITIVE IMPAIRMENTS, FOR WHICH THE ACTION OF CLASSICAL ANTIDEPRESSANT COMPOUNDS REMAINS UNSATISFACTORY. IN THIS CONTEXT, WE INVESTIGATED THE EFFECTS OF CHRONIC SOCIAL DEFEAT STRESS (CSDS) ON ANXIETY-, SOCIAL- AND COGNITIVE-RELATED BEHAVIORS, AS WELL AS HIPPOCAMPAL BDNF, SYNAPTIC PLASTICITY MARKERS (PSD-95, SYNAPTOPHYSIN, SPINOPHILIN, SYNAPSIN I AND MAP-2), AND EPIGENETIC MODIFYING ENZYMES (MYST2, HDAC2, HDAC6, MLL3, KDM5B, DNMT3B, GADD45B) GENE EXPRESSION IN C57BL/6J MICE. CSDS FOR 10 DAYS PROVOKED LONG-LASTING ANXIOUS-LIKE PHENOTYPE IN THE OPEN FIELD AND EPISODIC MEMORY DEFICITS IN THE NOVEL OBJECT RECOGNITION TEST. WHILE TOTAL BDNF MRNA LEVEL WAS UNCHANGED, BDNF EXON IV, MAP-2, HDAC2, HDAC6 AND MLL3 GENE EXPRESSION WAS SIGNIFICANTLY DECREASED IN THE CSDS MOUSE HIPPOCAMPUS. IN CSDS MICE TREATED 3 WEEKS WITH 50 MG/KG/D AGOMELATINE, AN ANTIDEPRESSANT WITH MELATONERGIC RECEPTOR AGONIST AND 5-HT(2C) RECEPTOR ANTAGONIST PROPERTIES, THE ANXIOUS-LIKE PHENOTYPE WAS NOT REVERSED, BUT THE TREATMENT SUCCESSFULLY PREVENTED THE COGNITIVE IMPAIRMENTS AND HIPPOCAMPAL GENE EXPRESSION MODIFICATIONS. ALTOGETHER, THESE DATA EVIDENCED THAT, IN MICE, AGOMELATINE WAS EFFECTIVE IN ALLEVIATING STRESS-INDUCED ALTERED COGNITIVE FUNCTIONS, POSSIBLY THROUGH A MECHANISM INVOLVING BDNF SIGNALING, SYNAPTIC PLASTICITY AND EPIGENETIC REMODELING.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8  1201  33 CORTICOTROPIN-RELEASING FACTOR RECEPTOR-1 MODULATES BIOMARKERS OF DNA OXIDATION IN ALZHEIMER'S DISEASE MICE. INCREASED PRODUCTION OF HYDROXYL RADICAL IS THE MAIN SOURCE OF OXIDATIVE DAMAGE IN MAMMALIAN DNA THAT ACCUMULATES IN ALZHEIMER'S DISEASE (AD). REACTIVE OXYGEN SPECIES (ROS) REACT WITH BOTH NUCLEAR DNA (NDNA) AND MITOCHONDRIAL DNA (MTDNA) TO GENERATE 8-HYDROXY-2'-DEOXYGUANOSINE (8-OHDG), BOTH OF WHICH CAN BE MEASURED IN THE URINE. KNOWLEDGE OF THIS PATHWAY HAS POSITIONED MEASUREMENT OF URINE 8-OHDG AS A RELIABLE INDEX OF DNA OXIDATION AND A POTENTIAL BIOMARKER TARGET FOR TRACKING EARLY CELLULAR DYSFUNCTION IN AD. FURTHERMORE, EPIGENETIC STUDIES DEMONSTRATE DECREASED GLOBAL DNA METHYLATION LEVELS (E.G. 5-METHYL-2'-DEOXYCYTIDINE, 5-MDC) IN AD TISSUES. MOREOVER, STRESS HORMONES CAN ACTIVATE NEURONAL OXIDATIVE STRESS WHICH WILL STIMULATE THE RELEASE OF ADDITIONAL STRESS HORMONES AND RESULT IN DAMAGES TO HIPPOCAMPAL NEURONS IN THE AD BRAIN. OUR PREVIOUS WORK SUGGESTS THAT TREATING AD TRANSGENIC MICE THE TYPE-1 CORTICOTROPIN-RELEASING FACTOR RECEPTOR (CRFR1) ANTAGONIST, R121919, TO REDUCE STRESS SIGNALING, PREVENTED ONSET OF COGNITIVE IMPAIRMENT, SYNAPTIC/DENDRITIC LOSS AND ABETA PLAQUE ACCUMULATION. THEREFORE, TO INVESTIGATE WHETHER LEVELS OF DNA OXIDATION CAN BE IMPACTED BY THE SAME THERAPEUTIC APPROACH, URINE LEVELS OF HYDROGEN PEROXIDE, 8-OHDG, 5-MDC AND TOTAL ANTIOXIDANT CAPACITY (TAC) WERE ANALYZED USING AN AD TG MOUSE MODEL. WE FOUND THAT TG ANIMALS HAD AN 80% INCREASE IN HYDROGEN PEROXIDE LEVELS COMPARED TO WILD TYPE (WT) COUNTERPARTS, AN EFFECT THAT COULD BE DRAMATICALLY REVERSED BY THE CHRONIC ADMINISTRATION WITH R121919. A SIGNIFICANT DECREASE OF 8-OHDG LEVELS WAS OBSERVED IN TG MICE TREATED WITH CRFR1 ANTAGONIST. COLLECTIVELY OUR DATA SUGGEST THAT THE BENEFICIAL EFFECTS OF CRFR1 ANTAGONISM SEEN IN TG MICE MAY BE MECHANISTICALLY LINKED TO THE MODULATION OF OXIDATIVE STRESS PATHWAYS.	2017	
                                                                                                                                                                                                                                               
9  1740  30 EARLY ENRICHED ENVIRONMENT PREVENTS EPIGENETIC P11 GENE CHANGES INDUCED BY ADULTHOOD STRESS IN MICE. POSITIVE EXPERIENCES IN EARLY LIFE MAY IMPROVE THE CAPACITY TO COPE WITH ADULTHOOD STRESS THROUGH EPIGENETIC MODIFICATION. WE INVESTIGATED WHETHER AN ENRICHED ENVIRONMENT (EE) IN THE POSTNATAL PERIOD AFFECTED EPIGENETIC CHANGES IN THE P11 GENE INDUCED BY CHRONIC UNPREDICTABLE STRESS (CUS) IN ADULT C57BL/6J MICE. EE WAS INTRODUCED FOR 5 WEEKS DURING POSTNATAL DAYS 21-55. AFTER EE, THE MICE WERE SUBJECTED TO CUS FOR 4 WEEKS. EE PREVENTED DEPRESSION-LIKE BEHAVIOR INDUCED BY ADULT CUS. EE PREVENTED A DECREASE IN P11 MRNA AND HISTONE H3 ACETYLATION INDUCED BY CUS, WITH CHANGES IN THE EXPRESSION OF HISTONE DEACETYLASE 5. MOREOVER, EE PREVENTED CHANGES IN TRIMETHYLATION OF HISTONE H3 LYSINE 4 (H3K4) AND H3K27 INDUCED BY CUS. FURTHERMORE, EE HAD POSITIVE EFFECTS ON BEHAVIOR AND EPIGENETIC ALTERATIONS IN ADULT MICE WITHOUT CUS. THESE RESULTS SUGGEST THAT ONE OF THE UNDERLYING MECHANISMS OF EARLY-LIFE EE MAY INVOLVE EPIGENETIC MODIFICATION OF THE HIPPOCAMPAL P11 GENE PROMOTER.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10  5480  23 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	
                                                                                                                                                                                                                                                                                                                                       
11  3785  15 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
12  6492  26 TRAFFIC-RELATED AIR POLLUTION AND GROUND-LEVEL OZONE ASSOCIATED GLOBAL DNA HYPOMETHYLATION AND BULKY DNA ADDUCT FORMATION. STUDIES HAVE INDICATED THAT AIR POLLUTION, INCLUDING SURFACE-LEVEL OZONE (O(3)), CAN SIGNIFICANTLY INFLUENCE THE RISK OF CHRONIC DISEASES. TO BETTER UNDERSTAND THE CARCINOGENIC MECHANISMS OF AIR POLLUTANTS AND IDENTIFY PREDICTIVE DISEASE BIOMARKERS, WE EXAMINED THE ASSOCIATION BETWEEN TRAFFIC-RELATED POLLUTANTS WITH DNA METHYLATION ALTERATIONS AND BULKY DNA ADDUCTS, TWO BIOMARKERS OF CARCINOGEN EXPOSURE AND CANCER RISK, IN THE PERIPHERAL BLOOD OF 140 VOLUNTEERS-95 TRAFFIC POLICE OFFICERS, AND 45 UNEXPOSED SUBJECTS. THE DNA METHYLATION AND ADDUCT MEASUREMENTS WERE PERFORMED BY BISULFITE-PCR AND PYROSEQUENCING AND (32)P-POSTLABELING ASSAY. AIRBORNE LEVELS OF BENZO(A)PYRENE [B(A)P], CARBON MONOXIDE, AND TROPOSPHERIC O(3) WERE DETERMINED BY PERSONAL EXPOSURE BIOMONITORING OR BY FIXED MONITORING STATIONS. OVERALL, AIR POLLUTION EXPOSURE WAS ASSOCIATED WITH A SIGNIFICANT REDUCTION (1.41 UNITS) IN GLOBAL DNA METHYLATION (95% C.I. -2.65-0.04, P = 0.026). THE DECREMENT IN ALU REPETITIVE ELEMENTS WAS GREATEST IN THE POLICEMEN WORKING DOWNTOWN (95% C.I. -3.23--0.49, P = 0.008). THE DNA ADDUCTS WERE FOUND TO BE SIGNIFICANTLY INCREASED (0.45 UNITS) IN THE MUNICIPAL OFFICERS WITH RESPECT TO UNEXPOSED SUBJECTS (95% C.I. 0.02-0.88, P = 0.039), MAINLY IN THOSE WHO WERE CONTROLLING TRAFFIC IN DOWNTOWN AREAS (95% C.I. 0.39-1.29, P < 0.001). REGRESSION MODELS INDICATED AN INCREMENT OF ALU METHYLATION AT HIGHER B(A)P CONCENTRATIONS (95% C.I. 0.03-0.60, P = 0.032). MOREOVER, STATISTICAL MODELS SHOWED A DECREMENT IN ALU METHYLATION AND AN INCREMENT OF DNA DAMAGE ONLY ABOVE THE CUT-OFF VALUE OF 30 MICROG/M(3) O(3). A SIGNIFICANT INCREMENT OF 0.73 UNITS OF IL-6 GENE METHYLATION WAS ALSO FOUND IN SMOKERS WITH RESPECT TO NON-SMOKERS. OUR RESULTS HIGHLIGHTED THE ROLE OF AIR POLLUTION ON EPIGENETIC ALTERATIONS AND GENOTOXIC EFFECTS, ESPECIALLY ABOVE THE TARGET VALUE OF 30 MICROG/M(3) SURFACE-LEVEL O(3), SUPPORTING THE NECESSITY FOR DEVELOPING PUBLIC HEALTH STRATEGIES AIMED TO REDUCE TRAFFIC-RELATED AIR POLLUTION MOLECULAR ALTERATIONS.	2023	

13  5877  24 SYNERGIC ACTION OF L-ACETYLCARNITINE AND L-METHYLFOLATE IN MOUSE MODELS OF STRESS-RELATED DISORDERS AND HUMAN IPSC-DERIVED DOPAMINERGIC NEURONS. THE EPIGENETIC AGENTS, L-ACETYLCARNITINE (LAC) AND L-METHYLFOLATE (MF) ARE PUTATIVE CANDIDATES AS ADD-ON DRUGS IN DEPRESSION. WE EVALUATED THE EFFECT OF A COMBINED TREATMENT WITH LAC AND MF IN TWO DIFFERENT PARADIGMS OF CHRONIC STRESS IN MICE AND IN HUMAN INDUCIBLE PLURIPOTENT STEM CELLS (HIPSCS) DIFFERENTIATED INTO DOPAMINERGIC NEURONS. TWO GROUPS OF MICE WERE EXPOSED TO CHRONIC UNPREDICTABLE STRESS (CUS) FOR 28 DAYS OR CHRONIC RESTRAINT STRESS (CRS) FOR 21 DAY, AND LAC (30 OR 100 MG/KG) AND/OR MF (0.75 OR 3 MG/KG) WERE ADMINISTERED I.P. ONCE A DAY FOR 14 DAYS, STARTING FROM THE LAST WEEK OF STRESS. IN BOTH STRESS PARADIGMS, LAC AND MF ACTED SYNERGISTICALLY IN REDUCING THE IMMOBILITY TIME IN THE FORCED SWIM TEST AND ENHANCING BDNF PROTEIN LEVELS IN THE FRONTAL CORTEX AND HIPPOCAMPUS. IN ADDITION, LAC AND MF ACTED SYNERGISTICALLY IN ENHANCING TYPE-2 METABOTROPIC GLUTAMATE RECEPTOR (MGLU2) PROTEIN LEVELS IN THE HIPPOCAMPUS OF MICE EXPOSED TO CRS. INTERESTINGLY, CRS MICE TREATED WITH MF SHOWED AN UP-REGULATION OF NFKAPPAB P65, WHICH IS A SUBSTRATE FOR LAC-INDUCED ACETYLATION. WE COULD ALSO DEMONSTRATE A SYNERGISM BETWEEN LAC AND MF IN CULTURED HIPSCS DIFFERENTIATED INTO DOPAMINE NEURONS, BY MEASURING DENDRITE LENGTH AND NUMBER, AND AREA OF THE CELL SOMA AFTER 3 DAYS OF DRUG EXPOSURE. THESE FINDINGS SUPPORT THE COMBINED USE OF LAC AND MF IN THE TREATMENT OF MDD AND OTHER STRESS-RELATED DISORDERS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  5152  28 PPM1F IN DENTATE GYRUS MODULATES ANXIETY-RELATED BEHAVIORS BY REGULATING BDNF EXPRESSION VIA AKT/JNK/P-H3S10 PATHWAY. ANXIETY IS A SERIOUS PSYCHIATRIC DISORDER, WITH A HIGHER INCIDENCE RATE IN WOMEN THAN IN MEN. PROTEIN PHOSPHATASE MG(2+)/MN(2+)-DEPENDENT 1F (PPM1F), A SERINE/THREONINE PHOSPHATASE, HAS BEEN SHOWN TO HAVE MULTIPLE BIOLOGICAL AND CELLULAR FUNCTIONS. HOWEVER, THE EFFECTS OF PPM1F AND ITS NEURONAL SUBSTRATES ON ANXIETY REMAIN LARGELY UNCLEAR. IN THIS STUDY, WE SHOWED THAT CHRONIC RESTRAINT STRESS (CRS) INDUCED ANXIETY-RELATED BEHAVIORS ONLY IN FEMALE MICE, WHILE ACUTE RESTRAINT STRESS (ARS) PRODUCED ANXIETY-RELATED BEHAVIORS IN BOTH MALE AND FEMALE MICE IN LIGHT-DARK AND ELEVATED PLUS MAZE TESTS AND INDUCED UPREGULATION OF PPM1F AND DOWNREGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION IN THE HIPPOCAMPUS. ADENO-ASSOCIATED VIRUS-MEDIATED OVEREXPRESSION OF PPM1F OR CONDITIONAL KNOCKOUT OF BDNF IN DENTATE GYRUS (DG) LED TO A MORE PRONOUNCED ANXIETY-RELATED BEHAVIOR IN FEMALE THAN IN MALE MICE AS INDICATED BY THE BEHAVIORAL EVALUATIONS. MEANWHILE, OVEREXPRESSION OF PPM1F IN THE DG DECREASED TOTAL BDNF EXON-SPECIFIC MESSENGER RNA EXPRESSION IN THE HIPPOCAMPUS WITH THE DECREASED BINDING ACTIVITY OF PHOSPHORYLATED H3S10 TO ITS INDIVIDUAL PROMOTERS IN FEMALE MICE. FURTHERMORE, WE IDENTIFIED THAT OVEREXPRESSION OF PPM1F DECREASED THE PHOSPHORYLATION LEVELS OF AKT AND JNK IN THE HIPPOCAMPUS OF FEMALE MICE. THESE RESULTS MAY SUGGEST THAT PPM1F REGULATES ANXIETY-RELATED BEHAVIORS BY MODULATING BDNF EXPRESSION AND H3S10 PHOSPHORYLATION-MEDIATED EPIGENETIC MODIFICATION, WHICH MAY BE SERVED AS POTENTIALLY PATHOLOGICAL GENES ASSOCIATED WITH ANXIETY OR OTHER MENTAL DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  5752  25 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	
                                                                                                                                                                                                                                                                            
16  5874  30 SWIMMING EXERCISE REVERSES CUMS-INDUCED CHANGES IN DEPRESSION-LIKE BEHAVIORS AND HIPPOCAMPAL PLASTICITY-RELATED PROTEINS. BACKGROUND: STRESS-INDUCED FAILED RESILIENCE OF BRAIN PLASTICITY CAN CONTRIBUTE TO THE ONSET AND RECURRENCE OF DEPRESSION. CHRONIC STRESS HAS BEEN REPORTED TO OPEN WINDOWS OF EPIGENETIC PLASTICITY IN HIPPOCAMPUS. HOWEVER, HOW HIPPOCAMPAL PLASTICITY UNDERLIES DEPRESSION-LIKE BEHAVIORS AND HOW IT ADAPTS IN RESPONSE TO STRESS HAS NOT BEEN ADDRESSED. THE PRESENT STUDY AIMED TO INVESTIGATE THE SIGNALING MECHANISMS OF CUMS AFFECTING HIPPOCAMPAL PLASTICITY-RELATED PROTEINS EXPRESSION AND THE REGULATION OF SWIMMING EXERCISE IN MICE. METHODS: MALE C57BL/6 MICE WERE SUBJECTED TO CHRONIC UNPREDICTABLE MILD STRESS (CUMS) FOR 7 WEEKS. FROM THE 4TH WEEK, CUMS MICE WERE TRAINED IN A MODERATE SWIMMING PROGRAM FOR A TOTAL OF 4 WEEKS. A VIDEOCOMPUTERIZED TRACKING SYSTEM WAS USED TO RECORD BEHAVIORS OF ANIMALS FOR A 5-MIN SESSION. REAL-TIME PCR AND WESTERN BLOTTING WERE USED TO EXAMINE GENE EXPRESSION IN MOUSE HIPPOCAMPUS. RESULTS: OUR RESULTS DEMONSTRATED THAT CUMS INDUCED DEPRESSION-LIKE BEHAVIORS, WHICH WERE REVERSED BY SWIMMING EXERCISE. MOREOVER, THE BEHAVIORAL CHANGES INDUCED BY CUMS AND EXERCISE WERE CORRELATED WITH HIPPOCAMPAL PLASTICITY-RELATED PROTEINS EXPRESSION OF GROWTH-ASSOCIATED PROTEIN-43 (GAP-43) AND SYNAPTOPHYSIN (SYN). THE MOLECULAR MECHANISMS REGULATING THIS PLASTICITY MAY INCLUDE SIRT1/MIRCORNA, CREB/BDNF, AND AKT/GSK-3BETA SIGNALING PATHWAYS. LIMITATIONS: WE DID NOT ESTABLISH A CORRELATION BETWEEN DEPRESSION-LIKE BEHAVIORS INDUCED BY CHRONIC STRESS AND EPIGENETIC CHANGES OF HIPPOCAMPAL PLASTICITY, EITHER A CAUSAL MOLECULAR SIGNALING UNDERLING THIS PLASTICITY. CONCLUSIONS: OUR FINDINGS HAVE IDENTIFIED SWIMMING EXERCISE EFFECTS ON CUMS-INDUCED CHANGES IN DEPRESSION-LIKE BEHAVIORS AND HIPPOCAMPAL PLASTICITY-RELATED PROTEINS, WHICH PROVIDE A FRAMEWORK FOR DEVELOPING NEW STRATEGIES TO TREAT STRESS-INDUCED DEPRESSION.	2018	
                                                                                                                                                                                                    
17    73  22 A MULTI-GENERATIONAL STUDY ON LOW-DOSE BPA EXPOSURE IN WISTAR RATS: EFFECTS ON MATERNAL BEHAVIOR, FLAVOR INTAKE AND DEVELOPMENT. BISPHENOL A (BPA) IS A COMMON ENDOCRINE DISRUPTOR FOUND AS AN ENVIRONMENTAL AND FOOD CONTAMINANT. IT EXERTS BOTH DEVELOPMENTAL AND BEHAVIORAL EFFECTS, MAINLY WHEN EXPOSURE OCCURS IN EARLY LIFE. THE AIM OF THIS STUDY WAS TO DETERMINE THE MULTI-GENERATIONAL EFFECTS OF CHRONIC, HUMAN-RELEVANT LOW-DOSE EXPOSURE TO BPA ON DEVELOPMENT, MATERNAL BEHAVIOR AND FLAVOR PREFERENCE IN WISTAR RATS. BPA WAS ORALLY ADMINISTERED AT A DAILY DOSE OF 5 MUG/KG BODY WEIGHT TO F0 PREGNANT DAMS FROM THE FIRST DAY OF GESTATION (GD 1) UNTIL THE LAST DAY OF LACTATION (LD 21), AND THEN TO F1 OFFSPRING FROM WEANING (PND 21) TO ADULTHOOD (PND 100). F2 OFFSPRING WERE NOT EXPOSED. DEVELOPMENT AND CLINICAL SIGNS OF TOXICITY WERE ASSESSED DAILY. MATERNAL BEHAVIOR WAS EVALUATED BY OBSERVING NURSING AND PUP-CARING ACTIONS, AS WELL AS "NON-MATERNAL" BEHAVIORS IN F0 AND F1 DAMS FROM PARTURITION UNTIL LD 8. THE FLAVOR PREFERENCES OF F1 AND F2 OFFSPRING WERE EVALUATED BASED ON THE INTAKE OF SWEET, SALT AND FAT SOLUTIONS USING THE TWO-BOTTLE CHOICE TEST ON PND 21-34 AND PND 86-99. BPA EXPOSURE: 1) DECREASED MATERNAL BEHAVIOR IN F1 DAMS, 2) CAUSED DEVELOPMENTAL DEFECTS IN BOTH F1 AND F2 OFFSPRING, WITH A NOTICEABLE DECREASE IN ANOGENITAL DISTANCE IN MALE RATS, AND 3) DID NOT AFFECT FLAVORED SOLUTION INTAKE IN F1, BUT INDUCED CHANGES IN SWEET PREFERENCE IN F2 JUVENILES AND IN SALT AND FAT SOLUTION INTAKES IN F2 ADULTS, AND 4) INDUCED A BODY WEIGHT INCREASE IN THE F2 GENERATION ONLY, WHEREAS FOOD INTAKE AND WATER CONSUMPTION DID NOT CHANGE. TAKEN AS A WHOLE, OUR FINDINGS SHOWED THAT BOTH GESTATIONAL (F0) AND LIFELONG (F1) EXPOSURES TO A HUMAN-RELEVANT DOSE OF BPA COULD INDUCE MULTI-GENERATIONAL EFFECTS ON BOTH DEVELOPMENT AND BEHAVIOR. THESE RESULTS SUGGEST POSSIBLE SELECTIVE NEUROENDOCRINE DEFECTS AND/OR EPIGENETIC CHANGES CAUSED BY BPA EXPOSURE.	2014	
                                                                                                                                                                                                        
18   199  28 ACTIVATED HISTONE ACETYLTRANSFERASE P300/CBP-RELATED SIGNALLING PATHWAYS MEDIATE UP-REGULATION OF NADPH OXIDASE, INFLAMMATION, AND FIBROSIS IN DIABETIC KIDNEY. ACCUMULATING EVIDENCE IMPLICATES THE HISTONE ACETYLATION-BASED EPIGENETIC MECHANISMS IN THE PATHOETIOLOGY OF DIABETES-ASSOCIATED MICRO-/MACROVASCULAR COMPLICATIONS. DIABETIC KIDNEY DISEASE (DKD) IS A PROGRESSIVE CHRONIC INFLAMMATORY MICROVASCULAR DISORDER ULTIMATELY LEADING TO GLOMERULOSCLEROSIS AND KIDNEY FAILURE. WE HYPOTHESIZED THAT HISTONE ACETYLTRANSFERASE P300/CBP MAY BE INVOLVED IN MEDIATING DIABETES-ACCELERATED RENAL DAMAGE. IN THIS STUDY, WE AIMED AT INVESTIGATING THE POTENTIAL ROLE OF P300/CBP IN THE UP-REGULATION OF RENAL NADPH OXIDASE (NOX), REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, INFLAMMATION, AND FIBROSIS IN DIABETIC MICE. DIABETIC C57BL/6J MICE WERE RANDOMIZED TO RECEIVE 10 MG/KG C646, A SELECTIVE P300/CBP INHIBITOR, OR ITS VEHICLE FOR 4 WEEKS. WE FOUND THAT IN THE KIDNEY OF C646-TREATED DIABETIC MICE, THE LEVEL OF H3K27AC, AN EPIGENETIC MARK OF ACTIVE GENE EXPRESSION, WAS SIGNIFICANTLY REDUCED. PHARMACOLOGICAL INHIBITION OF P300/CBP SIGNIFICANTLY DOWN-REGULATED THE DIABETES-INDUCED ENHANCED EXPRESSION OF NOX SUBTYPES, PRO-INFLAMMATORY, AND PRO-FIBROTIC MOLECULES IN THE KIDNEY OF MICE, AND THE GLOMERULAR ROS OVERPRODUCTION. OUR STUDY PROVIDES EVIDENCE THAT THE ACTIVATION OF P300/CBP ENHANCES ROS PRODUCTION, POTENTIALLY GENERATED BY UP-REGULATED NOX, INFLAMMATION, AND THE PRODUCTION OF EXTRACELLULAR MATRIX PROTEINS IN THE DIABETIC KIDNEY. THE DATA SUGGEST THAT P300/CBP-PHARMACOLOGICAL INHIBITORS MAY BE ATTRACTIVE TOOLS TO MODULATE DIABETES-ASSOCIATED PATHOLOGICAL PROCESSES TO EFFICIENTLY REDUCE THE BURDEN OF DKD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
19   907  24 CHRONIC EXPOSURE TO ENVIRONMENTALLY RELEVANT CONCENTRATION OF FLUORIDE ALTERS OGG1 AND RAD51 EXPRESSIONS IN MICE: INVOLVEMENT OF EPIGENETIC REGULATION. CHRONIC EXPOSURE TO FLUORIDE (F) BEYOND THE PERMISSIBLE LIMIT (1.5 PPM) IS KNOWN TO CAUSE DETRIMENTAL HEALTH EFFECTS BY INDUCTION OF OXIDATIVE STRESS-MEDIATED DNA DAMAGE OVERPOWERING THE DNA REPAIR MACHINERY. IN THE PRESENT STUDY, WE ASSESSED F INDUCED OXIDATIVE STRESS THROUGH MONITORING BIOCHEMICAL PARAMETERS AND LOOKED INTO THE EFFECT OF CHRONIC F EXPOSURE ON TWO CRUCIAL DNA REPAIR GENES OGG1 AND RAD51 HAVING IMPORTANT ROLE AGAINST ROS INDUCED DNA DAMAGES. TO ADDRESS THIS ISSUE, WE EXPOSED SWISS ALBINO MICE TO AN ENVIRONMENTALLY RELEVANT CONCENTRATION OF FLUORIDE (15 PPM NAF) FOR 8 MONTHS. RESULTS REVEALED HISTOARCHITECTURAL DAMAGES IN LIVER, BRAIN, KIDNEY AND SPLEEN. DEPLETION OF GSH, INCREASE IN LIPID PEROXIDATION AND CATALASE ACTIVITY IN LIVER AND BRAIN CONFIRMED THE GENERATION OF OXIDATIVE STRESS. QRT-PCR RESULT SHOWED THAT EXPRESSIONS OF OGG1 AND RAD51 WERE ALTERED AFTER F EXPOSURE IN THE AFFECTED ORGANS. PROMOTER HYPERMETHYLATION WAS ASSOCIATED WITH THE DOWNREGULATION OF RAD51. F-INDUCED DNA DAMAGE AND THE COMPROMISED DNA REPAIR MACHINERY TRIGGERED INTRINSIC PATHWAY OF APOPTOSIS IN LIVER AND BRAIN. THE PRESENT STUDY INDICATES THE POSSIBLE ASSOCIATION OF EPIGENETIC REGULATION WITH F INDUCED NEUROTOXICITY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  3940  37 LNCRNA DLEU2 REGULATES SIRTUINS AND MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX IV: A NOVEL PATHWAY IN OBESITY AND OFFSPRING'S HEALTH. BACKGROUND: LONG NON-CODING RNAS (LNCRNAS) HAVE EMERGED AS A RAPIDLY EXPANDING AREA OF INTEREST IN CHRONIC DISEASES. THEY ARE MOSTLY UNKNOWN FOR ROLES IN METABOLIC REGULATION. SIRTUINS, AN EPIGENETIC MODULATOR CLASS, REGULATE METABOLIC PATHWAYS. HOWEVER, HOW SIRTUINS ARE REGULATED VIA LNCRNA IS UNKNOWN. WE HYPOTHESIZED THAT A HIGH-FAT HIGH-FRUCTOSE DIET (HFD-HF) DURING PREGNANCY WOULD INCREASE THE RISK FOR OBESITY VIA LNCRNA-SIRTUIN PATHWAYS. METHODS: FEMALE C57BL/6 MICE (F0) WERE FED EITHER CHOW DIET (CD) OR HFD-HF FOR 6 WEEKS TILL BIRTH. THE PUPS (F1) WERE FED EITHER CD OR HFD-HF FOR 20 WEEKS. EXPRESSION OF DLEU2, SIRTUINS, MITOCHONDRIAL RESPIRATORY COMPLEXES, AND OXIDATIVE STRESS WERE INVESTIGATED IN THE F1 LIVERS. FASTING BLOOD GLUCOSE, INSULIN SENSITIVITY, GLUCOSE TOLERANCE, BODY AND TISSUES WEIGHT WERE MEASURED. A MECHANISTIC INTERACTION WAS THEN CARRIED OUT USING A DLEU2 KNOCKDOWN EXPERIMENT IN THE HEPG2 CELL. RESULTS: DLEU2 AND SIRTUINS WERE BOTH SIGNIFICANTLY DECREASED IN THE LIVERS OF HFD-HF FED MALE F1 WHOSE MOTHERS WERE EITHER FED CD OR HFD-HF DURING REPRODUCTIVE AND PREGNANCY WINDOWS. CONFIRMING THIS CONNECTION, UPON SILENCING DLEU2, TRANSCRIPTION LEVELS OF SIRT1 THROUGH 6 AND TRANSLATIONAL LEVELS OF SIRT1, 3, 5, AND 6 WERE SIGNIFICANTLY DOWNREGULATED. KNOCKDOWN OF DLEU2 SIGNIFICANTLY DECREASED THE PROTEIN LEVEL OF CYTOCHROME-C OXIDASE (COMPLEX IV, MTCO1) WITHOUT ALTERING OTHER MITOCHONDRIAL COMPLEXES, DECREASED MITOCHONDRIAL MEMBRANE POTENTIAL, DECREASED ATP, AND INCREASED REACTIVE OXYGEN SPECIES. INTERESTINGLY, IN F1 LIVERS, THE PROTEIN LEVEL OF MTCO1 WAS ALSO SIGNIFICANTLY DECREASED UNDER AN HFD-HF DIET OR EVEN UNDER CHOW DIET IF THE MOTHER WAS EXPOSED TO HFD-HF. CONCLUSION: OUR FINDINGS REVEAL FOR THE FIRST TIME THAT ONE LNCRNA CAN REGULATE SIRTUINS AND A SPECIFIC MITOCHONDRIAL COMPLEX. FURTHERMORE, DIET OR MATERNAL DIET CAN MODULATE DLEU2 AND ITS DOWNSTREAM REGULATORS IN OFFSPRING, SUGGESTING A POTENTIAL ROLE OF DLEU2 IN METABOLIC DISORDERS OVER ONE OR MORE GENERATIONS.	2022