1 2706 231 EXERCISE ATTENUATES LOW BACK PAIN AND ALTERS EPIGENETIC REGULATION IN INTERVERTEBRAL DISCS IN A MOUSE MODEL. BACKGROUND CONTEXT: CHRONIC LOW BACK PAIN (LBP) IS A MULTIFACTORIAL DISORDER WITH COMPLEX UNDERLYING MECHANISMS, INCLUDING ASSOCIATIONS WITH INTERVERTEBRAL DISC (IVD) DEGENERATION IN SOME INDIVIDUALS. IT HAS BEEN DEMONSTRATED THAT EPIGENETIC PROCESSES ARE INVOLVED IN THE PATHOLOGY OF IVD DEGENERATION. EPIGENETICS REFERS TO SEVERAL MECHANISMS, INCLUDING DNA METHYLATION, THAT HAVE THE ABILITY TO CHANGE GENE EXPRESSION WITHOUT INDUCING ANY CHANGE IN THE UNDERLYING DNA SEQUENCE. DNA METHYLATION CAN ALTER THE ENTIRE STATE OF A TISSUE FOR AN EXTENDED PERIOD OF TIME AND THUS COULD POTENTIALLY BE HARNESSED FOR LONG-TERM PAIN RELIEF. LIFESTYLE FACTORS, SUCH AS PHYSICAL ACTIVITY, HAVE A STRONG INFLUENCE ON EPIGENETIC REGULATION. EXERCISE IS A COMMONLY PRESCRIBED TREATMENT FOR CHRONIC LBP, AND SEX-SPECIFIC EPIGENETIC ADAPTATIONS IN RESPONSE TO ENDURANCE EXERCISE HAVE BEEN REPORTED. HOWEVER, WHETHER EXERCISE INTERVENTIONS THAT ATTENUATE LBP ARE ASSOCIATED WITH EPIGENETIC ALTERATIONS IN DEGENERATING IVDS HAS NOT BEEN EVALUATED. PURPOSE: WE HYPOTHESIZE THAT THE THERAPEUTIC EFFICACY OF PHYSICAL ACTIVITY IS MEDIATED, AT LEAST IN PART, AT THE EPIGENETIC LEVEL. THE PURPOSE OF THIS STUDY WAS TO USE THE SPARC-NULL MOUSE MODEL OF LBP ASSOCIATED WITH IVD DEGENERATION TO CLARIFY (1) IF IVD DEGENERATION IS ASSOCIATED WITH ALTERED EXPRESSION OF EPIGENETIC REGULATORY GENES IN THE IVDS, (2) IF EPIGENETIC REGULATORY MACHINERY IS SENSITIVE TO THERAPEUTIC ENVIRONMENTAL INTERVENTION, AND (3) IF THERE ARE SEX-SPECIFIC DIFFERENCES IN (1) AND/OR (2). STUDY DESIGN: EIGHT-MONTH-OLD MALE AND FEMALE SPARC-NULL AND AGE-MATCHED CONTROL (WT) MICE (N=108) WERE ASSIGNED TO EXERCISE (N=56) OR SEDENTARY (N=52) GROUPS. DELETION OF SPARC IS ASSOCIATED WITH PROGRESSIVE IVD DEGENERATION AND BEHAVIORAL SIGNS OF LBP. THE EXERCISE GROUP RECEIVED A CIRCULAR PLASTIC HOME CAGE RUNNING WHEEL ON WHICH THEY COULD RUN FREELY. THE SEDENTARY GROUP RECEIVED AN IDENTICAL WHEEL SECURED IN PLACE TO PREVENT ROTATION. AFTER 6 MONTHS, THE RESULTS OBTAINED IN EACH GROUP WERE COMPARED. METHODS: AFTER 6 MONTHS OF EXERCISE, LBP-RELATED BEHAVIORAL INDICES WERE DETERMINED, AND GLOBAL DNA METHYLATION (5-METHYLCYTOSINE) AND EPIGENETIC REGULATORY GENE MRNA EXPRESSION IN IVDS WERE ASSESSED. THIS PROJECT WAS SUPPORTED BY THE CANADIAN INSTITUTES FOR HEALTH RESEARCH. THE AUTHORS HAVE NO CONFLICTS OF INTEREST. RESULTS: LUMBAR IVDS FROM WT SEDENTARY AND SPARC-NULL SEDENTARY MICE HAD SIMILAR LEVELS OF GLOBAL DNA METHYLATION (%5-MC) AND COMPARABLE MRNA EXPRESSION OF EPIGENETIC REGULATORY GENES (DNMT1,3A,B, MECP2, MBD2A,B, TET1-3) IN BOTH SEXES. EXERCISE ATTENUATED LBP-RELATED BEHAVIORS, DECREASED GLOBAL DNA METHYLATION IN BOTH WT (P<.05) AND SPARC-NULL MICE (P<.01) AND REDUCED MRNA EXPRESSION OF MECP2 IN SPARC-NULL MICE (P<.05). SEX-SPECIFIC EFFECTS OF EXERCISE ON EXPRESSION OF MRNA WERE ALSO OBSERVED. CONCLUSIONS: EXERCISE ALLEVIATES LBP IN A MOUSE MODEL. THIS MAY BE MEDIATED, IN PART, BY CHANGES IN THE EPIGENETIC REGULATORY MACHINERY IN DEGENERATING IVDS. EPIGENETIC ALTERATIONS DUE TO A LIFESTYLE CHANGE COULD HAVE A LONG-LASTING THERAPEUTIC IMPACT BY CHANGING TISSUE HOMEOSTASIS IN IVDS. CLINICAL SIGNIFICANCE: THIS STUDY CONFIRMED THE THERAPEUTIC BENEFITS OF EXERCISE ON LBP AND SUGGESTS THAT EXERCISE RESULTS IN SEX-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION IN IVDS. ELUCIDATING THE EFFECTS OF EXERCISE ON EPIGENETIC REGULATION MAY ENABLE THE DISCOVERY OF NOVEL GENE TARGETS OR NEW STRATEGIES TO IMPROVE THE TREATMENT OF CHRONIC LBP.	2021	

2 2297  41 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3 1567  46 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4 2119  40 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
5 6720  50 VITAMIN D METABOLISM GENES ARE DIFFERENTIALLY METHYLATED IN INDIVIDUALS WITH CHRONIC KNEE PAIN. CONTEXT: RECENT EVIDENCE SUGGESTS THAT VITAMIN D MAY INTERACT WITH THE EPIGENOME AND PLAY A ROLE IN THE PAIN EXPERIENCE. IN ORDER FOR PROPER FUNCTIONING TO OCCUR, THERE MUST BE AN ADEQUATE LEVEL OF VITAMIN D PRESENT, MADE POSSIBLE BY ENZYMATIC REACTIONS THAT ALLOW VITAMIN D TO BE BIOLOGICALLY ACTIVE. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE EPIGENETIC LANDSCAPE OF GENES INVOLVED IN VITAMIN D METABOLISM IN INDIVIDUALS WITH AND WITHOUT CHRONIC KNEE PAIN. PROCEDURES: COMMUNITY-DWELLING INDIVIDUALS RECRUITED AS PART OF A LARGER STUDY FOCUSED ON KNEE PAIN PROVIDED DEMOGRAPHIC, CLINICAL AND PAIN-RELATED INFORMATION, AS WELL AS AN INTRAVENOUS BLOOD SAMPLE TO DETERMINE DNA METHYLATION LEVELS AT CPG SITES. MAIN FINDINGS: THERE WERE DIFFERENCES IN DNA METHYLATION BETWEEN THOSE WITH AND WITHOUT PAIN IN GENES THAT CODE FOR ENZYMES RELATED TO VITAMIN D METABOLISM: CYP24A1 (24-HYDROXYLASE) AND CYP27B1 (1-?-HYDROXYLASE). THERE WAS ALSO HYPERMETHYLATION ON THE GENE THAT CODES FOR THE VITAMIN D RECEPTOR (VDR). PRINCIPAL CONCLUSIONS: THE PRESENCE OF CHRONIC PAIN IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS IN GENES RESPONSIBLE FOR THE EXPRESSION OF ENZYMES INVOLVED IN VITAMIN D METABOLISM AND CELLULAR FUNCTION. THESE RESULTS LAY GROUNDWORK IN UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION BETWEEN VITAMIN D AND CHRONIC PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6 5894  50 T CELL EPIGENETIC REMODELING AND ACCELERATED EPIGENETIC AGING ARE LINKED TO LONG-TERM IMMUNE ALTERATIONS IN CHILDHOOD CANCER SURVIVORS. BACKGROUND: CANCER TREATMENTS HAVE SUBSTANTIALLY IMPROVED CHILDHOOD CANCER SURVIVAL BUT ARE ACCOMPANIED BY LONG-TERM COMPLICATIONS, NOTABLY CHRONIC INFLAMMATORY DISEASES. WE HYPOTHESIZE THAT CANCER TREATMENTS COULD LEAD TO LONG-TERM EPIGENETIC CHANGES IN IMMUNE CELLS, RESULTING IN INCREASED PREVALENCE OF INFLAMMATORY DISEASES IN CANCER SURVIVORS. RESULTS: TO TEST THIS HYPOTHESIS, WE ESTABLISHED THE EPIGENETIC AND TRANSCRIPTOMIC PROFILES OF IMMUNE CELLS FROM 44 CHILDHOOD CANCER SURVIVORS (CCS, > 16 YEARS OLD) ON FULL REMISSION (> 5 YEARS) WHO HAD RECEIVED CHEMOTHERAPY ALONE OR IN COMBINATION WITH TOTAL BODY IRRADIATION (TBI) AND HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). WE FOUND THAT MORE THAN 10 YEARS POST-TREATMENT, CCS TREATED WITH TBI/HSCT SHOWED AN ALTERED DNA METHYLATION SIGNATURE IN T CELL, PARTICULARLY AT GENES CONTROLLING IMMUNE AND INFLAMMATORY PROCESSES AND OXIDATIVE STRESS. DNA METHYLATION REMODELING IN T CELL WAS PARTIALLY ASSOCIATED WITH CHRONIC EXPRESSION CHANGES OF NEARBY GENES, INCREASED FREQUENCY OF TYPE 1 CYTOKINE-PRODUCING T CELL, ELEVATED SYSTEMIC LEVELS OF THESE CYTOKINES, AND OVER-ACTIVATION OF RELATED SIGNALING PATHWAYS. SURVIVORS EXPOSED TO TBI/HSCT WERE FURTHER CHARACTERIZED BY AN EPIGENETIC-AGING-SIGNATURE OF T CELL CONSISTENT WITH ACCELERATED EPIGENETIC AGING. TO INVESTIGATE THE POTENTIAL CONTRIBUTION OF IRRADIATION TO THESE CHANGES, WE ESTABLISHED TWO CELL CULTURE MODELS. WE IDENTIFIED THAT RADIATION PARTIALLY RECAPITULATED THE IMMUNE CHANGES OBSERVED IN SURVIVORS THROUGH A BYSTANDER EFFECT THAT COULD BE MEDIATED BY CIRCULATING FACTORS. CONCLUSION: CANCER TREATMENTS, IN PARTICULAR TBI/HSCT, ARE ASSOCIATED WITH LONG-TERM IMMUNE DISTURBANCES. WE PROPOSE THAT EPIGENETIC REMODELING OF IMMUNE CELLS FOLLOWING CANCER THERAPY AUGMENTS INFLAMMATORY- AND AGE-RELATED DISEASES, INCLUDING METABOLIC COMPLICATIONS, IN CHILDHOOD CANCER SURVIVORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7 3076  46 GENOME-WIDE EPIGENOMIC ANALYSES IN PATIENTS WITH NOCICEPTIVE AND NEUROPATHIC CHRONIC PAIN SUBTYPES REVEALS ALTERATIONS IN METHYLATION OF GENES INVOLVED IN THE NEURO-MUSCULOSKELETAL SYSTEM. NOCICEPTIVE PAIN INVOLVES THE ACTIVATION OF NOCICEPTORS WITHOUT DAMAGE TO THE NERVOUS SYSTEM, WHEREAS NEUROPATHIC PAIN IS RELATED TO AN ALTERATION IN THE CENTRAL OR PERIPHERAL NERVOUS SYSTEM. CHRONIC PAIN ITSELF AND THE TRANSITION FROM ACUTE TO CHRONIC PAIN MAY BE EPIGENETICALLY CONTROLLED. IN THIS CROSS-SECTIONAL STUDY, A GENOME-WIDE DNA METHYLATION ANALYSIS WAS PERFORMED USING THE BLOOD DNA REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) TECHNIQUE. THREE PROSPECTIVE COHORTS INCLUDING 20 HEALTHY CONTROLS (CTL), 18 PATIENTS WITH CHRONIC NOCICEPTIVE PAIN (NOCI), AND 19 PATIENTS WITH CHRONIC NEUROPATHIC PAIN (NEURO) WERE COMPARED AT BOTH THE SINGLE CPG AND DIFFERENTIALLY METHYLATED REGION (DMR) LEVELS. GENES WITH DMRS WERE SEEN IN THE NOCI AND NEURO GROUPS BELONGED TO THE NEURO-MUSCULOSKELETAL SYSTEM AND DIFFERED BETWEEN NOCI AND NEURO PATIENTS. OUR RESULTS DEMONSTRATE THAT THE EPIGENETIC DISTURBANCES ACCOMPANYING NOCICEPTIVE PAIN ARE VERY DIFFERENT FROM THOSE ACCOMPANYING NEUROPATHIC PAIN. IN THE FORMER, AMONG OTHERS, THE EPIGENETIC DISTURBANCE OBSERVED WOULD AFFECT THE FUNCTION OF THE OPIOID ANALGESIC SYSTEM, WHEREAS IN THE LATTER IT WOULD AFFECT THAT OF THE GABAERGIC REWARD SYSTEM. THIS STUDY PRESENTS BIOLOGICAL FINDINGS THAT HELP TO CHARACTERIZE NOCI- AND NEURO-AFFECTED PATHWAYS AND OPENS THE POSSIBILITY OF DEVELOPING EPIGENETIC DIAGNOSTIC ASSAYS. PERSPECTIVE: OUR RESULTS HELP TO EXPLAIN THE VARIOUS BIOLOGICAL PATHWAYS MODIFICATIONS UNDERLYING THE DIFFERENT CLINICAL MANIFESTATIONS OF NOCICEPTIVE AND NEUROPATHIC PAINS. FURTHERMORE, THE NEW TARGETS IDENTIFIED IN OUR STUDY MIGHT HELP TO DISCOVER MORE SPECIFIC TREATMENTS FOR NOCICEPTIVE OR NEUROPATHIC PAINS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8 2408  36 EPIGENETIC REWIRING OF SKELETAL MUSCLE ENHANCERS AFTER EXERCISE TRAINING SUPPORTS A ROLE IN WHOLE-BODY FUNCTION AND HUMAN HEALTH. OBJECTIVES: REGULAR PHYSICAL EXERCISE IMPROVES HEALTH BY REDUCING THE RISK OF A PLETHORA OF CHRONIC DISORDERS. WE HYPOTHESIZED THAT ENDURANCE EXERCISE TRAINING REMODELS THE ACTIVITY OF GENE ENHANCERS IN SKELETAL MUSCLE AND THAT THIS REMODELING CONTRIBUTES TO THE BENEFICIAL EFFECTS OF EXERCISE ON HUMAN HEALTH. METHODS AND RESULTS: BY STUDYING CHANGES IN HISTONE MODIFICATIONS, WE MAPPED THE GENOME-WIDE POSITIONS AND ACTIVITIES OF ENHANCERS IN SKELETAL MUSCLE BIOPSIES COLLECTED FROM YOUNG SEDENTARY MEN BEFORE AND AFTER 6 WEEKS OF ENDURANCE EXERCISE. WE IDENTIFIED EXTENSIVE REMODELING OF ENHANCER ACTIVITIES AFTER EXERCISE TRAINING, WITH A LARGE SUBSET OF THE REMODELED ENHANCERS LOCATED IN THE PROXIMITY OF GENES TRANSCRIPTIONALLY REGULATED AFTER EXERCISE. BY OVERLAPPING THE POSITION OF ENHANCERS WITH GENETIC VARIANTS, WE IDENTIFIED AN ENRICHMENT OF DISEASE-ASSOCIATED GENETIC VARIANTS WITHIN THE EXERCISE-REMODELED ENHANCERS. CONCLUSION: OUR DATA PROVIDE EVIDENCE OF A FUNCTIONAL LINK BETWEEN EPIGENETIC REWIRING OF ENHANCERS TO CONTROL THEIR ACTIVITY AFTER EXERCISE TRAINING AND THE MODULATION OF DISEASE RISK IN HUMANS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9 2108  41 EPIGENETIC FACTORS RELATED TO LOW BACK PAIN: A SYSTEMATIC REVIEW OF THE CURRENT LITERATURE. LOW BACK PAIN (LBP) IS ONE OF THE MOST COMMON CAUSES OF PAIN AND DISABILITY. AT PRESENT, TREATMENT AND INTERVENTIONS FOR ACUTE AND CHRONIC LOW BACK PAIN OFTEN FAIL TO PROVIDE SUFFICIENT LEVELS OF PAIN RELIEF, AND FULL FUNCTIONAL RESTORATION CAN BE CHALLENGING. CONSIDERING THE SIGNIFICANT SOCIO-ECONOMIC BURDEN AND RISK-TO-BENEFIT RATIO OF MEDICAL AND SURGICAL INTERVENTION IN LOW BACK PAIN PATIENTS, THE IDENTIFICATION OF RELIABLE BIOMARKERS SUCH AS EPIGENETIC FACTORS ASSOCIATED WITH LOW BACK PAIN COULD BE USEFUL IN CLINICAL PRACTICE. THE AIM OF THIS STUDY WAS TO REVIEW THE AVAILABLE LITERATURE REGARDING THE EPIGENETIC FACTORS ASSOCIATED WITH LOW BACK PAIN. THIS REVIEW WAS CARRIED OUT IN ACCORDANCE WITH PREFERENTIAL REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES (PRISMA) GUIDELINES. THE SEARCH WAS CARRIED OUT IN OCTOBER 2022. ONLY PEER-REVIEWED ARTICLES WERE CONSIDERED FOR INCLUSION. FOURTEEN STUDIES WERE INCLUDED AND SHOWED PROMISING RESULTS IN TERMS OF RELIABLE MARKERS. EPIGENETIC MARKERS FOR LBP HAVE THE POTENTIAL TO SIGNIFICANTLY MODIFY DISEASE MANAGEMENT. MOST RECENT EVIDENCE SUGGESTS THAT EPIGENETICS IS A MORE PROMISING FIELD FOR THE IDENTIFICATION OF FACTORS ASSOCIATED WITH LBP, OFFERING A RATIONALE FOR FURTHER INVESTIGATION IN THIS FIELD WITH THE LONG-TERM GOAL OF FINDING EPIGENETIC BIOMARKERS THAT COULD CONSTITUTE BIOLOGICAL TARGETS FOR DISEASE MANAGEMENT AND TREATMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10 1820  50 EFFECTS OF CHRONIC RESTRAINT STRESS ON THE GLOBAL DNA METHYLATION PROFILE OF RAT LUNG CELLS: MODULATION BY PHYSICAL EXERCISE. THE POTENTIAL OF BEHAVIORAL STRESS TO AFFECT EPIGENETIC MECHANISMS OF NON-ENCEPHALIC TISSUES IS STILL UNDERESTIMATED. IN THE PRESENT STUDY WE EVALUATED THE EFFECTS OF CHRONIC BEHAVIORAL STRESS ON THE DNA METHYLATION PROFILE OF RAT LUNG CELLS. FURTHERMORE, WE EVALUATED THE POTENTIAL OF PHYSICAL EXERCISE TO MODULATE THE CHANGES EVOKED BY BEHAVIORAL STRESS IN LUNG CELLS. MALE WISTAR RATS WERE DIVIDED INTO FOUR EXPERIMENTAL GROUPS: (1) ANIMALS SUBMITTED TO CHRONIC RESTRAINT STRESS (CRS) (ST GROUP) DURING THE PERIOD OF THE 67TH-80TH POSTNATAL DAY (PND); (2) ANIMALS SUBMITTED TO PHYSICAL EXERCISE (EX GROUP) DURING THE 53RD-79TH PND; (3) ANIMALS SUBMITTED TO SWIMMING DURING THE 53RD-79TH PND AND TO CRS DURING THE 67TH-80TH PND (EX-ST GROUP); AND (4) ANIMALS NOT SUBMITTED TO STRESS OR SWIMMING PROTOCOLS (CTL). GLOBAL DNA METHYLATION WAS QUANTIFIED USING AN ELISA-BASED APPROACH AND GENE EXPRESSION WAS EVALUATED BY REAL TIME PCR. A DECREASED GLOBAL DNA METHYLATION PROFILE WAS OBSERVED IN THE ST GROUP, HOWEVER PHYSICAL EXERCISE DEMONSTRATED PROTECTION OF LUNG CELLS FROM THIS STRESS-RELATED HYPOMETHYLATION. INCREASED EXPRESSION OF THE DNMT1 GENE WAS EVIDENCED IN THE ST GROUP, WHEREAS PHYSICAL EXERCISE WAS SHOWN TO PROTECT LUNG CELLS FROM THIS STRESS-RELATED EFFECT IN THE EX-ST GROUP. COMPARATIVE ANALYSIS OF THE ST AND EX GROUPS REVEALED OPPOSITE EFFECTS ON THE EXPRESSION OF DNMT3A AND DNMT3B; HOWEVER, A STRESS-RELATED INCREASE IN EXPRESSION OF DNMT3A AND DNMT3B WAS NOT SEEN IN THE EX-ST GROUP. OUR DATA SHOWED THAT BEHAVIORAL STRESS INDUCED SIGNIFICANT CHANGES IN THE DNA METHYLATION PROFILE OF RAT LUNG CELLS AND THAT THIS COULD BE MODULATED BY PHYSICAL EXERCISE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11 6794  49 [EFFECT OF BENZO(A)PYRENE ON THE EXPRESSION OF AHR-REGULATED MICRORNA IN FEMALE AND MALE RAT LUNGS]. SMOKING IS THE MAIN RISK FACTOR FOR LUNG CANCER, MAINLY DUE TO PRESENCE OF NITROSAMINES AND POLYCYCLIC AROMATIC HYDROCARBONS, INCLUDING BENZO[A]PYRENE (BP) IN TOBACCO SMOKE COMPOSITION. THE GENOTOXIC EFFECT OF BP IS BASED ON THE HIGH DNA-BINDING ABILITY OF ITS METABOLITES, WHILE THE EPIGENETIC EFFECTS ARE MEDIATED BY A CHANGE IN THE EXPRESSION OF CANCER RELATED GENES OR REGULATORY RNAS. IT HAS BEEN SHOWN THAT WOMEN HAVE A HIGHER RISK TO DEVELOP LUNG CANCER UPON SMOKING RATHER THAN MEN. WE HYPOTHESIZED THAT CROSSTALK BETWEEN SIGNALING PATHWAYS ACTIVATED BY BP AND ESTROGENS COULD UNDERLIE THE SEX-DEPENDENT DIFFERENCES IN MIRNAS EXPRESSION. TO TEST THIS HYPOTHESIS, MALE AND FEMALE RATS WERE SUBJECTED TO SHORT-TERM OR LONG-TERM BP EXPOSURE. USING IN SILICO ANALYSIS, MIRNAS CONTAINING THE ER- AND AHR-BINDING SITES IN THE PROMOTERS OF THE GENES (OR HOST GENES) WERE SELECTED. DURING CHRONIC EXPOSURE OF BP THE EXPRESSION OF MIR-22-3P, -29A-3P, -126A-3P, -193B-5P IN THE LUNGS OF MALE RATS WERE SIGNIFICANTLY INCREASED, WHILE THE LEVEL OF MIRNA-483-3P WERE DECREASED. EXPRESSION OF MIRNA-483-3P WAS UP-REGULATED DURING CHRONIC BP EXPOSURE IN THE LUNGS OF FEMALE RATS AND THE LEVELS OF OTHER STUDIED MIRNAS WERE UNCHANGED. IN TURN, CHANGES IN THE EXPRESSION OF MIRNAS WERE FOLLOWED BY CHANGES IN THE EXPRESSION OF THEIR TARGET GENES, INCLUDING PTEN, EMP2, IGF1, ITGA6, SLC34A2, AND THE OBSERVED CHANGES IN FEMALE AND MALE RAT LUNGS WERE VARIED. THUS, OUR RESULTS SUGGEST THAT SEX-DEPENDENT EPIGENETIC EFFECTS OF BP MAY BE BASED ON DIFFERENT EXPRESSION OF AHR- AND ER- REGULATED MIRNAS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12  344  54 ALTERED BDNF METHYLATION IN PATIENTS WITH CHRONIC MUSCULOSKELETAL PAIN AND HIGH BIOPSYCHOSOCIAL COMPLEXITY. PURPOSE: THE INTERMED INSTRUMENT, WHICH WAS DEVELOPED TO MEASURE PATIENT'S BIOPSYCHOSOCIAL (BPS) COMPLEXITY, REPRESENTS A POWERFUL DIAGNOSTIC AND THERAPEUTIC TOOL. EPIGENETIC CHANGES ARE THE INTERFACE BETWEEN SIGNALS FROM THE ENVIRONMENT AND GENETIC MODIFICATIONS, AFFECTING GENE EXPRESSION, IN PARTICULAR, BY DNA METHYLATION OF CPG DINUCLEOTIDES IN PROMOTOR REGIONS OF THE CORRESPONDING GENES. THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) GENE PLAYS A CRUCIAL ROLE IN THE CENTRAL SENSITIZATION (CS) OF PAIN. IN THIS STUDY, WE HYPOTHESIZED THAT CHRONIC PAIN MODIFIES THE METHYLATION LEVELS OF THE BDNF GENE IN A MANNER THAT IS INTERCONNECTED WITH THE BPS STATUS. PATIENTS AND METHODS: FIFTY-EIGHT CHRONIC MUSCULOSKELETAL PAIN PATIENTS (CMSP) WERE ENROLLED IN THE STUDY. DNA WAS EXTRACTED FROM BLOOD SAMPLES, THE METHYLATION LEVELS OF 13 CPG SITES IN THE BDNF PROMOTER WERE MEASURED BY PYROSEQUENCING, AND ASSOCIATION STUDIES WITH VARIOUS PATIENT PARAMETERS AND THE INTERMED SCORES WERE PERFORMED. RESULTS: INTERESTINGLY, A NEGATIVE CORRELATION (-0.40) WAS FOUND BETWEEN THE TOTAL INTERMED SCORES AND THE AVERAGE CPG METHYLATION VALUES OF THE BDNF GENE, BUT NO CORRELATION WAS OBSERVED WITH THE SEVERITY OF PAIN, DEGREE OF ANXIETY, DEPRESSION, OR KINESIOPHOBIA AND CATASTROPHISM. MOREOVER, THE ASSOCIATION WAS INDEPENDENT OF AGE, SEX AND LEVEL OF COMORBIDITIES. CONCLUSION: THIS RESULT SHOWS THAT CMSP, IN ASSOCIATION WITH ITS BIOPSYCHOSOCIAL CONTEXT, EPIGENETICALLY DECREASES THE DEGREE OF METHYLATION OF THE BDNF PROMOTER AND SHOULD THEREFORE INCREASE THE LEVEL OF BDNF TRANSCRIPTION. IT ALSO SUGGESTS A ROLE OF THE INTERMED TOOL TO DETECT A RELATIONSHIP BETWEEN THE BPS COMPLEXITY AND THE EPIGENETIC CONTROL OF A TARGET GENE. THE POSSIBLE UPREGULATION OF BDNF EXPRESSION MIGHT BE, AT LEAST IN PART, THE SIGNAL FOR CHRONIC PAIN-INDUCED CENTRAL SENSITIZATION (CS). THIS COULD PARTLY EXPLAIN WHY PATIENTS WITH A HIGHER LEVEL OF COMPLEXITY FEEL MORE PAIN THAN THOSE WITH LOWER COMPLEXITY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13 6564  54 TRANSIENT EXPOSURE TO ELEVATED GLUCOSE LEVELS CAUSES PERSISTENT CHANGES IN DERMAL MICROVASCULAR ENDOTHELIAL CELL RESPONSES TO INJURY. BACKGROUND: THE PURPOSE OF THIS STUDY WAS TO DETERMINE WHETHER ELEVATED GLUCOSE CAN INDUCE A DERMAL MICROVASCULAR ENDOTHELIAL CELL METABOLIC MEMORY, THUS AFFECTING ANGIOGENESIS IN THE REPAIR PROCESS OF MAMMALIAN CUTANEOUS WOUND. WE HYPOTHESIZED THAT TRANSIENT ELEVATED GLUCOSE LEVELS CAUSE SUSTAINED ALTERATION OF ENDOTHELIAL CELL RESPONSES TO INJURY AND PERSISTENT EPIGENETIC CHANGES IN GENE EXPRESSION. METHODS: HUMAN DERMAL MICROVASCULAR ENDOTHELIAL CELLS WERE EXPOSED TO EXPERIMENTAL CONDITIONS WITH OR WITHOUT 30 MM D-GLUCOSE. THE CONTROL GROUP WAS MAINTAINED AT 5 MM D-GLUCOSE; WHILE IN THE TRANSIENT GLUCOSE GROUP, AFTER BEING EXPOSED TO 30 MM D-GLUCOSE FOR TWO DAYS, THEN BEING PUT UNDER THE CONTROL CONDITIONS DURING THE EXPERIMENT. BESIDES, IN THE WHOLE PROCESS OF THE EXPERIMENT, THE CHRONIC GLUCOSE GROUP WAS KEPT IN THE CONDITION WITH 30 MM D-GLUCOSE. PROLIFERATION, MIGRATION, TUBE FORMATION, GENE EXPRESSION AND HISTONE METHYLATION WERE ASSESSED FOR INDIVIDUAL CONDITIONS. RESULTS: TRANSIENT ELEVATED GLUCOSE CAUSED SUSTAINED EFFECTS ON ENDOTHELIAL CELL MIGRATION, TUBE FORMATION AND TIMP3 GENE EXPRESSION. THE EFFECTS ON TIMP3 EXPRESSION WERE ASSOCIATED WITH PERSISTENT CHANGES IN HISTONE MODIFICATION AT THE 5' END OF THE TIMP3 GENE, SUGGESTING AN EPIGENETIC EFFECT. CONCLUSIONS: HYPERGLYCEMIA INDUCED METABOLIC MEMORY COULD PROMOTE THE REGULATION OF TIMP3, AND IT CAN BE USED AS A POSSIBLE INNOVATIVE MOLECULAR TARGET FOR THERAPEUTIC INTERVENTION IN THE TREATMENT OF CHRONIC NON-HEALING DIABETIC WOUNDS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
14 6895  37 [SYSTEMIC CONTROL OF THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF LONG-LASTING CONSEQUENCES OF STRESS]. BASED ON M.E. LOBASHEV'S VIEWS OF THE SYSTEMIC CONTROL OF GENETIC AND CYTOGENEITC PROCESSES AND A SUBSTANTIAL EFFECT OF EXCITABILITY ON PLASTIC CHANGES IN THE CENTRAL NERVOUS SYSTEM (CNS), THE EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS (PEPS) ON THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF INJURY MEMORY WAS STUDIED IN RAT STRAINS BRED FOR A CERTAIN EXCITABILITY OF THE NERVOUS SYSTEM. PEPS WAS FOR THE FIRST TIME FOUND TO CAUSE LONG-LASTING (2 MONTHS) MORPHOLOGICAL ALTERATIONS OF THE CA3 REGION OF THE HIPPOCAMPUS AND TO MODIFY THE GENOME ACTIVITY OF ITS PYRAMIDAL NEURONS. THE TWO PHENOMENA WERE POTENTIATED BY A GENETICALLY DETERMINED LOW FUNCTIONAL STATE OF THE CNS. THE POST-STRESS REGULATION OF THE GENOME FUNCTION IN HIPPOCAMPAL NEURONS WAS MEDIATED BY CHANGES IN HETEROCHROMATIN CONFORMATION, ACTIVATION OF METHYL-CPG-BINDING PROTEIN (MECP2) SYNTHESIS, AND SUBSEQUENT CHANGES IN ACETYLATION OF HISTONE H4. GENETICALLY DETERMINED HIGH EXCITABILITY OF THE NERVOUS SYSTEM PROVED TO BE A RISK FACTOR THAT AFFECTS THE SPECIFICS AND TIME COURSE OF THE OBSERVED MOLECULAR, CELL, AND GENETIC TRANSFORMATIONS OF NEURONS. THE RESULTS PROVIDE FOR A BETTER UNDERSTANDING OF THE EPIGENETIC MECHANISMS OF INJURY MEMORY, WHICH FORMS A PATHOGENETIC BASIS FOR POSTTRAUMATIC STRESS DISORDER AND OTHER HUMAN PSYCHOGENIC CONDITIONS CHARACTERIZED BY A PROLONGED DURATION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  405  41 ANALYSIS OF EPIGENETIC MECHANISMS REGULATING OPIOID RECEPTOR GENE TRANSCRIPTION. OPIOID DRUGS ARE GENERALLY USED FOR MODERATE AND SEVERE PAIN REDUCTIONS WHICH ACT THROUGH OPIOID RECEPTORS. STUDIES ON TRANSCRIPTIONAL REGULATION OF OPIOID RECEPTORS ARE STILL INVALUABLE BECAUSE NOT ONLY TRANSCRIPTION IS THE FIRST STEP TO PRODUCE PROTEIN PRODUCTS IN CELLS, BUT THE RECEPTOR TRANSCRIPTION LEVELS ALSO AFFECT THE PAIN REDUCTION BY OPIOIDS, AS OBSERVED IN STUDIES OF HETEROZYGOUS OPIOID RECEPTOR KNOCKOUT MICE.THERE ARE GROWING EVIDENCES THAT EPIGENETIC REGULATION HAS PLAYED SIGNIFICANT ROLES IN TRANSCRIPTIONAL REGULATION OF GENES, INCLUDING OPIOID RECEPTORS. IN GENERAL, EPIGENETIC MECHANISMS INCLUDE THREE MAIN REGULATORY FACTORS: DNA METHYLATION, CHROMATIN MODIFICATION, AND NONCODING RNAS (SUCH AS MICRORNA). FROM PREVIOUS STUDIES OF OURS AND OTHERS ON OPIOID RECEPTORS, THOSE EPIGENETIC FACTORS WERE CLEARLY INVOLVED IN REGULATING OPIOID RECEPTOR EXPRESSION IN VIVO AND IN VITRO. IN THIS CHAPTER, AMONG THOSE THREE TECHNIQUES WE DESCRIBE MORE DETAILS OF DNA METHYLATION METHODS BECAUSE OF EMERGING CONCEPTS OF DNA METHYLATION WITH THE RECENT DISCOVERY OF 5-HYDROXYMETHYLCYTOSINE CONVERTING ENZYME, TET1. ANOTHER ANALYTICAL METHOD OF THE EPIGENETIC FACTORS, CHROMATIN MODIFICATION, WILL BE DESCRIBED BRIEFLY AND INFORMATION OF ANALYZING NONCODING RNAS IS BRIEFLY MENTIONED IN SUBHEADING 1.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16 2736  56 EXPLORING THE TRANSCRIPTOME OF RESIDENT SPINAL MICROGLIA AFTER COLLAGEN ANTIBODY-INDUCED ARTHRITIS. RECENT STUDIES HAVE SUGGESTED A SEXUALLY DIMORPHIC ROLE OF SPINAL GLIAL CELLS IN THE MAINTENANCE OF MECHANICAL HYPERSENSITIVITY IN RODENT MODELS OF CHRONIC PAIN. WE HAVE USED THE COLLAGEN ANTIBODY-INDUCED ARTHRITIS (CAIA) MOUSE MODEL TO EXAMINE DIFFERENCES BETWEEN MALES AND FEMALES IN THE CONTEXT OF SPINAL REGULATION OF ARTHRITIS-INDUCED PAIN. WE HAVE FOCUSED ON THE LATE PHASE OF THIS MODEL WHEN JOINT INFLAMMATION HAS RESOLVED, BUT MECHANICAL HYPERSENSITIVITY PERSISTS. ALTHOUGH THE INTENSITY OF SUBSTANCE P, CALCITONIN GENE-RELATED PEPTIDE, AND GALANIN IMMUNOREACTIVITY IN THE SPINAL CORD WAS NOT DIFFERENT FROM CONTROLS, THE INTENSITY OF MICROGLIA (IBA-1) AND ASTROCYTE (GLIAL FIBRILLARY ACIDIC PROTEIN) MARKERS WAS ELEVATED IN BOTH MALES AND FEMALES. INTRATHECAL ADMINISTRATION OF THE GLIAL INHIBITORS MINOCYCLINE AND PENTOXIFYLLINE REVERSED MECHANICAL THRESHOLDS IN MALE, BUT NOT IN FEMALE MICE. WE ISOLATED RESIDENT MICROGLIA FROM THE LUMBAR DORSAL HORNS AND OBSERVED A SIGNIFICANTLY LOWER NUMBER OF MICROGLIAL CELLS IN FEMALES BY FLOW CYTOMETRY ANALYSIS. HOWEVER, ALTHOUGH GENOME-WIDE RNA SEQUENCING RESULTS POINTED TO SEVERAL TRANSCRIPTIONAL DIFFERENCES BETWEEN MALE AND FEMALE MICROGLIA, NO CONVINCING DIFFERENCES WERE IDENTIFIED BETWEEN CONTROL AND CAIA GROUPS. TAKEN TOGETHER, THESE FINDINGS SUGGEST THAT THERE ARE SUBTLE SEX DIFFERENCES IN MICROGLIAL EXPRESSION PROFILES INDEPENDENT OF ARTHRITIS. OUR EXPERIMENTS FAILED TO IDENTIFY THE UNDERLYING MRNA CORRELATES OF MICROGLIAL ACTIONS IN THE LATE PHASE OF THE CAIA MODEL. IT IS LIKELY THAT TRANSCRIPTIONAL CHANGES ARE EITHER SUBTLE AND HIGHLY LOCALISED AND THEREFORE DIFFICULT TO IDENTIFY WITH BULK ISOLATION TECHNIQUES OR THAT OTHER FACTORS, SUCH AS CHANGES IN PROTEIN EXPRESSION OR EPIGENETIC MODIFICATIONS, ARE AT PLAY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17 4093  46 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18 5189  44 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19 1584  35 DNA METHYLATION PROFILES OF SELECTED PRO-INFLAMMATORY CYTOKINES IN ALZHEIMER DISEASE. BY MEANS OF FUNCTIONAL GENOMICS ANALYSIS, WE RECENTLY DESCRIBED THE MRNA EXPRESSION PROFILES OF VARIOUS GENES INVOLVED IN THE NEUROINFLAMMATORY RESPONSE IN THE BRAINS OF SUBJECTS WITH LATE-ONSET ALZHEIMER DISEASE (LOAD). SOME OF THESE GENES, NAMELY INTERLEUKIN (IL)-1BETA AND IL-6, SHOWED DISTINCT EXPRESSION PROFILES WITH PEAK EXPRESSION DURING THE FIRST STAGES OF THE DISEASE AND CONTROL-LIKE LEVELS AT LATER STAGES. IL-1BETA AND IL-6 GENES ARE MODULATED BY DNA METHYLATION IN DIFFERENT CHRONIC AND DEGENERATIVE DISEASES; IT IS ALSO WELL KNOWN THAT LOAD MAY HAVE AN EPIGENETIC BASIS. INDEED, WE AND OTHERS HAVE PREVIOUSLY REPORTED GENE-SPECIFIC DNA METHYLATION ALTERATIONS IN LOAD AND IN RELATED ANIMAL MODELS. BASED ON THESE DATA, WE STUDIED THE DNA METHYLATION PROFILES, AT SINGLE CYTOSINE RESOLUTION, OF IL-1BETA AND IL-6 5'-FLANKING REGION BY BISULPHITE MODIFICATION IN THE CORTEX OF HEALTHY CONTROLS AND LOAD PATIENTS AT 2 DIFFERENT DISEASE STAGES: BRAAK I-II/A AND BRAAK V-VI/C. OUR ANALYSIS PROVIDES EVIDENCE THAT NEUROINFLAMMATION IN LOAD IS ASSOCIATED WITH (AND POSSIBLY MEDIATED BY) EPIGENETIC MODIFICATIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20 6195  36 THE IMPACT OF RECENT ALCOHOL USE ON GENOME WIDE DNA METHYLATION SIGNATURES. CHRONIC ALCOHOL INTAKE IS ASSOCIATED WITH A WIDE VARIETY OF ADVERSE HEALTH OUTCOMES INCLUDING DEPRESSION, DIABETES, AND HEART DISEASE. UNFORTUNATELY, THE MOLECULAR MECHANISMS THROUGH WHICH THESE EFFECTS ARE CONVEYED ARE NOT CLEARLY UNDERSTOOD. TO EXAMINE THE POTENTIAL ROLE OF EPIGENETIC FACTORS IN THIS PROCESS, WE EXAMINED THE RELATIONSHIP OF RECENT ALCOHOL INTAKE TO GENOME WIDE METHYLATION PATTERNS USING THE ILLUMINA 450 METHYLATION BEAD CHIP AND LYMPHOBLAST DNA DERIVED FROM 165 FEMALE SUBJECTS PARTICIPATING IN THE IOWA ADOPTION STUDIES. WE FOUND THAT THE PATTERN OF ALCOHOL USE OVER THE 6-MONTHS IMMEDIATELY PRIOR TO PHLEBOTOMY WAS ASSOCIATED WITH, SEVERITY-DEPENDENT CHANGES IN THE DEGREE OF GENOME WIDE METHYLATION THAT PREFERENTIALLY HYPERMETHYLATE THE CENTRAL PORTION OF CPG ISLANDS WITH METHYLATION AT CG05600126, A PROBE IN ABR, AND THE 5' UNTRANSLATED REGION OF BLCAP ATTAINING GENOME WIDE SIGNIFICANCE IN TWO POINT AND SLIDING WINDOW ANALYSES OF PROBE METHYLATION DATA, RESPECTIVELY. WE CONCLUDE THAT RECENT ALCOHOL USE IS ASSOCIATED WITH WIDESPREAD CHANGES IN DNA METHYLATION IN WOMEN AND THAT FURTHER STUDY TO CONFIRM THESE FINDINGS AND DETERMINE THEIR RELATIONSHIP TO SOMATIC FUNCTION ARE IN ORDER.	2012