1 2834 239 FOLIC ACID MODULATES MATRIX METALLOPROTEINASE-2 EXPRESSION, ALLEVIATES NEUROPATHIC PAIN, AND IMPROVES FUNCTIONAL RECOVERY IN SPINAL CORD-INJURED RATS. BACKGROUND: THE MOLECULAR UNDERPINNINGS OF SPINAL CORD INJURY (SCI) ASSOCIATED WITH NEUROPATHIC PAIN (NP) ARE UNKNOWN. RECENT STUDIES HAVE DEMONSTRATED THAT MATRIX METALLOPROTEINASES (MMPS) SUCH AS MMP2 PLAY A CRITICAL ROLE IN INDUCING NP FOLLOWING SCI. PROMOTER METHYLATION OF MMPS IS KNOWN TO SUPPRESS THEIR TRANSCRIPTION AND REDUCE NP. IN THIS CONTEXT, IT HAS BEEN SHOWN IN RODENTS THAT FOLIC ACID (FA), AN FDA APPROVED DIETARY SUPPLEMENT AND KEY METHYL DONOR IN THE CENTRAL NERVOUS SYSTEM (CNS), INCREASES AXONAL REGENERATION AND REPAIR OF INJURED CNS IN PART VIA METHYLATION. PURPOSE: BASED ON ABOVE OBSERVATIONS, IN THIS STUDY, WE TEST WHETHER FA COULD DECREASE MMP2 EXPRESSION AND THEREBY DECREASE SCI-INDUCED NP. METHODS: SPRAGUE-DAWLEY MALE RATS WEIGHING 250-270 G RECEIVED CONTUSION SPINAL CORD INJURIES (CSCIS) WITH A CUSTOM SPINAL CORD IMPACTOR DEVICE THAT DROPS A 10 G WEIGHT FROM A HEIGHT OF 12.5 MM. THE INJURED RATS RECEIVED EITHER I.P. INJECTIONS OF FA (80 MICROG/KG) OR WATER (CONTROL) 3 DAYS PRIOR AND 17 DAYS POST-CSCI (MID PHASE) OR FOR 3 DAYS PRE-CSCI AND 14 DAYS POST-CSCI ENDING ON THE 42ND DAY OF CSCI (LATE PHASE). THE FUNCTIONAL NEUROLOGICAL DEFICITS DUE TO CSCI WERE THEN ASSESSED BY BASSO, BEATTIE, AND BRESNAHAN (BBB) SCORES EITHER ON POST-IMPACTION DAYS 0 THROUGH 18 POST-CSCI (MID PHASE) OR ON DAYS 0, 2, 7, 14, 21, 28, 35, AND 42 (LATE PHASE). BASELINE MEASUREMENTS WERE TAKEN THE DAY BEFORE STARTING TREATMENTS. THERMAL HYPERALGESIA (TH) TESTING FOR PAIN WAS PERFORMED ON 4 DAYS PRE-CSCI (BASELINE DATA) AND ON DAYS 18, 21, 28, 35, AND 42 POST-CSCI. FOLLOWING TH TESTING, ANIMALS WERE EUTHANIZED AND SPINAL CORDS HARVESTED FOR MMP-2 EXPRESSION ANALYSIS. RESULT: THE FA-TREATED GROUPS SHOWED HIGHER BBB SCORES DURING MID PHASE (DAY 18) AND IN LATE PHASE (DAY 42) OF INJURY COMPARED TO CONTROLS, SUGGESTING ENHANCED FUNCTIONAL RECOVERY. THERE IS A TRANSIENT DECLINE IN TH IN ANIMALS FROM THE FA-TREATED GROUP COMPARED TO CONTROLS WHEN TESTED ON DAYS 18, 21, 28, AND 35, INDICATIVE OF A DECREASE IN NP. HOWEVER, WHEN TESTED 25 DAYS AFTER STOPPING FA ADMINISTRATION ON DAY 42 OF CSCI, NO SIGNIFICANT DIFFERENCE IN TH WAS OBSERVED BETWEEN FA-TREATED AND CONTROL ANIMALS. WESTERN BLOT ANALYSIS OF THE INJURED SPINAL CORD FROM FA-TREATED ANIMALS SHOWED SIGNIFICANT DECLINE IN MMP2 EXPRESSION COMPARED TO SPINAL CORD SAMPLES FROM WATER-TREATED CONTROLS. CONCLUSION: TOGETHER, THESE DATA SUGGEST THAT FA COULD ALLEVIATE NP AND IMPROVE FUNCTIONAL RECOVERY POST-SCI, POSSIBLY BY REDUCING THE EXPRESSION OF MMP2. FURTHER STUDIES WILL OPEN UP A NOVEL AND EASY NATURAL THERAPY, IDEAL FOR CLINICAL TRANSLATION WITH MINIMAL SIDE EFFECTS, FOR MANAGING SCI-INDUCED NP. SUCH STUDIES MIGHT ALSO THROW LIGHT ON A POSSIBLE EPIGENETIC MECHANISM IN FA-INDUCED RECOVERY AFTER SCI.	2017	

2 1635  35 DOES A SINGLE BOUT OF EXERCISE IMPACTS BDNF, OXIDATIVE STRESS AND EPIGENETIC MARKERS IN SPINAL CORD INJURY PATIENTS? OUR AIM WAS TO EVALUATE THE IMPACT OF A SINGLE BOUT OF EXERCISE, CONSISTING OF A GAIT TRAINING SESSION WITH BODY WEIGHT SUPPORT (BWS), ON HISTONE ACETYLATION STATUS (GLOBAL HISTONE H4 AND H3 ACETYLATION LEVELS), BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS, AND OXIDATIVE STRESS MARKERS IN PERIPHERAL BLOOD OF INDIVIDUALS WITH CHRONIC SPINAL CORD INJURY (SCI). WE ALSO SET OUT TO COMPARE THESE RESPONSES WITH THOSE RECORDED AFTER GAIT TRAINING PERFORMED USING A WALKER AND WITH NO BWS. THE SUBJECTS (NEARLY ALL WITH AN INCOMPLETE SPINAL CORD LESION) WERE EACH SUBMITTED TO TWO 60-MINUTE EXPERIMENTAL SESSIONS ON SEPARATE DAYS WITH A 1- WEEK WASH-OUT PERIOD BETWEEN THE INTERVENTIONS. THE ORDER OF THE SESSIONS WAS RANDOMIZED. BLOOD SAMPLES WERE COLLECTED BEFORE AND AFTER EACH EXPERIMENTAL TRIAL FOR MEASUREMENT OF BIOMARKERS. THE HISTONE ACETYLATION STATUS AND BDNF LEVELS REMAINED UNCHANGED AFTER BOTH INTERVENTIONS. AFTER THE TREADMILL TRAINING, THE PARTICIPANTS SHOWED A STRONG INCREASE IN LEVELS OF OXIDATIVE STRESS MARKERS [PLASMA ADVANCED OXIDATION PROTEIN PRODUCTS (AOPPS), NITRITE AND THIOBARBITURIC ACID-REACTIVE SUBSTANCES] WITHOUT CHANGES IN ANTIOXIDANT MEDIATORS. INSTEAD, ELEVATIONS IN AOPP AND NITRITE CONCENTRATIONS, IN ADDITION TO INCREASED LEVELS OF GLUTATHIONE AND CATALASE ACTIVITY, WERE FOUND AFTER THE WALKER TRAINING. A SINGLE BOUT OF GAIT TRAINING, BE IT CONDUCTED ON A TREADMILL WITH BWS OR USING A WALKER WITHOUT BWS, IS NOT ABLE TO ALTER BDNF LEVELS AND HISTONE ACETYLATION STATUS IN SCI PATIENTS. HOWEVER, THESE TRIALS CAN MODULATE OXIDATIVE STRESS PARAMETERS, SEEMINGLY IN A PROTOCOL-DEPENDENT MANNER.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3 5205  40 PRENATAL STRESS CHANGES THE GLYCOPROTEIN GPM6A GENE EXPRESSION AND INDUCES EPIGENETIC CHANGES IN RAT OFFSPRING BRAIN. PRENATAL STRESS (PS) EXERTS STRONG IMPACT ON FETAL BRAIN DEVELOPMENT AND ON ADULT OFFSPRING BRAIN FUNCTIONS. PREVIOUS WORK DEMONSTRATED THAT CHRONIC STRESS ALTERS THE MRNA EXPRESSION OF GPM6A, A NEURONAL GLYCOPROTEIN INVOLVED IN FILOPODIUM EXTENSION. IN THIS WORK, WE ANALYZED THE EFFECT OF PS ON GPM6A EXPRESSION AND THE EPIGENETIC MECHANISMS INVOLVED. PREGNANT WISTAR RATS RECEIVED RESTRAINT STRESS DURING THE LAST WEEK OF GESTATION. MALE OFFSPRING WERE SACRIFICED ON POSTNATAL DAYS 28 AND 60. HIPPOCAMPUS AND PREFRONTAL CORTEX SAMPLES WERE ANALYZED FOR GENE EXPRESSION (QPCR FOR MRNAS AND MICRORNAS), METHYLATION STATUS (BISULFITE CONVERSION) AND PROTEIN LEVELS. HIPPOCAMPAL NEURONS IN CULTURE WERE USED TO ANALYZE MICRORNA OVEREXPRESSION EFFECTS. PRENATAL STRESS INDUCED CHANGES IN GPM6A LEVELS IN BOTH TISSUES AND AT BOTH AGES ANALYZED, INDICATING A PERSISTENT EFFECT. TWO CPG ISLANDS IN THE GPM6A GENE WERE IDENTIFIED. VARIATIONS IN THE METHYLATION PATTERN AT THREE SPECIFIC CPGS WERE FOUND IN HIPPOCAMPUS, BUT NOT IN PFC SAMPLES FROM PS OFFSPRING. MICRORNAS PREDICTED TO TARGET GPM6A WERE IDENTIFIED IN SILICO. QPCR MEASUREMENTS SHOWED THAT PS MODIFIED THE EXPRESSION OF SEVERAL MICRORNAS IN BOTH TISSUES, BEING MICRORNA-133B THE MOST SIGNIFICANTLY ALTERED. FURTHER STUDIES OVEREXPRESSING THIS MICRORNA IN NEURONAL CULTURES SHOWED A REDUCTION IN GMP6A MRNA AND PROTEIN LEVEL. MOREOVER FILOPODIUM DENSITY WAS ALSO REDUCED, SUGGESTING THAT GPM6A FUNCTION WAS AFFECTED. GESTATIONAL STRESS AFFECTED GPM6A GENE EXPRESSION IN OFFSPRING LIKELY THROUGH CHANGES IN METHYLATION STATUS AND IN POSTTRANSCRIPTIONAL REGULATION BY MICRORNAS. THUS, OUR FINDINGS PROPOSE GPM6A AS A NOVEL TARGET FOR EPIGENETIC REGULATION DURING PRENATAL STRESS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4 3122  49 GESTATIONAL VALPROIC ACID EXPOSURE INDUCES EPIGENETIC MODIFICATIONS IN MURINE DECIDUA. INTRODUCTION: VALPROIC ACID (VPA), A WIDELY PRESCRIBED ANTIEPILEPTIC DRUG AND AN EFFECTIVE TREATMENT FOR BIPOLAR DISORDER AND NEUROPATHIC PAIN, RESULTS IN MULTIPLE DEVELOPMENTAL DEFECTS FOLLOWING IN UTERO EXPOSURE. UTERINE DECIDUA PROVIDES NUTRITIONAL AND PHYSICAL SUPPORT DURING IMPLANTATION AND EARLY EMBRYONIC DEVELOPMENT. PERTURBATIONS IN THE MOLECULAR MECHANISMS WITHIN DECIDUAL TISSUE DURING EARLY PREGNANCY MIGHT AFFECT EARLY EMBRYONIC GROWTH, RESULT IN EARLY PREGNANCY LOSS OR CAUSE COMPLICATIONS IN THE LATER GESTATIONAL STAGE. VPA IS A KNOWN HISTONE DEACETYLASE INHIBITOR AND EPIGENETIC CHANGES SUCH AS HISTONE HYPERACETYLATION AND METHYLATION HAVE BEEN PROPOSED AS A MECHANISM OF VPA-INDUCED TERATOGENESIS. METHODS: THIS STUDY INVESTIGATED THE EFFECTS OF IN UTERO VPA EXPOSURE ON HISTONE MODIFICATIONS IN MURINE DECIDUAL TISSUE. PREGNANT CD-1 MICE WERE EXPOSED TO 400 MG/KG VPA OR SALINE ON GD9 VIA SUBCUTANEOUS INJECTION. DECIDUAL TISSUE FROM EACH GESTATIONAL SAC WAS HARVESTED AT 1, 3 AND 6 H FOLLOWING EXPOSURE. LEVELS OF ACETYLATED HISTONES H3, H4 AND H3K56, AS WELL AS METHYLATED HISTONES H3K9 AND H3K27 WERE ACID EXTRACTED AND ASSESSED BY WESTERN BLOTTING FOLLOWED BY ACID HISTONE EXTRACTION. RESULTS: VPA EXPOSURE INDUCED A SIGNIFICANT INCREASE (P < 0.05) IN THE LEVELS OF ACETYLATED H3 AT 1, 3 H; ACETYLATED H4 AT 1, 3 AND 6 H AND TRIMETHYLATED H3K9 AT 6 H. IN CONTRAST, NO SIGNIFICANT PERTURBATIONS WERE NOTED IN THE LEVELS OF MONOMETHYLATED H3K9, TRIMETHYLATED H3K27 AND ACETYLATED H3K56. DISCUSSION: THE RESULTS FROM THIS STUDY SUGGEST THAT VPA-INDUCED DECIDUAL HISTONE MODIFICATIONS MIGHT PLAY AN IMPORTANT ROLE AS A MECHANISM OF VPA-INDUCED TERATOGENESIS DURING EARLY EMBRYONIC GROWTH.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5 6148  55 THE EXPRESSION OF TRANSCRIPTION FACTORS MECP2 AND CREB IS MODULATED IN INFLAMMATORY PELVIC PAIN. EARLY ACTIVATION OF TRANSCRIPTION FACTORS IS ONE OF THE EPIGENETIC MECHANISMS CONTRIBUTING TO THE INDUCTION AND MAINTENANCE OF CHRONIC PAIN STATES. PREVIOUS STUDIES IDENTIFIED THE CHANGES IN A NUMBER OF NOCICEPTION-RELATED GENES, SUCH AS CALCITONIN GENE-RELATED PEPTIDE (CGRP), SUBSTANCE P (SP), AND BRAIN-DERIVED NEUROTROPIC FACTOR (BDNF) IN THE PELVIC ORGANS AFTER TRANSIENT COLONIC INFLAMMATION. THE GENE AND PROTEIN EXPRESSION OF THESE NEUROPEPTIDES COULD BE MODULATED BY TRANSCRIPTION FACTORS METHYL-CPG-BINDING PROTEIN 2 (MECP2) AND CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB). IN THIS STUDY, WE AIMED TO EVALUATE TIME-DEPENDENT CHANGES IN THE EXPRESSION LEVELS OF MECP2 AND CREB IN THE LUMBOSACRAL (LS) SPINAL CORD AND SENSORY GANGLIA AFTER INFLAMMATION-INDUCED PELVIC PAIN IN RAT. ADULT SPRAGUE-DAWLEY RATS WERE TREATED WITH 2,4,6-TRINITROBENZENESULFONIC ACID (TNBS) TO INDUCE TRANSIENT COLONIC INFLAMMATION. LS (L6-S2) SPINAL CORD SEGMENTS AND RESPECTIVE DORSAL ROOT GANGLIAS (DRGS) WERE ISOLATED FROM CONTROL AND EXPERIMENTAL ANIMALS AT 1, 2, 6, 24 H AND 3 DAYS POST-TNBS TREATMENT. IMMUNOHISTOCHEMICAL (IHC) LABELING AND WESTERN BLOTTING EXPERIMENTS WERE PERFORMED TO ASSESS THE EXPRESSION OF MECP2, CREB AND THEIR PHOSPHORYLATED FORMS. TOTAL MECP2 EXPRESSION, BUT NOT PHOSPHORYLATED P-MECP2 (PS421MECP2) EXPRESSION WAS DETECTED IN THE CELLS OF THE SPINAL DORSAL HORN UNDER CONTROL CONDITIONS. COLONIC INFLAMMATION TRIGGERED A SIGNIFICANT DECREASE IN THE NUMBER OF MECP2-EXPRESSING NEURONS IN PARALLEL WITH ELEVATED NUMBERS OF PS421MECP2-EXPRESSING CELLS AT 2 H AND 6 H POST-TNBS. THE MAJORITY OF MECP2-POSITIVE CELLS (80 +/- 6%) CO-EXPRESSED CREB. TNBS TREATMENT CAUSED A TRANSIENT UP-REGULATION OF CREB-EXPRESSING CELLS AT 1 H POST-TNBS ONLY. THE NUMBER OF CELLS EXPRESSING PHOSPHORYLATED CREB (PS133CREB) DID NOT CHANGE AT 1 H AND 2 H POST-TNBS, BUT WAS DOWN-REGULATED BY THREE FOLDS AT 6 H POST-TNBS. ANALYSIS OF DRG SECTIONS REVEALED THAT THE NUMBER OF MECP2-POSITIVE NEURONS WAS UP-REGULATED BY TNBS TREATMENT, REACHING THREE-FOLD INCREASE AT 2 H POST-TNBS, AND EIGHT-FOLD INCREASE AT 6 H POST-TNBS (P </= 0.05 TO CONTROL). THESE DATA SHOWED EARLY CHANGES IN MECP2 AND CREB EXPRESSION IN THE DORSAL HORN OF THE SPINAL CORD AND SENSORY GANGLIA AFTER COLONIC INFLAMMATION, SUGGESTING A POSSIBLE CONTRIBUTION MECP2 AND CREB SIGNALING IN THE DEVELOPMENT OF VISCERAL HYPERALGESIA AND PELVIC PAIN FOLLOWING PERIPHERAL INFLAMMATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                
6 5273  42 PROMOTER METHYLATION AND BDNF AND DAT1 GENE EXPRESSION PROFILES IN PATIENTS WITH DRUG ADDICTION. BACKGROUND: DRUG ADDICTION IS A BRAIN DISORDER THAT HAS NEGATIVE CONSEQUENCES FOR INDIVIDUALS AND SOCIETY. ADDICTIONS ARE CHRONIC RELAPSING DISEASES OF THE BRAIN THAT ARE CAUSED BY DIRECT DRUG-INDUCED EFFECTS AND PERSEVERING NEUROADAPTATIONS AT THE EPIGENETIC, NEUROPEPTIDE AND NEUROTRANSMITTER LEVELS. BECAUSE THE DOPAMINERGIC SYSTEM HAS A SIGNIFICANT ROLE IN DRUG ABUSE, THE PURPOSE OF THIS STUDY WAS TO ANALYZE THE METHYLATION AND EXPRESSION PROFILE OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND DOPAMINE TRANSPORTER (DAT1) GENES IN INDIVIDUALS WITH DRUG ADDICTION. MATERIALS AND METHODS: BDNF AND DAT1 PROMOTER METHYLATION WERE INVESTIGATED WITH A METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) TECHNIQUE IN BLOOD SAMPLES FROM 75 INDIVIDUALS WITH DRUG ADDICTION AND 65 HEALTHY CONTROLS. THE EXPRESSION LEVELS OF BDNF AND DAT1 WERE ASSESSED IN 12 MRNA SAMPLES FROM THE BLOOD OF PATIENTS AND COMPARED TO THE SAMPLES OF HEALTHY CONTROLS (N = 12) WITH REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION PCR. RESULTS: NO SIGNIFICANT DIFFERENCES WERE FOUND IN THE METHYLATION OF BDNF AND DAT1 BETWEEN PATIENTS AND CONTROLS, BUT THE RELATIVE LEVELS OF EXPRESSION OF BDNF AND DAT1 MRNA DIFFERED SIGNIFICANTLY IN THE PATIENTS COMPARED TO CONTROLS (P < 0.0001). CONCLUSION: THESE RESULTS SHOWED THAT THE METHYLATION STATUS OF THE BDNF AND DAT1 GENES HAD NO SIGNIFICANT FUNCTION IN THE PROCESSES OF DRUG ADDICTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
7 1504  42 DNA METHYLATION AND HISTONE DEACETYLATION REGULATING INSULIN SENSITIVITY DUE TO CHRONIC COLD EXPOSURE. IN THIS STUDY, WE INVESTIGATED THE CAUSAL RELATIONSHIP BETWEEN CHRONIC COLD EXPOSURE AND INSULIN RESISTANCE AND THE MECHANISMS OF HOW DNA METHYLATION AND HISTONE DEACETYLATION REGULATE COLD-REDUCED INSULIN RESISTANCE. 46 ADULT MALE MICE FROM POSTNATAL DAY 90-180 WERE RANDOMLY ASSIGNED TO CONTROL GROUP AND COLD-EXPOSURE GROUP. MICE IN COLD-EXPOSURE GROUP WERE PLACED AT TEMPERATURE FROM -1 TO 4 DEGREES C FOR 30 DAYS TO MIMIC CHRONIC COLD ENVIRONMENT. THEN, FASTING BLOOD GLUCOSE, BLOOD INSULIN LEVEL AND INSULIN RESISTANCE INDEX WERE MEASURED WITH ENZYMATIC METHODS. IMMUNOFLUORESCENT LABELING WAS CARRIED OUT TO VISUALIZE THE INSULIN RECEPTOR SUBSTRATE 2 (IRS2), OBESE RECEPTOR (OB-R, A LEPTIN RECEPTOR), VOLTAGE-DEPENDENT ANION CHANNEL PROTEIN 1 (VDAC1), CYTOCHROME C (CYTC), 5-METHYLCYTOSINE (5-MC) POSITIVE CELLS IN HIPPOCAMPAL CA1 AREA. FURTHERMORE, THE EXPRESSIONS OF SOME PROTEINS MENTIONED ABOVE WERE DETECTED WITH WESTERN BLOT. THE RESULTS SHOWED: 1 IN CIRCLE CHRONIC COLD EXPOSURE COULD REDUCE THE INSULIN RESISTANCE INDEX (P < 0.01) AND INCREASE THE NUMBER OF IRS2 POSITIVE CELLS AND OB-R POSITIVE CELLS IN HIPPOCAMPUS (P < 0.01). 2 IN CIRCLE THE EXPRESSIONS OF MITOCHONDRIAL ENERGY-RELATIVE PROTEINS, VDAC1 AND CYTC, WERE HIGHER IN COLD-EXPOSURE GROUP THAN IN CONTROL GROUP WITH BOTH IMMUNOHISTOCHEMICAL STAINING AND WESTERN BLOT (P < 0.01). 3 IN CIRCLE CHRONIC COLD EXPOSURE INCREASED DNA METHYLATION AND HISTONE DEACETYLATION IN THE PYRAMIDAL CELLS OF CA1 AREA AND LED TO AN INCREASE IN THE EXPRESSION OF HISTONE DEACETYLASE 1 (HDAC1) AND DNA METHYLATION RELATIVE ENZYMES (P < 0.01). IN CONCLUSION, CHRONIC COLD EXPOSURE CAN IMPROVE INSULIN SENSITIVITY, WITH THE INVOLVEMENT OF DNA METHYLATION, HISTONE DEACETYLATION AND THE REGULATION OF MITOCHONDRIAL ENERGY METABOLISM. THESE EPIGENETIC MODIFICATIONS PROBABLY FORM THE BASIC MECHANISM OF COLD-REDUCED INSULIN RESISTANCE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8 1182  47 CONVERGING AND DIFFERENTIAL BRAIN PHOSPHOLIPID DYSREGULATION IN THE PATHOGENESIS OF REPETITIVE MILD TRAUMATIC BRAIN INJURY AND ALZHEIMER'S DISEASE. REPETITIVE MILD TRAUMATIC BRAIN INJURY (RMTBI) IS A MAJOR EPIGENETIC RISK FACTOR FOR ALZHEIMER'S DISEASE (AD). THE PRECISE NATURE OF HOW RMTBI LEADS TO OR PRECIPITATES AD PATHOLOGY IS CURRENTLY UNKNOWN. NUMEROUS NEUROLOGICAL CONDITIONS HAVE SHOWN AN IMPORTANT ROLE FOR DYSFUNCTIONAL PHOSPHOLIPID METABOLISM AS A DRIVING FACTOR FOR THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES. HOWEVER, THE PRECISE ROLE IN RMTBI AND AD REMAINS ELUSIVE. WE HYPOTHESIZED THAT A DETAILED PHOSPHOLIPID CHARACTERIZATION WOULD REVEAL PROFILES OF RESPONSE TO INJURY IN TBI THAT OVERLAP WITH AGE-DEPENDENT CHANGES IN AD AND THUS PROVIDE INSIGHTS INTO THE TBI-AD RELATIONSHIP. WE EMPLOYED A LIPIDOMIC APPROACH EXAMINING BRAIN PHOSPHOLIPID PROFILES FROM MOUSE MODELS OF RMTBI AND AD. CORTEX AND HIPPOCAMPAL TISSUE WERE COLLECTED AT 24 H, 3, 6, 9, AND 12 MONTHS POST-RMTBI, AND AT AGES REPRESENTING 'PRE', 'PERI' AND 'POST' ONSET OF AMYLOID PATHOLOGY (I.E., 3, 9, 15 MONTHS-OLD). TOTAL LEVELS OF PHOSPHATIDYLCHOLINE (PC), PHOSPHATIDYLETHANOLAMINE (PE), LYSOPE, AND PHOSPHATIDYLINOSITOL (PI), INCLUDING THEIR MONOUNSATURATED, POLYUNSATURATED AND SATURATED FATTY ACID (FA) CONTAINING SPECIES WERE SIGNIFICANTLY INCREASED AT ACUTE AND/OR CHRONIC TIME POINTS POST-INJURY IN BOTH BRAIN REGIONS. HOWEVER, LEVELS OF MOST PHOSPHOLIPID SPECIES IN PS1/APP MICE WERE NOMINAL IN THE HIPPOCAMPUS, WHILE IN THE CORTEX, LEVELS WERE SIGNIFICANTLY DECREASED AT AGES POST-ONSET OF AMYLOID PATHOLOGY. SPHINGOMYELIN AND LYSOPC LEVELS SHOWED COINCIDENTAL TRENDS IN OUR RMTBI AND AD MODELS WITHIN THE HIPPOCAMPUS, AN INCREASE AT ACUTE AND/OR CHRONIC TIME POINTS EXAMINED. THE RATIO OF ARACHIDONIC ACID (OMEGA-6 FA) TO DOCOSAHEXAENOIC ACID (OMEGA-3 FA)-CONTAINING PE SPECIES WAS INCREASED AT EARLY TIME POINTS IN THE HIPPOCAMPUS OF INJURED VERSUS SHAM MICE, AND IN PS1/APP MICE THERE WAS A COINCIDENTAL INCREASE COMPARED TO WILD TYPE LITTERMATES AT ALL TIME POINTS. THIS STUDY DEMONSTRATES SOME OVERLAPPING AND DIVERSE PHOSPHOLIPID PROFILES IN RMTBI AND AD MODELS. FUTURE STUDIES ARE REQUIRED TO CORROBORATE OUR FINDINGS IN HUMAN POST-MORTEM TISSUE. INVESTIGATION OF SECONDARY MECHANISMS TRIGGERED BY ABERRANT DOWNSTREAM ALTERATIONS IN BIOACTIVE METABOLITES OF THESE PHOSPHOLIPIDS, AND THEIR MODULATION AT THE APPROPRIATE TIME-WINDOWS OF OPPORTUNITY COULD HELP FACILITATE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES TO AMELIORATE THE NEURODEGENERATIVE CONSEQUENCES OF RMTBI OR THE POTENTIAL TRIGGERING OF AD PATHOGENESIS BY RMTBI.	2019	
                                                                                                                                                                                                                                                                                                                       
9 3986  46 LONG-TERM OVARIECTOMY INCREASES BDNF GENE METHYLATION STATUS IN MOUSE HIPPOCAMPUS. ESTRADIOL (E) HAS BEEN SUGGESTED TO HAVE A NEUROPROTECTIVE EFFECT IN YOUNG ANIMALS BUT HAS NEUTRAL OR HARMFUL EFFECTS WHEN IT IS ADMINISTERED TO AGED ANIMALS. IN THE PRESENT STUDY, WE DETERMINED WHETHER THE POST-OVARIECTOMY (POST-OVX) TIMEFRAME ELAPSED BEFORE THE INITIATION OF CHRONIC E TREATMENT IS CRITICAL FOR THE ESTROGENIC INDUCTION OF NEUROTROPHINS (BRAIN-DERIVED NEUROTROPHIC FACTOR, BDNF, AND SYNAPTOPHYSIN, SYN) IN THE RODENT HIPPOCAMPUS. ADULT MICE WERE OVX AND, A SHORT PERIOD (SHORT-TERM E (STE) ANIMALS) OR A LONG PERIOD (LONG-TERM E (LTE) ANIMALS) AFTER THE OVX, WERE DAILY TREATED WITH E. CONTROL ANIMALS WERE TREATED WITH SESAME OIL (SHORT-TERM CONTROL (STC) AND LONG-TERM CONTROL (LTC) ANIMALS). PROTEIN EXPRESSION WAS DETERMINED USING AN IMMUNOHISTOCHEMICAL APPROACH. TRANSCRIPTIONAL ACTIVITY IN THE HIPPOCAMPUS OF INDIVIDUAL BDNF PROMOTERS WAS ASSESSED BY REAL-TIME QUANTITATIVE RT-PCR, AND THE METHYLATION LEVELS OF REGULATORY REGIONS WERE ANALYZED BY METHYLATION-SPECIFIC PCR AND COMBINED BISULFITE RESTRICTION ANALYSIS. STE ANIMALS SHOWED INCREASED BDNF AND SYN PROTEIN EXPRESSION AND A HIGHER ACTIVITY OF BDNF II, IV, AND V PROMOTERS. IN CONTRAST, LTE ANIMALS DID NOT SHOW E INDUCTION OF NEUROTROPHINS. IN THESE ANIMALS, THE METHYLATION LEVELS OF REGULATORY SEQUENCES OF THE BDNF WERE HIGHER THAN IN THE STE ANIMALS IN A CPG ISLAND OF PROMOTER V AND IN THE CRE REGULATORY SITE LOCATED IN PROMOTER IV. WITH THIS EXPERIMENT, WE DETERMINED THAT A PROLONGED PERIOD OF HYPOESTROGENICITY DISRUPTS THE E-INDUCTION OF NEUROTROPHINS, AND WE POSTULATED THAT DNA METHYLATION IS ONE OF THE EPIGENETIC MECHANISMS THAT COULD EXPLAIN THE E-INSENSITIVITY OF THE BDNF AFTER A LONG PERIOD POST-OVX.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10 3206  54 HDAC9 IS AN EPIGENETIC REPRESSOR OF KIDNEY ANGIOTENSINOGEN ESTABLISHING A SEX DIFFERENCE. BACKGROUND: SEXUAL DIFFERENCE HAS BEEN SHOWN IN THE PATHOGENESIS OF CHRONIC KIDNEY DISEASE INDUCED BY HYPERTENSION. FEMALES ARE PROTECTED FROM HYPERTENSION AND RELATED END-ORGAN DAMAGE. AUGMENTATION OF RENAL PROXIMAL TUBULAR ANGIOTENSINOGEN (AGT) EXPRESSION CAN PROMOTE INTRARENAL ANGIOTENSIN FORMATION AND THE DEVELOPMENT OF ASSOCIATED HYPERTENSION AND KIDNEY INJURY. FEMALE RODENTS EXHIBIT LOWER INTRARENAL AGT LEVELS THAN MALES UNDER NORMAL CONDITIONS, SUGGESTING THAT THE SUPPRESSED INTRARENAL AGT PRODUCTION BY PROGRAMMED MECHANISMS IN FEMALES MAY PROVIDE PROTECTION FROM THESE DISEASES. THIS STUDY WAS PERFORMED TO EXAMINE WHETHER EPIGENETIC MECHANISMS SERVE AS REPRESSORS OF AGT. METHODS: MALE AND FEMALE SPRAGUE DAWLEY RATS WERE USED TO INVESTIGATE SEX DIFFERENCES OF SYSTEMIC, HEPATIC, AND INTRARENAL AGT LEVELS. ALL HISTONE DEACETYLASE (HDAC) MRNA LEVELS IN THE KIDNEYS WERE DETERMINED USING A PCR ARRAY. HDAC9 PROTEIN EXPRESSION IN THE KIDNEYS AND CULTURED RENAL PROXIMAL TUBULAR CELLS (PTC) WAS ANALYZED BY WESTERN BLOT ANALYSIS AND IMMUNOHISTOCHEMISTRY. THE EFFECTS OF HDAC9 ON AGT EXPRESSION WERE EVALUATED BY USING AN INHIBITOR AND SIRNA. CHIP ASSAY WAS PERFORMED TO INVESTIGATE THE INTERACTION BETWEEN THE AGT PROMOTER AND HDAC9. RESULTS: PLASMA AND LIVER AGT LEVELS DID NOT SHOW DIFFERENCES BETWEEN MALE AND FEMALE SPRAGUE-DAWLEY RATS. IN CONTRAST, FEMALES EXHIBITED LOWER AGT LEVELS THAN MALES IN THE RENAL CORTEX AND URINE. IN THE ABSENCE OF SUPPLEMENTED SEX HORMONES, PRIMARY CULTURED RENAL CORTICAL CELLS ISOLATED FROM FEMALE RATS SUSTAINED LOWER AGT LEVELS THAN THOSE FROM MALES, SUGGESTING THAT THE KIDNEYS HAVE A UNIQUE MECHANISM OF AGT REGULATION CONTROLLED BY EPIGENETIC FACTORS RATHER THAN SEX HORMONES. HDAC9 MRNA AND PROTEIN LEVELS WERE HIGHER IN THE RENAL CORTEX OF FEMALE RATS VERSUS MALE RATS (7.09 +/- 0.88, RATIO TO MALE) WHILE OTHER HDACS DID NOT EXHIBIT A SEX DIFFERENCE. HDAC9 EXPRESSION WAS LOCALIZED IN PTC WHICH ARE THE PRIMARY SOURCE OF INTRARENAL AGT. IMPORTANTLY, HDAC9 KNOCKDOWN AUGMENTED AGT MRNA (1.92 +/- 0.35-FOLD) AND PROTEIN (2.25 +/- 0.50-FOLD) LEVELS, SIMILAR TO AN HDAC9 INHIBITOR. FURTHERMORE, AN INTERACTION BETWEEN HDAC9 AND A DISTAL 5' FLANKING REGION OF AGT VIA A HISTONE COMPLEX CONTAINING H3 AND H4 WAS DEMONSTRATED. CONCLUSIONS: THESE RESULTS INDICATE THAT HDAC9 IS A NOVEL SUPPRESSING FACTOR INVOLVED IN AGT REGULATION IN PTC, LEADING TO LOW LEVELS OF INTRARENAL AGT IN FEMALES. THESE FINDINGS WILL HELP TO DELINEATE MECHANISMS UNDERLYING SEX DIFFERENCES IN THE DEVELOPMENT OF HYPERTENSION AND RENIN-ANGIOTENSIN SYSTEM (RAS) ASSOCIATED KIDNEY INJURY.	2017	
                                                                                                                                                                                                                                             
11 5347  41 RARBETA AGONIST DRUG (C286) DEMONSTRATES EFFICACY IN A PRE-CLINICAL NEUROPATHIC PAIN MODEL RESTORING MULTIPLE PATHWAYS VIA DNA REPAIR MECHANISMS. NEUROPATHIC PAIN (NP) IS ASSOCIATED WITH PROFOUND GENE EXPRESSION ALTERATIONS WITHIN THE NOCICEPTIVE SYSTEM. DNA MECHANISMS, SUCH AS EPIGENETIC REMODELING AND REPAIR PATHWAYS HAVE BEEN IMPLICATED IN NP. HERE WE HAVE USED A RAT MODEL OF PERIPHERAL NERVE INJURY TO STUDY THE EFFECT OF A RECENTLY DEVELOPED RARBETA AGONIST, C286, CURRENTLY UNDER CLINICAL RESEARCH, IN NP. A 4-WEEK TREATMENT INITIATED 2 DAYS AFTER THE INJURY NORMALIZED PAIN SENSATION. GENOME-WIDE AND PATHWAY ENRICHMENT ANALYSIS SHOWED THAT MULTIPLE MECHANISMS PERSISTENTLY ALTERED IN THE SPINAL CORD WERE RESTORED TO PREINJURY LEVELS BY THE AGONIST. CONCOMITANT UPREGULATION OF DNA REPAIR PROTEINS, ATM AND BRCA1, THE LATTER BEING REQUIRED FOR C286-MEDIATED PAIN MODULATION, SUGGESTS THAT EARLY DNA REPAIR MAY BE IMPORTANT TO PREVENT PHENOTYPIC EPIGENETIC IMPRINTS IN NP. THUS, C286 IS A PROMISING DRUG CANDIDATE FOR NEUROPATHIC PAIN AND DNA REPAIR MECHANISMS MAY BE USEFUL THERAPEUTIC TARGETS TO EXPLORE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12 4742  48 NOVEL HISTONE MODIFICATIONS IN MICROGLIA DERIVED FROM A MOUSE MODEL OF CHRONIC PAIN. AS THE RESIDENT IMMUNE CELLS IN THE CENTRAL NERVOUS SYSTEM, MICROGLIA PLAY AN IMPORTANT ROLE IN THE MAINTENANCE OF ITS HOMEOSTASIS. DYSREGULATION OF MICROGLIA HAS BEEN ASSOCIATED WITH THE DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, THE RELEVANT MOLECULAR PATHWAYS REMAIN POORLY DEFINED. IN THIS STUDY, WE USED A MASS SPECTROMETRY-BASED PROTEOMIC APPROACH TO SCREEN POTENTIAL CHANGES OF HISTONE PROTEIN MODIFICATIONS IN MICROGLIA ISOLATED FROM THE BRAIN OF CONTROL AND CISPLATIN-INDUCED NEUROPATHIC PAIN ADULT C57BL/6J MALE MICE. WE IDENTIFIED SEVERAL NOVEL MICROGLIAL HISTONE MODIFICATIONS ASSOCIATED WITH PAIN, INCLUDING STATISTICALLY SIGNIFICANTLY DECREASED HISTONE H3.1 LYSINE 27 MONO-METHYLATION (H3.1K27ME1, 54.8% OF CONTROL) AND H3 LYSINE 56 TRI-METHYLATION (7.5% OF CONTROL), AS WELL AS A TREND SUGGESTING INCREASED H3 TYROSINE 41 NITRATION. WE FURTHER INVESTIGATED THE FUNCTIONAL ROLE OF H3.1K27ME1 AND FOUND THAT TREATMENT OF CULTURED MICROGLIAL CELLS FOR 4 CONSECUTIVE DAYS WITH 1-10 MUM OF NCDM-64, A POTENT AND SELECTIVE INHIBITOR OF LYSINE DEMETHYLASE 7A, AN ENZYME RESPONSIBLE FOR THE DEMETHYLATION OF H3K27ME1, DOSE-DEPENDENTLY ELEVATED ITS LEVELS WITH A GREATER THAN A TWO-FOLD INCREASE OBSERVED AT 10 MUM COMPARED TO VEHICLE-TREATED CONTROL CELLS. MOREOVER, PRETREATMENT OF MICE WITH NCDM-64 (10 OR 25 MG/KG/DAY, I.P.) PRIOR TO CISPLATIN TREATMENT PREVENTED THE DEVELOPMENT OF NEUROPATHIC PAIN IN MICE. THE IDENTIFICATION OF SPECIFIC CHROMATIN MARKS IN MICROGLIA ASSOCIATED WITH CHRONIC PAIN MAY YIELD CRITICAL INSIGHT INTO THE CONTRIBUTION OF MICROGLIA TO THE DEVELOPMENT AND MAINTENANCE OF PAIN, AND OPENS NEW AVENUES FOR THE DEVELOPMENT OF NOVEL NONOPIOID THERAPEUTICS FOR THE EFFECTIVE MANAGEMENT OF CHRONIC PAIN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13 2967  51 GENETIC AND EPIGENETIC REGULATION OF CATECHOL-O-METHYLTRANSFERASE IN RELATION TO INFLAMMATION IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA. BACKGROUND: CATECHOL-O-METHYLTRANSFERASE (COMT) HAS BEEN SHOWN TO INFLUENCE CLINICAL PAIN, DESCENDING MODULATION, AND EXERCISE-INDUCED SYMPTOM WORSENING. COMT REGULATES NOCICEPTIVE PROCESSING AND INFLAMMATION, KEY PATHOPHYSIOLOGICAL FEATURES OF CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA (CFS/FM). WE AIMED TO DETERMINE THE INTERACTIONS BETWEEN GENETIC AND EPIGENETIC MECHANISMS REGULATING COMT AND ITS INFLUENCE ON INFLAMMATORY MARKERS AND SYMPTOMS IN PATIENTS WITH CFS/FM. METHODS: A CASE-CONTROL STUDY WITH REPEATED-MEASURES DESIGN WAS USED TO REDUCE THE CHANCE OF FALSE POSITIVE AND INCREASE THE POWER OF OUR FINDINGS. FIFTY-FOUR PARTICIPANTS (28 PATIENTS WITH CFS/FM AND 26 CONTROLS) WERE ASSESSED TWICE WITHIN 4 DAYS. THE ASSESSMENT INCLUDED CLINICAL QUESTIONNAIRES, NEUROPHYSIOLOGICAL ASSESSMENT (PAIN THRESHOLDS, TEMPORAL SUMMATION, AND CONDITIONED PAIN MODULATION), AND BLOOD WITHDRAWAL IN ORDER TO ASSESS RS4818, RS4633, AND RS4680 COMT POLYMORPHISMS AND PERFORM HAPLOTYPE ESTIMATION, DNA METHYLATION IN THE COMT GENE (BOTH MB-COMT AND S-COMT PROMOTERS), AND CYTOKINE EXPRESSION (TNF-ALPHA, IFN-GAMMA, IL-6, AND TGF-BETA). RESULTS: COMT HAPLOTYPES WERE ASSOCIATED WITH DNA METHYLATION IN THE S-COMT PROMOTER, TGF-BETA EXPRESSION, AND SYMPTOMS. HOWEVER, THIS WAS NOT SPECIFIC FOR ONE CONDITION. SIGNIFICANT BETWEEN-GROUP DIFFERENCES WERE FOUND FOR INCREASED DNA METHYLATION IN THE MB-COMT PROMOTER AND DECREASED IFN-GAMMA EXPRESSION IN PATIENTS. DISCUSSION: OUR RESULTS ARE CONSISTENT WITH BASIC AND CLINICAL RESEARCH, PROVIDING INTERESTING INSIGHTS INTO GENETIC-EPIGENETIC REGULATORY MECHANISMS. MB-COMT DNA METHYLATION MIGHT BE AN INDEPENDENT FACTOR CONTRIBUTING TO THE PATHOPHYSIOLOGY OF CFS/FM. FURTHER RESEARCH ON DNA METHYLATION IN COMPLEX CONDITIONS SUCH AS CFS/FM IS WARRANTED. WE RECOMMEND FUTURE RESEARCH TO EMPLOY A REPEATED-MEASURE DESIGN TO CONTROL FOR BIOMARKERS VARIABILITY AND WITHIN-SUBJECT CHANGES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14 2680  41 EVALUATION OF EPIGENETIC (HDAC, DNMT) AND PAIN (GAD65, TGF) FACTORS FOLLOWING PHOTOBIOMODULATION THERAPY IN A NEUROPATHIC PAIN MODEL. PHOTOBIOMODULATION THERAPY (PBMT) IS CONVERTED TO THE MOST COMMON ANALGESIC TREATMENT BEFORE THE WHOLE MECHANISM IS YET TO BE DISCOVERED. THIS STUDY FOR THE FIRST TIME WAS DESIGNED TO INVESTIGATE ALTERNATIONS OF EPIGENETIC FACTORS AFTER PAIN AND PBMT. THE CCI MODEL WAS CHOSEN TO INDUCE PAIN. PAIN EVALUATION TESTS INCLUDING PLANTAR, ACETONE, VON FREY, AND PINCH WERE DONE WEEKLY. THEN SPINAL CORD TISSUE WAS ISOLATED FOR EVALUATING MRNA EXPRESSION OF DNMT3A, HDAC1, AND NRSF USING RT-QPCR METHOD, AND PROTEIN EXPRESSION FACTORS OF HDAC2 AND DNMT3A USING WESTERN BLOTTING. GAD65 AND TGF-BETA PROTEINS WERE ASSESSED BY THE IHC METHOD. PBMT INCREASED THE PAIN THRESHOLD UP TO THE POINT WHERE IT ROUGHLY MET THE PAIN THRESHOLD OF THE CONTROL GROUP. AFTER THREE WEEKS OF TREATMENT, BOTH PBMT PROTOCOLS DEMONSTRATED A REDUCTION IN ALLODYNIA AND HYPERALGESIA. WHILE SOME MOLECULES, SUCH AS TGF-BETA AND GAD65, INCREASED FOLLOWING PBMT, WE OBSERVED NO INHIBITION OF NRSF, HDAC1, AND DNMT3A EXPRESSION DESPITE IMPLEMENTING TWO DIFFERENT PROTOCOLS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15 2714  41 EXERCISE-CONDITIONED PLASMA ATTENUATES NUCLEAR CONCENTRATIONS OF DNA METHYLTRANSFERASE 3B IN HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS. DNA METHYLATION IS MODIFIABLE BY ACUTE AND CHRONIC EXERCISE. DNA METHYLTRANSFERASES (DNMT) CATALYZE THIS PROCESS; HOWEVER, THERE IS A LACK OF LITERATURE CONCERNING THE SPECIFIC MECHANISMS BY WHICH EXERCISE-INDUCED MODIFICATIONS OCCUR. INTERLEUKIN 6 (IL-6) STIMULATION OF VARIOUS CELL LINES HAS BEEN SHOWN TO AUGMENT DNMT EXPRESSION AND NUCLEAR TRANSLOCATION, WHICH SUGGESTS A POSSIBLE PATHWAY BY WHICH EXERCISE IS ABLE TO ELICIT CHANGES IN EPIGENETIC ENZYMES. THE PRESENT STUDY SOUGHT TO ELUCIDATE THE RESPONSE OF THE DE NOVO METHYLTRANSFERASES DNMT3A AND DNMT3B TO CIRCULATORY FACTORS FOUND IN PLASMA ISOLATED FROM WHOLE BLOOD BEFORE AND AFTER 120-MIN OF TREADMILL RUNNING AT AN INTENSITY OF 60% OF INDIVIDUAL VELOCITY AT V O2MAX (VV O2MAX) INTERSPERSED WITH 30-SEC SPRINTS AT 90% OF VV O2MAX EVERY 10-MIN. PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) ISOLATED FROM A RESTING PARTICIPANT WERE INCUBATED WITH PLASMA ISOLATED FROM EXERCISING PARTICIPANTS (N = 10) OR RECOMBINANT IL-6 (RIL-6), FOLLOWED BY NUCLEAR PROTEIN EXTRACTION AND QUANTIFICATION OF DNMT3A AND DNMT3B CONCENTRATIONS. NUCLEAR CONCENTRATIONS OF DNMT3B SIGNIFICANTLY DECREASED FOLLOWING THE EXPERIMENTAL PROTOCOL (P = 0.03), WITH NO CHANGE OBSERVED IN DNMT3A (P = 0.514).VARIOUS CONCENTRATIONS OF RIL-6 CAUSED AN ELEVATION IN BOTH DNMT3A AND DNMT3B NUCLEAR CONCENTRATION COMPARED WITH THE BLANK CONTROL. THE CONFLICTING RESULTS BETWEEN EXERCISING AND RIL-6 CONDITIONS SUGGESTS THAT IL-6 DOES REGULATE DNMT NUCLEAR TRANSPORT, HOWEVER, OTHER PLASMA MEDIATORS MAY ALSO EXERT SIGNIFICANT INFLUENCE ON THE NUCLEAR CONCENTRATIONS OF THESE ENZYMES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16  905  36 CHRONIC EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE CAUSES LONG-LASTING BEHAVIORAL DEFICITS IN ADULT MICE. REGULAR USE OF MARIJUANA DURING ADOLESCENCE ENHANCES THE RISK OF LONG-LASTING NEUROBIOLOGICAL CHANGES IN ADULTHOOD. THE PRESENT STUDY WAS AIMED AT ASSESSING THE EFFECT OF LONG-TERM ADMINISTRATION OF THE SYNTHETIC CANNABINOID WIN55212.2 DURING ADOLESCENCE IN YOUNG ADULT MICE. ADOLESCENT MICE AGED 5 WEEKS WERE SUBJECTED DAILY TO THE PHARMACOLOGICAL ACTION OF WIN55212.2 FOR 3 WEEKS AND WERE THEN LEFT UNDISTURBED IN THEIR HOME CAGE FOR A 5-WEEK PERIOD AND FINALLY EVALUATED BY BEHAVIORAL TESTING. MICE THAT RECEIVED THE DRUG DURING ADOLESCENCE SHOWED MEMORY IMPAIRMENT IN THE MORRIS WATER MAZE, AS WELL AS A DOSE-DEPENDENT MEMORY IMPAIRMENT IN FEAR CONDITIONING. IN ADDITION, THE ADMINISTRATION OF 3 MG/KG WIN55212.2 IN ADOLESCENCE INCREASED ADULT HIPPOCAMPAL AEA LEVELS AND PROMOTED DNA HYPERMETHYLATION AT THE INTRAGENIC REGION OF THE INTRACELLULAR SIGNALING MODULATOR RGS7, WHICH WAS ACCOMPANIED BY A LOWER RATE OF MRNA TRANSCRIPTION OF THIS GENE, SUGGESTING A POTENTIAL CAUSAL RELATION. ALTHOUGH THE CONCRETE MECHANISMS UNDERLYING THE BEHAVIORAL OBSERVATIONS REMAIN TO BE ELUCIDATED, WE DEMONSTRATE THAT LONG-TERM ADMINISTRATION OF 3 MG/KG OF WIN DURING ADOLESCENCE LEADS TO INCREASED ENDOCANNABINOID LEVELS AND ALTERED RGS7 EXPRESSION IN ADULTHOOD AND ESTABLISH A POTENTIAL LINK TO EPIGENETIC CHANGES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17 6156  29 THE GENETIC INFLUENCE ON THE CORTICAL PROCESSING OF EXPERIMENTAL PAIN AND THE MODERATING EFFECT OF PAIN STATUS. BACKGROUND: RESEARCH SUGGESTS THAT THE COMT VAL(158)MET, BDNF VAL(66)MET AND OPRM1 A(118)G POLYMORPHISMS MODERATE THE EXPERIENCE OF PAIN. IN ORDER TO OBTAIN EXPERIMENTAL CONFIRMATION AND EXTENSION OF FINDINGS, CORTICAL PROCESSING OF EXPERIMENTALLY-INDUCED PAIN WAS USED. METHOD: A SAMPLE OF 78 INDIVIDUALS WITH CHRONIC LOW BACK PAIN COMPLAINTS AND 37 HEALTHY CONTROLS UNDERWENT EEG REGISTRATION. EVENT-RELATED POTENTIALS WERE MEASURED IN RESPONSE TO ELECTRICAL NOCICEPTIVE STIMULI AND MODERATION BY COMT VAL(158)MET, BDNF VAL(66)MET AND OPRM1 A(118)G POLYMORPHISMS WAS ASSESSED. RESULTS: GENETIC VARIATION DID NOT HAVE A DIRECT EFFECT ON CORTICAL PROCESSING OF EXPERIMENTAL PAIN. HOWEVER, GENETIC EFFECTS (COMT VAL(158)MET AND BDNF VAL(66)MET) ON EXPERIMENTAL PAIN WERE MODERATED BY THE PRESENCE OF CHRONIC PAIN. IN THE PRESENCE OF CHRONIC PAIN, THE COMT MET ALLELE AND THE BDNF MET ALLELE AUGMENTED CORTICAL PAIN PROCESSING, WHILST REDUCING PAIN PROCESSING IN PAIN-FREE CONTROLS. NO SIGNIFICANT EFFECTS WERE FOUND CONCERNING THE OPRM1 A(118)G POLYMORPHISM. CONCLUSIONS: THE CURRENT STUDY SUGGESTS THAT CHRONIC EXPERIENCE OF PAIN ENHANCES GENETIC SENSITIVITY TO EXPERIMENTALLY INDUCED MILDLY PAINFUL STIMULI, POSSIBLY THROUGH A PROCESS OF EPIGENETIC MODIFICATION.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18 1434  51 DIFFERENTIAL METHYLATION AND EXPRESSION OF GENES IN THE HYPOXIA-INDUCIBLE FACTOR 1 SIGNALING PATHWAY ARE ASSOCIATED WITH PACLITAXEL-INDUCED PERIPHERAL NEUROPATHY IN BREAST CANCER SURVIVORS AND WITH PRECLINICAL MODELS OF CHEMOTHERAPY-INDUCED NEUROPATHIC PAIN. BACKGROUND: PACLITAXEL IS AN IMPORTANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER. PACLITAXEL-INDUCED PERIPHERAL NEUROPATHY (PIPN) IS A MAJOR DOSE-LIMITING TOXICITY THAT CAN PERSIST INTO SURVIVORSHIP. WHILE NOT ALL SURVIVORS DEVELOP PIPN, FOR THOSE WHO DO, IT HAS A SUBSTANTIAL NEGATIVE IMPACT ON THEIR FUNCTIONAL STATUS AND QUALITY OF LIFE. NO INTERVENTIONS ARE AVAILABLE TO TREAT PIPN. IN OUR PREVIOUS STUDIES, WE IDENTIFIED THAT THE HIF-1 SIGNALING PATHWAY (H1SP) WAS PERTURBED BETWEEN BREAST CANCER SURVIVORS WITH AND WITHOUT PIPN. PRECLINICAL STUDIES SUGGEST THAT THE H1SP IS INVOLVED IN THE DEVELOPMENT OF BORTEZOMIB-INDUCED AND DIABETIC PERIPHERAL NEUROPATHY, AND SCIATIC NERVE INJURY. THE PURPOSE OF THIS STUDY WAS TO IDENTIFY H1SP GENES THAT HAVE BOTH DIFFERENTIAL METHYLATION AND DIFFERENTIAL GENE EXPRESSION BETWEEN BREAST CANCER SURVIVORS WITH AND WITHOUT PIPN. METHODS: A MULTI-STAGED INTEGRATED ANALYSIS WAS PERFORMED. IN PERIPHERAL BLOOD, METHYLATION WAS ASSAYED USING MICROARRAY AND GENE EXPRESSION WAS ASSAYED USING RNA-SEQ. CANDIDATE GENES IN THE H1SP HAVING BOTH DIFFERENTIALLY METHYLATION AND DIFFERENTIAL EXPRESSION WERE IDENTIFIED BETWEEN SURVIVORS WHO RECEIVED PACLITAXEL AND DID (N = 25) AND DID NOT (N = 25) DEVELOP PIPN. THEN, CANDIDATE GENES WERE EVALUATED FOR DIFFERENTIAL METHYLATION AND DIFFERENTIAL EXPRESSION IN PUBLIC DATA SETS OF PRECLINICAL MODELS OF PIPN AND SCIATIC NERVE INJURY. RESULTS: EIGHT CANDIDATE GENES WERE IDENTIFIED AS BOTH DIFFERENTIAL METHYLATION AND DIFFERENTIAL EXPRESSION IN SURVIVORS. OF THE EIGHT HOMOLOGS IDENTIFIED, ONE WAS FOUND TO BE DIFFERENTIAL EXPRESSION IN BOTH PIPN AND "NORMAL" MICE DORSAL ROOT GANGLIA; THREE WERE DIFFERENTIAL METHYLATION IN SCIATIC NERVE INJURY VERSUS SHAM RATS IN BOTH PRE-FRONTAL CORTEX AND T-CELLS; AND TWO WERE DIFFERENTIAL METHYLATION IN SCIATIC NERVE INJURY VERSUS SHAM RATS IN THE PRE-FRONTAL CORTEX. CONCLUSIONS: THIS STUDY IS THE FIRST TO EVALUATE FOR METHYLATION IN CANCER SURVIVORS WITH CHRONIC PIPN. THE FINDINGS PROVIDE EVIDENCE THAT THE EXPRESSION OF H1SP GENES ASSOCIATED WITH CHRONIC PIPN IN CANCER SURVIVORS MAY BE REGULATED BY EPIGENETIC MECHANISMS AND SUGGESTS GENES FOR VALIDATION AS POTENTIAL THERAPEUTIC TARGETS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19  433  42 ANTIDEPRESSANT TREATMENT IS ASSOCIATED WITH EPIGENETIC ALTERATIONS OF HOMER1 PROMOTER IN A MOUSE MODEL OF CHRONIC DEPRESSION. BACKGROUND: UNDERSTANDING THE NEUROBIOLOGY OF DEPRESSION AND THE MECHANISM OF ACTION OF THERAPEUTIC MEASURES IS CURRENTLY A RESEARCH PRIORITY. WE HAVE SHOWN THAT THE EXPRESSION OF THE SYNAPTIC PROTEIN HOMER1A CORRELATES WITH DEPRESSION-LIKE BEHAVIOR AND ITS INDUCTION IS A COMMON MECHANISM OF ACTION OF DIFFERENT ANTIDEPRESSANT TREATMENTS. HOWEVER, THE MECHANISM OF HOMER1A REGULATION IS STILL UNKNOWN. METHODS: WE COMBINED THE CHRONIC DESPAIR MOUSE MODEL (CDM) OF CHRONIC DEPRESSION WITH DIFFERENT ANTIDEPRESSANT TREATMENTS. DEPRESSION-LIKE BEHAVIOR WAS CHARACTERIZED BY FORCED SWIM AND TAIL SUSPENSION TESTS, AND VIA AUTOMATIC MEASUREMENT OF SUCROSE PREFERENCE IN INTELLICAGE. THE HOMER1 MRNA EXPRESSION AND PROMOTER DNA METHYLATION WERE ANALYZED IN CORTEX AND PERIPHERAL BLOOD BY QRT-PCR AND PYROSEQUENCING. RESULTS: CDM MICE SHOW DECREASED HOMER1A AND HOMER1B/C MRNA EXPRESSION IN CORTEX AND BLOOD SAMPLES, WHILE CHRONIC TREATMENT WITH IMIPRAMINE AND FLUOXETINE OR ACUTE KETAMINE APPLICATION INCREASES THEIR LEVEL ONLY IN THE CORTEX. THE QUANTITATIVE ANALYSES OF THE METHYLATION OF 7 CPG SITES, LOCATED ON THE HOMER1 PROMOTER REGION CONTAINING SEVERAL CRE BINDING SITES, SHOW A SIGNIFICANT INCREASE IN DNA METHYLATION IN THE CORTEX OF CDM MICE. IN CONTRAST, ANTIDEPRESSANT TREATMENTS REDUCE THE METHYLATION LEVEL. LIMITATIONS: HOMER1 EXPRESSION AND PROMOTOR METHYLATION WERE NOT ANALYZED IN DIFFERENT BLOOD CELL TYPES. OTHER CPG SITES OF HOMER1 PROMOTER SHOULD BE INVESTIGATED IN FUTURE STUDIES. OUR EXPERIMENTAL APPROACH DOES NOT DISTINGUISH BETWEEN METHYLATION AND HYDROXYMETHYLATION. CONCLUSIONS: WE DEMONSTRATE THAT STRESS-INDUCED DEPRESSION-LIKE BEHAVIOR AND ANTIDEPRESSANT TREATMENTS ARE ASSOCIATED WITH EPIGENETIC ALTERATIONS OF HOMER1 PROMOTER, PROVIDING NEW INSIGHTS INTO THE MECHANISM OF ANTIDEPRESSANT TREATMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20 2470  54 EPIGENETIC TRANSCRIPTIONAL ACTIVATION OF MONOCYTE CHEMOTACTIC PROTEIN 3 CONTRIBUTES TO LONG-LASTING NEUROPATHIC PAIN. A MULTIPLEX ANALYSIS FOR PROFILING THE EXPRESSION OF CANDIDATE GENES ALONG WITH EPIGENETIC MODIFICATION MAY LEAD TO A BETTER UNDERSTANDING OF THE COMPLEX MACHINERY OF NEUROPATHIC PAIN. IN THE PRESENT STUDY, WE FOUND THAT PARTIAL SCIATIC NERVE LIGATION MOST REMARKABLY INCREASED THE EXPRESSION OF MONOCYTE CHEMOTACTIC PROTEIN 3 (MCP-3, KNOWN AS CCL7) A TOTAL OF 33 541 GENES IN THE SPINAL CORD, WHICH LASTED FOR 4 WEEKS. THIS INCREASE IN MCP-3 GENE TRANSCRIPTION WAS ACCOMPANIED BY THE DECREASED TRIMETHYLATION OF HISTONE H3 AT LYS27 AT THE MCP-3 PROMOTER. THE INCREASED MCP-3 EXPRESSION ASSOCIATED WITH ITS EPIGENETIC MODIFICATION OBSERVED IN THE SPINAL CORD WAS ALMOST ABOLISHED IN INTERLEUKIN 6 KNOCKOUT MICE WITH PARTIAL SCIATIC NERVE LIGATION. CONSISTENT WITH THESE FINDINGS, A SINGLE INTRATHECAL INJECTION OF RECOMBINANT PROTEINS OF INTERLEUKIN 6 SIGNIFICANTLY INCREASED MCP-3 MESSENGER RNA WITH A DECREASE IN THE LEVEL OF LYS27 TRIMETHYLATION OF HISTONE H3 AT THE MCP-3 PROMOTER IN THE SPINAL CORD OF MICE. FURTHERMORE, DELETION OF THE C-C CHEMOKINE RECEPTOR TYPE 2 (CCR2) GENE, WHICH ENCODES A RECEPTOR FOR MCP-3, FAILED TO AFFECT THE ACCELERATION OF MCP-3 EXPRESSION IN THE SPINAL CORD AFTER PARTIAL SCIATIC NERVE LIGATION. A ROBUST INCREASE IN MCP-3 PROTEIN, WHICH LASTED FOR UP TO 2 WEEKS AFTER SURGERY, IN THE DORSAL HORN OF THE SPINAL CORD OF MICE WITH PARTIAL SCIATIC NERVE LIGATION WAS SEEN MOSTLY IN ASTROCYTES, BUT NOT MICROGLIA OR NEURONS. ON THE OTHER HAND, THE INCREASES IN BOTH MICROGLIA AND ASTROCYTES IN THE SPINAL CORD BY PARTIAL SCIATIC NERVE LIGATION WERE MOSTLY ABOLISHED IN INTERLEUKIN 6 KNOCKOUT MICE. MOREOVER, THIS INCREASE IN MICROGLIA WAS ALMOST ABOLISHED BY CCR2 GENE DELETION, WHEREAS THE INCREASE IN ASTROCYTES WAS NOT AFFECTED IN NERVE-LIGATED MICE THAT LACKED THE CCR2 GENE. WE ALSO FOUND THAT EITHER IN VIVO OR IN VITRO TREATMENT WITH MCP-3 CAUSED ROBUST MICROGLIA ACTIVATION. UNDER THESE CONDITIONS, INTRATHECAL ADMINISTRATION OF MCP-3 ANTIBODY SUPPRESSED THE INCREASE IN MICROGLIA WITHIN THE MOUSE SPINAL CORD AND NEUROPATHIC PAIN-LIKE BEHAVIOURS AFTER NERVE INJURY. WITH THE USE OF A FUNCTIONAL MAGNETIC RESONANCE IMAGING ANALYSIS, WE DEMONSTRATED THAT A SINGLE INTRATHECAL INJECTION OF MCP-3 INDUCED DRAMATIC INCREASES IN SIGNAL INTENSITY IN PAIN-RELATED BRAIN REGIONS. THESE FINDINGS SUGGEST THAT INCREASED MCP-3 EXPRESSION ASSOCIATED WITH INTERLEUKIN 6 DEPENDENT EPIGENETIC MODIFICATION AT THE MCP-3 PROMOTER AFTER NERVE INJURY, MOSTLY IN SPINAL ASTROCYTES, MAY SERVE TO FACILITATE ASTROCYTE-MICROGLIA INTERACTION IN THE SPINAL CORD AND COULD PLAY A CRITICAL ROLE IN THE NEUROPATHIC PAIN-LIKE STATE.	2013