1  3619 139 IN VIVO ACUTE ON CHRONIC ETHANOL EFFECTS IN LIVER: A MOUSE MODEL EXHIBITING EXACERBATED INJURY, ALTERED METABOLIC AND EPIGENETIC RESPONSES. CHRONIC ALCOHOLICS WHO ALSO BINGE DRINK (I.E., ACUTE ON CHRONIC) ARE PRONE TO AN EXACERBATED LIVER INJURY BUT ITS MECHANISM IS NOT UNDERSTOOD. WE THEREFORE INVESTIGATED THE IN VIVO EFFECTS OF CHRONIC AND BINGE ETHANOL INGESTION AND COMPARED TO CHRONIC ETHANOL FOLLOWED BY THREE REPEAT BINGE ETHANOL ON THE LIVER OF MALE C57/BL6 MICE FED ETHANOL IN LIQUID DIET (4%) FOR FOUR WEEKS FOLLOWED BY BINGE ETHANOL (INTRAGASTRIC ADMINISTRATION, 3.5 G/KG BODY WEIGHT, THREE DOSES, 12H APART). CHRONIC FOLLOWED BY BINGE ETHANOL EXACERBATED FAT ACCUMULATION, NECROSIS, DECREASE IN HEPATIC SAM AND SAM:SAH RATIO, INCREASE IN ADENOSINE LEVELS, AND ELEVATED CYP2E1 LEVELS. HISTONE H3 LYSINE ACETYLATION (H3ACK9), DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10), AND PHOSPHORYLATED H2AX INCREASED AFTER BINGE WHEREAS PHOSPHORYLATION OF HISTONE H3 SER 10 (H3S10) AND H3 SER 28 (H3S28) INCREASED AFTER CHRONIC ETHANOL-BINGE. HISTONE H3 LYSINE 4 AND 9 DIMETHYLATION INCREASED WITH A MARKED DIMETHYLATION IN H3K9 IN CHRONIC ETHANOL BINGE GROUP. TRIMETHYLATED HISTONE H3 LEVELS DID NOT CHANGE. NUCLEAR LEVELS OF HISTONE ACETYL TRANSFERASE GCN5 AND HISTONE DEACETYLASE HDAC3 WERE ELEVATED WHEREAS PHOSPHO-CREB DECREASED IN A DISTINCTIVE MANNER. TAKEN TOGETHER, ACUTE ON CHRONIC ETHANOL INGESTION CAUSED AMPLIFICATION OF LIVER INJURY AND ELICITED CHARACTERISTIC PROFILES OF HISTONE MODIFICATIONS, METABOLIC ALTERATIONS, AND CHANGES IN NUCLEAR PROTEIN LEVELS. THESE FINDINGS DEMONSTRATE THAT CHRONIC ETHANOL EXPOSURE RENDERS LIVER MORE SUSCEPTIBLE TO REPEAT ACUTE/BINGE ETHANOL INDUCED ACCELERATION OF ALCOHOLIC LIVER DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  3321  36 HISTONE ACETYLATION OF THE HTR3A GENE IN THE PREFRONTAL CORTEX OF WISTAR RATS REGULATES ETHANOL-SEEKING BEHAVIOR. PREVIOUS REPORTS SHOWED THAT DECREASED HISTONE DEACETYLASE ACTIVITY SIGNIFICANTLY POTENTIATED THE REWARDING EFFECTS OF PSYCHOSTIMULANTS, AND THAT ENCODING OF THE 5-HT3 RECEPTOR BY THE HTR3A GENE WAS RELATED TO ETHANOL-SEEKING BEHAVIOR. HOWEVER, THE EFFECTS OF A HISTONE DEACETYLASE INHIBITOR ON ETHANOL-SEEKING BEHAVIOR AND EPIGENETIC REGULATION OF HTR3A MRNA EXPRESSION AFTER CHRONIC ETHANOL EXPOSURE ARE NOT FULLY UNDERSTOOD. USING QUANTITATIVE REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION AND CHROMATIN IMMUNOPRECIPITATION ANALYSIS, WE INVESTIGATED THE EFFECTS OF CHRONIC ETHANOL EXPOSURE AND ITS INTERACTION WITH A HISTONE DEACETYLASE INHIBITOR ON HISTONE-ACETYLATION-MEDIATED CHANGES IN HTR3A MRNA EXPRESSION IN THE HTR3A PROMOTER REGION. THE CONDITIONED PLACE PREFERENCE PROCEDURE WAS USED TO EVALUATE ETHANOL-SEEKING BEHAVIOR. CHRONIC EXPOSURE TO ETHANOL EFFECTIVELY ELICITED PLACE CONDITIONING. IN THE PREFRONTAL CORTEX, THE ACETYLATION OF H3K9 AND HTR3A MRNA EXPRESSION IN THE HTR3A PROMOTER REGION WERE SIGNIFICANTLY HIGHER IN THE ETHANOL GROUP THAN IN THE SALINE GROUP. THE HISTONE DEACETYLASE INHIBITOR SODIUM BUTYRATE POTENTIATED THE EFFECTS OF ETHANOL ON HTR3A MRNA EXPRESSION AND ENHANCED ETHANOL-INDUCED CONDITIONED PLACE PREFERENCES. THESE RESULTS SUGGEST THAT ETHANOL UPREGULATES HTR3A LEVELS THROUGH MECHANISMS INVOLVING H3K9 ACETYLATION, AND THAT HISTONE ACETYLATION MAY BE A THERAPEUTIC TARGET FOR TREATING ETHANOL ABUSE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
3  1920  37 ENVIRONMENTAL ENRICHMENT PREVENTS STRESS-INDUCED EPIGENETIC CHANGES IN THE EXPRESSION OF GLUCOCORTICOID RECEPTOR AND CORTICOTROPHIN RELEASING HORMONE IN THE CENTRAL NUCLEUS OF THE AMYGDALA TO INHIBIT VISCERAL HYPERSENSITIVITY. INTRODUCTION: STRESS IS A KNOWN TRIGGER FOR THE SYMPTOMS OF IRRITABLE BOWEL SYNDROME (IBS), A GASTROINTESTINAL (GI) DISORDER THAT PRESENTS WITH ABNORMAL BOWEL HABITS AND ABDOMINAL PAIN DUE TO VISCERAL HYPERSENSITIVITY. WHILE BEHAVIORAL THERAPIES HAVE BEEN USED TO ATTENUATE IBS SYMPTOMS, THE UNDERLYING MECHANISMS BY WHICH THESE THERAPIES INTERACT WITH STRESS-INDUCED PATHOLOGY REMAINS TO BE DELINEATED. HERE WE USE A RAT MODEL TO TEST THE HYPOTHESIS THAT EXPOSURE TO ENVIRONMENTAL ENRICHMENT (EE) INHIBITS STRESS-INDUCED CHANGES WITHIN THE BRAIN-GUT AXIS TO PREVENT VISCERAL AND SOMATIC HYPERSENSITIVITY AND COLONIC HYPERPERMEABILITY. METHODS: FEMALE RATS (N = 8/GROUP) WERE HOUSED IN EE ONE WEEK BEFORE AND ONE WEEK DURING EXPOSURE TO WATER AVOIDANCE STRESS (WAS) WHILE CONTROLS WERE HOUSED IN STANDARD CAGES (SH). ONE DAY AFTER THE FINAL WAS EXPOSURE, COLONIC AND SOMATIC SENSITIVITY WERE ASSESSED BY THE VISCEROMOTOR RESPONSE (VMR) TO COLORECTAL DISTENSION (CRD) AND WITHDRAWAL THRESHOLD ELICITED BY AN ELECTRONIC VON FREY ON THE HIND PAW OF THE RATS RESPECTIVELY. ALL RATS WERE RETURNED TO SH FOR 3 WEEKS BEFORE COLONIC AND SOMATIC SENSITIVITY WERE REASSESSED ON DAY 28. THE RATS WERE THEN IMMEDIATELY EUTHANIZED AND THE SPINAL CORD WAS COLLECTED TO ASSESS CHANGES IN NEURONAL ACTIVATION (ASSESSED VIA ERK PHOSPHORYLATION) IN RESPONSE TO NOXIOUS CRD. A SEPARATE COHORT OF ANIMALS (N = 8/GROUP) THAT DID NOT UNDERGO BEHAVIORAL ASSESSMENTS WAS EUTHANIZED THE DAY AFTER THE FINAL WAS EXPOSURE AND THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA) WAS COLLECTED TO INVESTIGATE WAS AND EE INDUCED EPIGENETIC CHANGES AT THE GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN RELEASING HORMONE (CRH) PROMOTER. THE COLON FROM THESE RATS WAS ALSO COLLECTED TO ASSESS COLONIC PERMEABILITY VIA CHANGES IN TRANSEPITHELIAL ELECTRICAL RESISTANCE (TEER) IN VITRO. RESULTS: EXPOSURE TO STRESS PERSISTENTLY INCREASED VMR TO CRD (P < 0.01) AND DECREASED THE HIND PAW WITHDRAWAL THRESHOLD (P < 0.001) IN FEMALE RATS. WAS ALSO DECREASED TEER IN THE COLON TISSUE OF FEMALE RATS (P = 0.05). IN THE CEA, WAS INDUCED A DECREASE IN HISTONE ACETYLATION AT THE GR PROMOTER BUT INCREASED HISTONE ACETYLATION AT THE CRH PROMOTER AND REDUCED GR-CRH INTERACTIONS IN THE CEA. ANALYSIS OF THE SPINAL CORD SHOWED THAT WAS INCREASED CRD-EVOKED ERK PHOSPHORYLATION IN THE DORSAL HORN. EXPOSURE TO EE PREVENTED WAS-INDUCED CHANGES IN THE CEA, DORSAL HORN AND COLON RESPECTIVELY TO PREVENT VISCERAL AND SOMATIC HYPERSENSITIVITY. CONCLUSION: OUR DATA REVEALS THAT BEHAVIORAL THERAPIES CAN PRODUCE LONG LASTING MOLECULAR AND EPIGENETIC CHANGES THAT CAN PREVENT STRESS-INDUCED PATHOLOGIES EVEN AFTER COMPLETION OF THE THERAPY. THESE RESULTS HIGHLIGHT THE POTENTIAL MECHANISMS BY WHICH BEHAVIORAL THERAPIES MAY AMELIORATE VISCERAL PAIN ASSOCIATED STRESS-RELATED PATHOLOGIES SUCH AS THE IRRITABLE BOWEL SYNDROME.	2021	

4  2120  69 EPIGENETIC HISTONE MODIFICATIONS IN A CLINICALLY RELEVANT RAT MODEL OF CHRONIC ETHANOL-BINGE-MEDIATED LIVER INJURY. PURPOSE: ETHANOL BINGE AUGMENTS LIVER INJURY AFTER CHRONIC ETHANOL CONSUMPTION IN HUMANS, BUT THE MECHANISM BEHIND THE ENHANCED LIVER INJURY BY ETHANOL BINGE IS NOT KNOWN. IN THIS STUDY WE USED A CLINICALLY RELEVANT RAT MODEL IN WHICH LIVER INJURY IS AMPLIFIED BY BINGE AFTER CHRONIC ETHANOL TREATMENT AND INVESTIGATED THE IMPORTANCE OF HISTONE MODIFICATIONS. METHODS: EIGHT-WEEK-OLD SPRAGUE-DAWLEY RATS WERE FED ETHANOL IN A LIQUID DIET FOR 4 WEEKS. CONTROL RATS WERE FED AN ISOCALORIC LIQUID DIET. THIS WAS FOLLOWED BY THREE BINGE ADMINISTRATIONS OF ETHANOL (INTRAGASTRIC 5 G/KG BODY WEIGHT, 12 H APART). IN THE CONTROL, ETHANOL WAS REPLACED BY WATER. FOUR HOURS AFTER THE LAST BINGE ADMINISTRATION, LIVER SAMPLES WERE ANALYZED FOR HISTONE MODIFICATIONS AND PARAMETERS OF LIVER INJURY. RESULTS: CHRONIC ETHANOL ADMINISTRATION ALONE CAUSED AN INCREASE IN HISTONE H3 SER10 AND SER28 (H3S10 OR S28) PHOSPHORYLATION, AND BINGE ETHANOL REDUCED THEIR LEVELS. LEVELS OF DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10) INCREASED AFTER ACUTE BINGE ETHANOL AND REMAINED SAME AFTER CHRONIC ETHANOL BINGE. IN CONTRAST, HISTONE H3 LYSINE-9 ACETYLATION (H3ACK9) WAS NOT INCREASED AFTER CHRONIC ETHANOL BUT INCREASED SIGNIFICANTLY AFTER ACUTE BINGE AND CHRONIC ETHANOL BINGE. INCREASE IN HISTONE ACETYLATION WAS ACCOMPANIED BY INCREASED PHOSPHO-ERK1/2 IN THE NUCLEAR EXTRACTS. INCREASED ACETYLATION AFTER CHRONIC ETHANOL BINGE WAS ALSO ACCOMPANIED BY INCREASED PROTEIN LEVELS OF GCN5 HISTONE ACETYL TRANSFERASE AND A MODEST INCREASE IN HDAC3 IN THE NUCLEUS. HISTONE LYSINE-9 DIMETHYLATION WAS SIGNIFICANTLY INCREASED AFTER CHRONIC ETHANOL BINGE. CHRONIC ETHANOL BINGE ALSO RESULTED IN A DECREASE IN THE SAM:SAH RATIO WITH A RELATIVE DECREASE OF SAM LEVELS AND A CORRESPONDING INCREASE IN SAH LEVELS. CONCLUSIONS: ETHANOL BINGE AFTER CHRONIC ETHANOL ALTERED THE PROFILE OF SITE-SPECIFIC HISTONE MODIFICATIONS AND MAY UNDERLIE THE MECHANISM OF AUGMENTED LIVER INJURY BY CHRONIC-ETHANOL-BINGE-TREATED RATS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5  3869  28 JNK1 REGULATES HISTONE ACETYLATION IN TRIGEMINAL NEURONS FOLLOWING CHEMICAL STIMULATION. TRIGEMINAL NERVE FIBERS IN NASAL AND ORAL CAVITIES ARE SENSITIVE TO VARIOUS ENVIRONMENTAL HAZARDOUS STIMULI, WHICH TRIGGER MANY NEUROTOXIC PROBLEMS SUCH AS CHRONIC MIGRAINE HEADACHE AND TRIGEMINAL IRRITATED DISORDERS. HOWEVER, THE ROLE OF JNK KINASE CASCADE AND ITS EPIGENETIC MODULATION OF HISTONE REMODELING IN TRIGEMINAL GANGLION (TG) NEURONS ACTIVATED BY ENVIRONMENTAL NEUROTOXINS REMAINS UNKNOWN. HERE WE INVESTIGATED THE ROLE OF JNK/C-JUN CASCADE IN THE REGULATION OF ACETYLATION OF H3 HISTONE IN TG NEURONS FOLLOWING IN VITRO STIMULATION BY A NEURO-INFLAMMATORY AGENT, MUSTARD OIL (MO). WE FOUND THAT MO STIMULATION ELICITED JNK/C-JUN PATHWAY SIGNIFICANTLY BY ENHANCING PHOSPHO-JNK1, PHOSPHO-C-JUN EXPRESSION, AND C-JUN ACTIVITY, WHICH WERE CORRELATED WITH AN ELEVATED ACETYLATED H3 HISTONE IN TG NEURONS. HOWEVER, INCREASES IN PHOSPHO-C-JUN AND C-JUN ACTIVITY WERE SIGNIFICANTLY BLOCKED BY A JNK INHIBITOR, SP600125. WE ALSO FOUND THAT ALTERED H3 HISTONE REMODELING, ASSESSED BY H3 ACETYLATION IN TRIGGERED TG NEURONS, WAS REDUCED BY SP600125. THE STUDY SUGGESTS THAT THE ACTIVATED JNK SIGNALING IN REGULATION OF HISTONE REMODELING MAY CONTRIBUTE TO NEURO-EPIGENTIC CHANGES IN PERIPHERAL SENSORY NEURONS FOLLOWING ENVIRONMENTAL NEUROTOXIC EXPOSURE.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6  3358  26 HISTONE H3K9 METHYLATION REGULATES CHRONIC STRESS AND IL-6-INDUCED COLON EPITHELIAL PERMEABILITY AND VISCERAL PAIN. BACKGROUND: CHRONIC STRESS IS ASSOCIATED WITH ACTIVATION OF THE HPA AXIS, ELEVATION IN PRO-INFLAMMATORY CYTOKINES, DECREASE IN INTESTINAL EPITHELIAL CELL TIGHT JUNCTION (TJ) PROTEINS, AND ENHANCED VISCERAL PAIN. IT IS UNKNOWN WHETHER EPIGENETIC REGULATORY PATHWAYS PLAY A ROLE IN CHRONIC STRESS-INDUCED INTESTINAL BARRIER DYSFUNCTION AND VISCERAL HYPERALGESIA. METHODS: YOUNG ADULT MALE RATS WERE SUBJECTED TO WATER AVOIDANCE STRESS +/- H3K9 METHYLATION INHIBITORS OR SIRNAS. VISCERAL PAIN RESPONSE WAS ASSESSED. DIFFERENTIATED CACO-2/BBE CELLS AND HUMAN COLONOIDS WERE TREATED WITH CORTISOL OR IL-6 +/- ANTAGONISTS. EXPRESSION OF TJ, IL-6, AND H3K9 METHYLATION STATUS AT GENE PROMOTERS WAS MEASURED. TRANSEPITHELIAL ELECTRICAL RESISTANCE AND FITC-DEXTRAN PERMEABILITY WERE EVALUATED. KEY RESULTS: CHRONIC STRESS INDUCED IL-6 UP-REGULATION PRIOR TO A DECREASE IN TJ PROTEINS IN THE RAT COLON. THE IL-6 LEVEL INVERSELY CORRELATED WITH OCCLUDIN EXPRESSION. TREATMENT WITH IL-6 DECREASED OCCLUDIN AND INDUCED VISCERAL HYPERALGESIA. CHRONIC STRESS AND IL-6 INCREASED H3K9 METHYLATION AND DECREASED TRANSCRIPTIONAL GR BINDING TO THE OCCLUDIN GENE PROMOTER, LEADING TO DOWN-REGULATION OF PROTEIN EXPRESSION AND INCREASE IN PARACELLULAR PERMEABILITY. INTRARECTAL ADMINISTRATION OF A H3K9 METHYLATION ANTAGONIST PREVENTED CHRONIC STRESS-INDUCED VISCERAL HYPERALGESIA IN THE RAT. IN A HUMAN COLONOID MODEL, CORTISOL DECREASED OCCLUDIN EXPRESSION, WHICH WAS PREVENTED BY THE GR ANTAGONIST RU486, AND IL-6 INCREASED H3K9 METHYLATION AND DECREASED TJ PROTEIN LEVELS, WHICH WERE PREVENTED BY INHIBITORS OF H3K9 METHYLATION. CONCLUSIONS & INFERENCES: OUR FINDINGS SUPPORT A NOVEL ROLE FOR METHYLATION OF THE REPRESSIVE HISTONE H3K9 TO REGULATE CHRONIC STRESS, PRO-INFLAMMATORY CYTOKINE-MEDIATED REDUCTION IN COLON TJ PROTEIN LEVELS, AND INCREASE IN PARACELLULAR PERMEABILITY AND VISCERAL HYPERALGESIA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7  1800  28 EFFECT OF HISTONE DEACETYLASE INHIBITOR ON ETHANOL WITHDRAWAL-INDUCED HYPERALGESIA IN RATS. BACKGROUND: INCREASED PAIN SENSITIVITY IS OBSERVED FOLLOWING ALCOHOL WITHDRAWAL, AND ATTEMPTS TO ALLEVIATE THIS HYPERALGESIA CAN CONTRIBUTE TO THE CYCLE OF ADDICTION. THE AIM OF THIS STUDY WAS TO DETERMINE IF ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA WAS OBSERVED IN A CHRONIC ETHANOL EXPOSURE MODEL AND IF THIS PAIN WAS AFFECTED BY HISTONE DEACETYLASE INHIBITORS, THUS REVEALING AN EPIGENETIC MECHANISM. METHODS: ADULT MALE SPRAGUE DAWLEY RATS RECEIVED LIEBER-DECARLI LIQUID CONTROL OR ETHANOL (9% V/V) DIET FOR 15 DAYS. MECHANICAL SENSITIVITY WAS MEASURED WITH VON FREY HAIR STIMULATION OF THE HINDPAW DURING ETHANOL ADMINISTRATION AND 24- AND 72-HOUR WITHDRAWAL. RESULTS: ETHANOL WITHDRAWAL PRODUCED SEVERE AND SUSTAINED MECHANICAL HYPERALGESIA, AN EFFECT NOT OBSERVED IN THE CONTROL OR ETHANOL-MAINTAINED GROUPS. FURTHERMORE, THIS HYPERALGESIA WAS ATTENUATED BY THE HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID TREATMENT. CONCLUSIONS: HEIGHTENED PAIN SENSITIVITY WAS OBSERVED FOLLOWING WITHDRAWAL FROM CHRONIC ETHANOL EXPOSURE, AND HISTONE DEACETYLASE INHIBITORS COULD BE NOVEL TREATMENTS FOR THIS ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8   821  36 CHARACTERIZATION OF ACETYLATION OF HISTONE H3 AT LYSINE 9 IN THE TRIGEMINAL GANGLION OF A RAT TRIGEMINAL NEURALGIA MODEL. TRIGEMINAL NEURALGIA (TN) IS A CHRONIC NEUROPATHIC PAIN DISORDER CHARACTERIZED BY SPONTANEOUS AND ELICITED PAROXYSMS OF ELECTRIC-SHOCK-LIKE OR STABBING PAIN IN A REGION OF THE FACE. THE EPIGENETIC REGULATION OF TN IS STILL OBSCURE. IN CURRENT STUDY, A RAT TN MODEL SUBJECT TO CARBAMAZEPINE (CBZ) TREATMENT WAS ESTABLISHED, AND TRANSCRIPTOME- AND GENOME-SCALE PROFILING OF H3K9AC AND HDAC3 WAS PERFORMED BY RNA-SEQ AND CHIP-SEQ. WE OBSERVED THAT H3K9AC LEVELS IN THE TRIGEMINAL GANGLION WERE LOWER IN THE TN RATS COMPARED WITH THOSE IN THE CONTROL, AND CBZ TREATMENT LED TO RECOVERY OF H3K9AC LEVELS. FURTHER, WE FOUND THAT HDAC3 WAS OVERACTIVATED, WHICH INTERFERED WITH H3K9 ACETYLATION DUE TO HIGHER PHOSPHORYLATION IN TN COMPARED WITH THAT IN THE CONTROL. FINALLY, THE PHOSPHOKINASE LEUCINE-RICH REPEAT KINASE 2 (LRRK2) WAS DEMONSTRATED TO CONTRIBUTE TO HDAC3 ACTIVITY VIA THE MAPK SIGNALING PATHWAY. TAKEN TOGETHER, WE IDENTIFIED A REGULATORY MECHANISM IN WHICH THE PHOSPHATE GROUPS TRANSFERRED FROM ACTIVATED ERK AND LRRK2 TO HDAC3 CAUSED GENOME-SCALE DEACETYLATION AT H3K9 AND RESULTED IN THE SILENCING OF A LARGE NUMBER OF GENES IN TN. THE KINASES OR IMPORTANT ENZYMES WITHIN THIS REGULATORY AXIS MAY REPRESENT IMPORTANT TARGETS FOR TN THERAPY AND PREVENTION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9  5268  29 PROMOTER DEMETHYLATION OF CYSTATHIONINE-BETA-SYNTHETASE GENE CONTRIBUTES TO INFLAMMATORY PAIN IN RATS. HYDROGEN SULFIDE (H(2)S), AN ENDOGENOUS GAS MOLECULE SYNTHESIZED BY CYSTATHIONINE-BETA-SYNTHETASE (CBS), IS INVOLVED IN INFLAMMATION AND NOCICEPTIVE SIGNALING. HOWEVER, THE MOLECULAR AND EPIGENETIC MECHANISMS OF CBS-H(2)S SIGNALING IN PERIPHERAL NOCICEPTIVE PROCESSING REMAIN UNKNOWN. WE DEMONSTRATED THAT PERIPHERAL INFLAMMATION INDUCED BY INTRAPLANTAR INJECTION OF COMPLETE FREUND ADJUVANT SIGNIFICANTLY UP-REGULATED EXPRESSION OF CBS AT BOTH PROTEIN AND MRNA LEVELS IN RAT DORSAL ROOT GANGLIA (DRG). THE CBS INHIBITORS HYDROXYLAMINE AND AMINOOXYACETIC ACID ATTENUATED MECHANICAL HYPERALGESIA IN A DOSE-DEPENDENT MANNER AND REVERSED HYPEREXCITABILITY OF DRG NEURONS IN INFLAMED RATS. INTRAPLANTAR ADMINISTRATION OF NAHS (ITS ADDITION MIMICS CBS PRODUCTION OF H(2)S) OR L-CYSTEINE IN HEALTHY RATS ELICITED MECHANICAL HYPERALGESIA. APPLICATION OF NAHS IN VITRO ENHANCED EXCITABILITY AND TETRODOTOXIN (TTX)-RESISTANT SODIUM CURRENT OF DRG NEURONS FROM HEALTHY RATS, WHICH WAS ATTENUATED BY PRETREATMENT OF PROTEIN KINASE A INHIBITOR H89. METHYLATION-SPECIFIC PCR AND BISULFITE SEQUENCING DEMONSTRATED THAT PROMOTER REGION OF CBS GENE WAS LESS METHYLATED IN DRG SAMPLES FROM INFLAMED RATS THAN THAT FROM CONTROLS. PERIPHERAL INFLAMMATION DID NOT ALTER EXPRESSION OF DNA METHYLTRANSFERASE 3A AND 3B, THE 2 MAJOR ENZYMES FOR DNA METHYLATION, BUT LED TO A SIGNIFICANT UP-REGULATION OF METHYL-BINDING DOMAIN PROTEIN 4 AND GROWTH ARREST AND DNA DAMAGE INDUCIBLE PROTEIN 45ALPHA, THE ENZYMES INVOLVED IN ACTIVE DNA DEMETHYLATION. OUR FINDINGS SUGGEST THAT EPIGENETIC REGULATION OF CBS EXPRESSION MAY CONTRIBUTE TO INFLAMMATORY HYPERALGESIA. H(2)S SEEMS TO INCREASE TTX-RESISTANT SODIUM CHANNEL CURRENT, WHICH MAY BE MEDIATED BY PROTEIN KINASE A PATHWAY, THUS IDENTIFYING A POTENTIAL THERAPEUTIC TARGET FOR THE TREATMENT OF CHRONIC PAIN.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  5851  31 SUBEROYLANILIDE HYDROXAMIC ACID TRIGGERS AUTOPHAGY BY INFLUENCING THE MTOR PATHWAY IN THE SPINAL DORSAL HORN IN A RAT NEUROPATHIC PAIN MODEL. HISTONE ACETYLATION LEVELS CAN BE UPREGULATED BY TREATING CELLS WITH HISTONE DEACETYLASE INHIBITORS (HDACIS), WHICH CAN INDUCE AUTOPHAGY. AUTOPHAGY FLUX IN THE SPINAL CORD OF RATS FOLLOWING THE LEFT FIFTH LUMBER SPINAL NERVE LIGATION (SNL) IS INVOLVED IN THE PROGRESSION OF NEUROPATHIC PAIN. SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), ONE OF THE HDACIS CAN INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION, WHICH HAS BEEN SHOWN TO EASE NEUROPATHIC PAIN. RECENT RESEARCH SUGGEST THAT SAHA CAN STIMULATE AUTOPHAGY VIA THE MAMMALIAN TARGET OF RAPAMYCIN (MTOR) PATHWAY IN SOME TYPES OF CANCER CELLS. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLE OF SAHA AND AUTOPHAGY IN NEUROPATHIC PAIN AFTER NERVE INJURY. IN THE PRESENT STUDY, WE AIM TO INVESTIGATE AUTOPHAGY FLUX AND THE ROLE OF THE MTOR PATHWAY ON SPINAL CELLS AUTOPHAGY ACTIVATION IN NEUROPATHIC PAIN INDUCED BY SNL IN RATS THAT RECEIVED SAHA TREATMENT. AUTOPHAGY-RELATED PROTEINS AND MTOR OR ITS ACTIVE FORM WERE ASSESSED BY USING WESTERN BLOT, IMMUNOHISTOCHEMISTRY, DOUBLE IMMUNOFLUORESCENCE STAINING AND TRANSMISSION ELECTRON MICROSCOPY (TEM). WE FOUND THAT SAHA DECREASED THE PAW MECHANICAL WITHDRAWAL THRESHOLD (PMWT) OF THE LOWER COMPARED WITH SNL. AUTOPHAGY FLUX WAS MAINLY DISRUPTED IN THE ASTROCYTES AND NEURONAL CELLS OF THE SPINAL CORD DORSAL HORN ON POSTSURGICAL DAY 28 AND WAS REVERSED BY DAILY INTRATHECAL INJECTION OF SAHA (N = 100 NMOL/DAY OR N = 200 NMOL/DAY). SAHA ALSO DECREASED MTOR AND PHOSPHORYLATED MTOR (P-MTOR) EXPRESSION, ESPECIALLY P-MTOR EXPRESSION IN ASTROCYTES AND NEURONAL CELLS OF THE SPINAL DORSAL HORN. THESE RESULTS SUGGEST THAT SAHA ATTENUATES NEUROPATHIC PAIN AND CONTRIBUTES TO AUTOPHAGY FLUX IN ASTROCYTES AND NEURONAL CELLS OF THE SPINAL DORSAL HORN VIA THE MTOR SIGNALING PATHWAY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11  5834  24 STRESS-INDUCED VISCERAL PAIN IN FEMALE RATS IS ASSOCIATED WITH EPIGENETIC REMODELING IN THE CENTRAL NUCLEUS OF THE AMYGDALA. STRESS AND ANXIETY CONTRIBUTE TO THE PATHOPHYSIOLOGY OF IRRITABLE BOWEL SYNDROME (IBS), A FEMALE-PREDOMINANT DISORDER OF THE GUT-BRAIN AXIS, CHARACTERIZED BY ABDOMINAL PAIN DUE TO HEIGHTENED VISCERAL SENSITIVITY. IN THE CURRENT STUDY, WE AIMED TO EVALUATE IN FEMALE RATS WHETHER EPIGENETIC REMODELING IN THE LIMBIC BRAIN, SPECIFICALLY IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA), IS A CONTRIBUTING FACTOR IN STRESS-INDUCED VISCERAL HYPERSENSITIVITY. OUR RESULTS SHOWED THAT 1 H EXPOSURE TO WATER AVOIDANCE STRESS (WAS) FOR 7 CONSECUTIVE DAYS DECREASED HISTONE ACETYLATION AT THE GR PROMOTER AND INCREASED HISTONE ACETYLATION AT THE CRH PROMOTER IN THE CEA. CHANGES IN HISTONE ACETYLATION WERE MEDIATED BY THE HISTONE DEACETYLASE (HDAC) SIRT-6 AND THE HISTONE ACETYLTRANSFERASE CBP, RESPECTIVELY. ADMINISTRATION OF THE HDAC INHIBITOR TRICHOSTATIN A (TSA) INTO THE CEA PREVENTED STRESS-INDUCED VISCERAL HYPERSENSITIVITY THROUGH BLOCKADE OF SIRT-6 MEDIATED HISTONE ACETYLATION AT THE GR PROMOTER. IN ADDITION, HDAC INHIBITION WITHIN THE CEA PREVENTED STRESS-INDUCED HISTONE ACETYLATION OF THE CRH PROMOTER. OUR RESULTS SUGGEST THAT, IN FEMALES, EPIGENETIC MODIFICATIONS IN THE LIMBIC BRAIN REGULATING GR AND CRH EXPRESSION CONTRIBUTE TO STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND OFFER A POTENTIAL EXPLANATION OF HOW STRESS CAN TRIGGER SYMPTOMS IN IBS PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12  1163  42 CONTRIBUTION OF AMYGDALA HISTONE ACETYLATION IN EARLY LIFE STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND EMOTIONAL COMORBIDITY. PATIENTS WITH IRRITABLE BOWEL SYNDROME (IBS) EXPERIENCE NOT ONLY ENHANCED VISCERAL PAIN BUT ALSO EMOTIONAL COMORBIDITIES, SUCH AS ANXIETY AND DEPRESSION. EARLY LIFE STRESS (ELS) IS A HIGH-RISK FOR THE DEVELOPMENT OF IBS. LITERATURES HAVE REPORTED AN IMPORTANT EPIGENETIC MODULATION IN SUSTAINING EXTRINSIC PHENOTYPES. THE AMYGDALA IS CLOSELY RELATED TO THE REGULATION OF VISCERAL FUNCTIONS AND EMOTIONAL EXPERIENCES. IN THIS STUDY, WE HYPOTHESIZED THAT ELS-INDUCED REPROGRAMMING INAPPROPRIATE ADAPTATION OF HISTONE ACETYLATION MODIFICATION IN THE AMYGDALA MAY RESULT IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN ELS RATS. TO TEST THIS HYPOTHESIS, THE MODEL OF ELS RATS WAS ESTABLISHED BY NEONATAL COLORECTAL DILATATION (CRD). VISCERAL HYPERSENSITIVITY WAS ASSESSED BASED ON THE ELECTROMYOGRAPHY RESPONSE OF THE ABDOMINAL EXTERNAL OBLIQUE MUSCLE TO CRD. EMOTIONAL COMORBIDITIES WERE EXAMINED USING THE ELEVATED PLUS MAZE TEST, OPEN FIELD TEST, AND SUCROSE PREFERENCE TEST. TRICHOSTATIN A (TSA) AND C646 WERE MICROINJECTED INTO THE CENTRAL AMYGDALA (CEA) INDIVIDUALLY TO INVESTIGATE THE EFFECTS OF DIFFERENT LEVELS OF HISTONE ACETYLATION MODIFICATION ON VISCERAL HYPERSENSITIVITY AND EMOTION. WE FOUND NEONATAL CRD RESULTED IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS AFTER ADULTHOOD. INHIBITING HISTONE DEACETYLASES (HDACS) IN THE CEA BY TSA ENHANCED VISCERAL SENSITIVITY BUT DID NOT AFFECT ANXIETY-LIKE BEHAVIORS, WHEREAS INHIBITING HAT BY C646 ATTENUATED VISCERAL HYPERSENSITIVITY IN ELS RATS. INTERESTINGLY, CEA TREATMENT WITH TSA INDUCED VISCERAL SENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN THE CONTROL RATS. WESTERN BLOT SHOWED THAT THE EXPRESSIONS OF ACETYLATED 9 RESIDUE OF HISTONE 3 (H3K9) AND PROTEIN KINASE C ZETA TYPE (PKMZETA) WERE HIGHER IN THE ELS RATS COMPARED TO THOSE OF THE CONTROLS. THE ADMINISTRATION OF THE PKMZETA INHIBITOR ZIP INTO THE CEA ATTENUATED VISCERAL HYPERSENSITIVITY OF ELS RATS. FURTHERMORE, THE EXPRESSION OF AMYGDALA PKMZETA WAS ENHANCED BY TSA TREATMENT IN CONTROL RATS. FINALLY, WESTERN BLOT AND IMMUNOFLUORESCENCE RESULTS INDICATED THE DECREASE OF HDAC1 AND HDAC2 EXPRESSIONS, BUT NOT HDAC3 EXPRESSION, CONTRIBUTED TO THE ENHANCEMENT OF HISTONE ACETYLATION IN ELS RATS. OUR RESULTS SUPPORT OUR HYPOTHESIS THAT AMYGDALA-ENHANCED HISTONE ACETYLATION INDUCED BY STRESS IN EARLY LIFE RESULTS IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN ELS RATS, AND REVERSING THE ABNORMAL EPIGENETIC MECHANISMS MAY BE CRUCIAL TO RELIEVE CHRONIC SYMPTOMS IN ELS RATS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13  2476  32 EPIGENETIC UPREGULATION OF CCL2 AND CCL3 VIA HISTONE MODIFICATIONS IN INFILTRATING MACROPHAGES AFTER PERIPHERAL NERVE INJURY. TO GAIN INSIGHT INTO THE EPIGENETIC REGULATION OF CC-CHEMOKINE LIGAND (CCL) 2 AND CCL3, KEY PLAYERS IN THE PERIPHERAL SENSITIZATION LEADING TO NEUROPATHIC PAIN, WE EXAMINED THE RELATIONSHIP BETWEEN HISTONE H3 MODIFICATION AND THE UPREGULATION OF THESE MOLECULES USING A MOUSE MODEL OF NEUROPATHIC PAIN AFTER PARTIAL SCIATIC NERVE LIGATION (PSL). WE FOUND THAT CIRCUITING BONE MARROW (BM)-DERIVED MACROPHAGES INFILTRATED INTO THE INJURED SCIATIC NERVE (SCN) USING ENHANCED GREEN FLUORESCENT PROTEIN CHIMERIC MICE. THE MRNA LEVELS OF CCL2, CCL3 AND THEIR RECEPTORS (CCR2 AND CCR1/CCR5, RESPECTIVELY) WERE INCREASED IN THE INJURED SCN. CHROMATIN IMMUNOPRECIPITATION ASSAY REVEALED THAT LEVELS OF LYSINE 9-ACETYLATED HISTONE H3 (H3K9AC) AND LYSINE 4-TRIMETHYLATED H3 (H3K4ME(3)) IN THE PROMOTER REGIONS OF THE CCL2 AND CCL3 GENES WERE INCREASED IN THE INJURED SCN AFTER PSL, INDICATING THE ENHANCEMENT OF GENE EXPRESSION. IMMUNOREACTIVITY FOR H3K9AC AND H3K4ME(3) WAS LOCALIZED IN THE NUCLEI OF INFILTRATING BM-DERIVED CELLS AND CCL-EXPRESSING CELLS IN THE INJURED SCN. WE OBSERVED H3K9AC AND H3K4ME(3) MAINLY IN THE NUCLEI OF RECRUITED MACROPHAGES ON DAY 7 AFTER PSL. FURTHERMORE, UPREGULATION OF CCLS AND CCRS WERE SUPPRESSED BY HISTONE ACETYLTRANSFERASE INHIBITOR, ANACARDIC ACID. TAKEN TOGETHER, OUR FINDINGS DEMONSTRATE THAT CCL2 AND CCL3 ARE UPREGULATED IN THE INJURED PERIPHERAL NERVE THROUGH EPIGENETIC HISTONE MODIFICATION IN INFILTRATING IMMUNE CELLS SUCH AS MACROPHAGES. THESE CHEMOKINE CASCADES MAY SUBSEQUENTLY ELICIT CHRONIC NEUROINFLAMMATION FOLLOWING NERVE INJURY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  2365  28 EPIGENETIC REGULATION OF SPINAL CXCR2 SIGNALING IN INCISIONAL HYPERSENSITIVITY IN MICE. BACKGROUND: THE REGULATION OF GENE EXPRESSION IN NOCICEPTIVE PATHWAYS CONTRIBUTES TO THE INDUCTION AND MAINTENANCE OF PAIN SENSITIZATION. HISTONE ACETYLATION IS A KEY EPIGENETIC MECHANISM CONTROLLING CHROMATIN STRUCTURE AND GENE EXPRESSION. CHEMOKINE CC MOTIF RECEPTOR 2 (CXCR2) IS A PROINFLAMMATORY RECEPTOR IMPLICATED IN NEUROPATHIC AND INFLAMMATORY PAIN AND IS KNOWN TO BE REGULATED BY HISTONE ACETYLATION IN SOME SETTINGS. THE AUTHORS SOUGHT TO INVESTIGATE THE ROLE OF HISTONE ACETYLATION ON SPINAL CXCR2 SIGNALING AFTER INCISION. METHODS: GROUPS OF 5-8 MICE UNDERWENT HIND PAW INCISION. SUBEROYLANILIDE HYDROXAMIC ACID AND ANACARDIC ACID WERE USED TO INHIBIT HISTONE DEACETYLASE AND HISTONE ACETYLTRANSFERASE, RESPECTIVELY. BEHAVIORAL MEASURES OF THERMAL AND MECHANICAL SENSITIZATION AS WELL AS HYPERALGESIC PRIMING WERE USED. BOTH MESSAGE RNA QUANTIFICATION AND CHROMATIN IMMUNOPRECIPITATION ANALYSIS WERE USED TO STUDY THE REGULATION OF CXCR2 AND LIGAND EXPRESSION. FINALLY, THE SELECTIVE CXCR2 ANTAGONIST SB225002 WAS ADMINISTERED INTRATHECALLY TO REVEAL THE FUNCTION OF SPINAL CXCR2 RECEPTORS AFTER HIND PAW INCISION. RESULTS: SUBEROYLANILIDE HYDROXAMIC ACID SIGNIFICANTLY EXACERBATED MECHANICAL SENSITIZATION AFTER INCISION. CONVERSELY, ANACARDIC ACID REDUCED INCISIONAL SENSITIZATION AND ALSO ATTENUATED INCISION-INDUCED HYPERALGESIC PRIMING. OVERALL, ACETYLATED HISTONE H3 AT LYSINE 9 WAS INCREASED IN SPINAL CORD TISSUES AFTER INCISION, AND ENHANCED ASSOCIATION OF ACETYLATED HISTONE H3 AT LYSINE 9 WITH THE PROMOTER REGIONS OF CXCR2 AND KERATINOCYTE-DERIVED CHEMOKINE (CXCL1) WAS OBSERVED AS WELL. BLOCKING CXCR2 REVERSED MECHANICAL HYPERSENSITIVITY AFTER HIND PAW INCISION. CONCLUSIONS: HISTONE MODIFICATION IS AN IMPORTANT EPIGENETIC MECHANISM REGULATING INCISION-INDUCED NOCICEPTIVE SENSITIZATION. THE SPINAL CXCR2 SIGNALING PATHWAY IS ONE EPIGENETICALLY REGULATED PATHWAY CONTROLLING EARLY AND LATENT SENSITIZATION AFTER INCISION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  1126  25 COMPLEX REGULATION OF THE REGULATOR OF SYNAPTIC PLASTICITY HISTONE DEACETYLASE 2 IN THE RODENT DORSAL HORN AFTER PERIPHERAL INJURY. HISTONE DEACETYLASES (HDACS), HDAC2 IN PARTICULAR, HAVE BEEN SHOWN TO REGULATE VARIOUS FORMS OF LEARNING AND MEMORY. SINCE COGNITIVE PROCESSES SHARE MECHANISMS WITH SPINAL NOCICEPTIVE SIGNALLING, WE DECIDED TO INVESTIGATE THE HDAC2 EXPRESSION IN THE DORSAL HORN AFTER PERIPHERAL INJURY. USING IMMUNOHISTOCHEMISTRY, WE FOUND THAT SPINAL HDAC2 WAS MAINLY SEEN IN NEURONS AND ASTROCYTES, WITH NEURONAL EXPRESSION IN NAIVE TISSUE 2.6 TIMES GREATER THAN THAT IN ASTROCYTES. CYSTEINE (S)-NITROSYLATION OF HDAC2 RELEASES HDAC2 GENE SILENCING AND IS CONTROLLED BY NITRIC OXIDE (NO). A DURATION OF 48 H AFTER INTRAPLANTAR INJECTION OF COMPLETE FREUND'S ADJUVANT, THERE WAS AN IPSILATERAL INCREASE IN THE MOST IMPORTANT NO-PRODUCING ENZYME IN PAIN STATES, NITRIC OXIDE SYNTHASE (NNOS), ACCOMPANIED BY AN INCREASE IN HDAC2 S-NITROSYLATION. MOREOVER, A SUBSET OF NNOS-POSITIVE NEURONS EXPRESSED CFOS, A KNOWN TARGET OF HDAC2, SUGGESTING THAT DEREPRESSION OF CFOS EXPRESSION FOLLOWING HDAC2 S-NITROSYLATION MIGHT OCCUR AFTER NOXIOUS STIMULATION. WE SAW NO CHANGE IN GLOBAL HDAC2 EXPRESSION IN BOTH SHORT- AND LONG-TERM PAIN STATES. HOWEVER, HDAC2 WAS INCREASED IN ASTROCYTES 7 DAYS AFTER NEUROPATHIC INJURY SUGGESTING THAT HDAC2 MIGHT INHIBIT ASTROCYTIC GENE EXPRESSION IN NEUROPATHIC PAIN STATES. ALL TOGETHER, OUR RESULTS INDICATE THAT THE EPIGENETIC REGULATION OF TRANSCRIPTIONAL PROGRAMMES IN THE DORSAL HORN AFTER INJURY IS CELL SPECIFIC. MOREOVER, THE PROMINENT ROLE OF NO IN PERSISTENT PAIN STATES SUGGESTS THAT HDAC2 S-NITROSYLATION COULD PLAY A CRUCIAL ROLE IN THE REGULATION OF GENE EXPRESSION LEADING TO HYPERSENSITIVITY. OUR MANUSCRIPT DESCRIBES FOR THE FIRST TIME THE REGULATION OF THE MEMORY REGULATOR HISTONE DEACETYLASE 2 (HDAC2) IN THE SUPERFICIAL DORSAL HORN OF ADULT RATS FOLLOWING PERIPHERAL INJURY. OUR CELL-SPECIFIC APPROACH HAS REVEALED A COMPLEX PATTERN OF EXPRESSION OF SPINAL HDAC2 THAT DEPENDS ON THE INJURY AND THE CELL TYPE, SUGGESTING A SOPHISTICATED REGULATION OF GENE EXPRESSION BY HDAC2.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16  2745  26 EXPRESS: HISTONE HYPERACETYLATION MODULATES SPINAL TYPE II METABOTROPIC GLUTAMATE RECEPTOR ALLEVIATING STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN FEMALE RATS. STRESS IS OFTEN A TRIGGER TO EXACERBATE CHRONIC PAIN INCLUDING VISCERAL HYPERSENSITIVITY ASSOCIATED WITH IRRITABLE BOWEL SYNDROME, A FEMALE PREDOMINANT FUNCTIONAL BOWEL DISORDER. EPIGENETIC MECHANISMS THAT MEDIATE STRESS RESPONSES ARE A POTENTIAL TARGET TO INTERFERE WITH VISCERAL PAIN. THE PURPOSE OF THIS STUDY WAS TO EXAMINE THE EFFECT OF A HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID, ON VISCERAL HYPERSENSITIVITY INDUCED BY A SUBCHRONIC STRESSOR IN FEMALE RATS AND TO INVESTIGATE THE INVOLVEMENT OF SPINAL GLUTAMATE RECEPTORS. THREE DAILY SESSIONS OF FORCED SWIM INDUCED VISCERAL HYPERSENSITIVITY. INTRATHECAL SUBEROYLANILIDE HYDROXAMIC ACID PREVENTED OR REVERSED THE STRESS-INDUCED VISCERAL HYPERSENSITIVITY, INCREASED SPINAL HISTONE 3 ACETYLATION AND INCREASED MGLUR2 AND MGLUR3 EXPRESSION. CHROMATIN IMMUNOPRECIPITATION (CHIP) ANALYSIS REVEALED ENRICHMENT OF H3K9AC AND H3K18AC AT SEVERAL PROMOTER GRM2 AND GRM3 REGIONS. THE MGLUR2/3 ANTAGONIST LY341495 REVERSED THE INHIBITORY EFFECT OF SUBEROYLANILIDE HYDROXAMIC ACID ON THE STRESS-INDUCED VISCERAL HYPERSENSITIVITY. IN SURPRISING CONTRAST, STRESS AND/OR SUBEROYLANILIDE HYDROXAMIC ACID HAD NO EFFECT ON SPINAL NMDA RECEPTOR EXPRESSION OR FUNCTION. THESE DATA REVEAL HISTONE MODIFICATION MODULATES MGLUR2/3 EXPRESSION IN THE SPINAL CORD TO ATTENUATE STRESSINDUCED VISCERAL HYPERSENSITIVITY. HDAC INHIBITORS MAY PROVIDE A POTENTIAL APPROACH TO RELIEVE VISCERAL HYPERSENSITIVITY ASSOCIATED WITH IRRITABLE BOWEL SYNDROME.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  2672  34 ETHANOL-INDUCED EPIGENETIC REGULATIONS AT THE BDNF GENE IN C57BL/6J MICE. HIGH ETHANOL INTAKE IS WELL KNOWN TO INDUCE BOTH ANXIOLYTIC AND ANXIOGENIC EFFECTS, IN CORRELATION WITH CHROMATIN REMODELING IN THE AMYGDALOID BRAIN REGION AND DEFICITS IN CELL PROLIFERATION AND SURVIVAL IN THE HIPPOCAMPUS OF RODENTS. WHETHER ONLY MODERATE BUT CHRONIC ETHANOL INTAKE IN C57BL/6J MICE COULD ALSO HAVE AN IMPACT ON CHROMATIN REMODELING AND NEUROPLASTICITY WAS ADDRESSED HERE. CHRONIC ETHANOL CONSUMPTION IN A FREE CHOICE PARADIGM WAS FOUND TO INDUCE MARKED CHANGES IN THE EXPRESSION OF GENES IMPLICATED IN NEURAL DEVELOPMENT AND HISTONE POST-TRANSLATIONAL MODIFICATIONS IN THE MOUSE HIPPOCAMPUS. TRANSCRIPTS ENCODING NEURAL BHLH ACTIVATORS AND THOSE FROM BDNF EXONS II, III AND VI WERE UPREGULATED, WHEREAS THOSE FROM BDNF EXON VIII AND HDACS WERE DOWNREGULATED BY ETHANOL COMPARED WITH WATER CONSUMPTION. THESE ETHANOL-INDUCED CHANGES WERE ASSOCIATED WITH ENRICHMENT IN BOTH ACETYLATED H3 AT BDNF PROMOTER PVI AND TRIMETHYLATED H3 AT PII AND PIII. CONVERSELY, ACETYLATED H3 AT PIII AND PVIII AND TRIMETHYLATED H3 AT PVIII WERE DECREASED IN ETHANOL-EXPOSED MICE. IN PARALLEL, HIPPOCAMPAL BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS AND TRKB-MEDIATED NEUROGENESIS IN THE DENTATE GYRUS WERE SIGNIFICANTLY ENHANCED BY ETHANOL CONSUMPTION. THESE RESULTS SUGGEST THAT, IN C57BL/6J MICE, CHRONIC AND MODERATE ETHANOL INTAKE PRODUCES MARKED EPIGENETIC CHANGES UNDERLYING BDNF OVEREXPRESSION AND DOWNSTREAM HIPPOCAMPAL NEUROGENESIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18  5781  31 SPINAL SIRT1 ACTIVATION ATTENUATES NEUROPATHIC PAIN IN MICE. ABNORMAL HISTONE ACETYLATION OCCURS DURING NEUROPATHIC PAIN THROUGH AN EPIGENETIC MECHANISM. SILENT INFORMATION REGULATOR 1 (SIR2 OR SIRT1), A NAD-DEPENDENT DEACETYLASE, PLAYS COMPLEX SYSTEMIC ROLES IN A VARIETY OF PROCESSES THROUGH DEACETYLATING ACETYLATED HISTONE AND OTHER SPECIFIC SUBSTRATES. BUT THE ROLE OF SIRT1 IN NEUROPATHIC PAIN IS NOT WELL ESTABLISHED YET. THE PRESENT STUDY WAS INTENDED TO DETECT SIRT1 CONTENT AND ACTIVITY, NICOTINAMIDE (NAM) AND NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD) IN THE SPINAL CORD USING IMMUNOBLOTTING OR MASS SPECTROSCOPY OVER TIME IN MICE FOLLOWING CHRONIC CONSTRICTION INJURY (CCI) OR SHAM SURGERY. IN ADDITION, THE EFFECT OF INTRATHECAL INJECTION OF NAD OR RESVERATROL ON THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA WAS EVALUATED IN CCI MICE. FINALLY, WE INVESTIGATED WHETHER SIRT1 INHIBITOR EX-527 COULD REVERSE THE ANTI-NOCICEPTIVE EFFECT OF NAD OR RESVERATROL. IT WAS FOUND THAT SPINAL SIRT1 EXPRESSION, DEACETYLASE ACTIVITY AND NAD/NAM DECREASED SIGNIFICANTLY 1, 3, 7, 14 AND 21 DAYS AFTER CCI SURGERY AS COMPARED WITH SHAM GROUP. IN ADDITION, DAILY INTRATHECAL INJECTION OF 5 MICROL 800 MM NAD 1 H BEFORE AND 1 DAY AFTER CCI SURGERY OR SINGLE INTRATHECAL INJECTION OF 5 MICROL 90 MM RESVERATROL 1 H BEFORE CCI SURGERY PRODUCED A TRANSIENT INHIBITORY EFFECT ON THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA IN CCI MICE. FINALLY, AN INTRATHECAL INJECTION OF 5 MICROL 1.2 MM EX-527 1 H BEFORE NAD OR RESVERATROL ADMINISTRATION REVERSED THE ANTI-NOCICEPTIVE EFFECT OF NAD OR RESVERATROL. THESE DATA INDICATE THAT THE REDUCTION IN SIRT1 DEACETYLASE ACTIVITY MAY BE A FACTOR CONTRIBUTING TO THE DEVELOPMENT OF NEUROPATHIC PAIN IN CCI MICE. OUR FINDINGS SUGGEST THAT THE ENHANCEMENT OF SPINAL NAD/NAM AND/OR SIRT1 ACTIVITY MAY BE A POTENTIALLY PROMISING STRATEGY FOR THE PREVENTION OR TREATMENT OF NEUROPATHIC PAIN.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19  2300  32 EPIGENETIC REGULATION OF BDNF EXPRESSION IN THE PRIMARY SENSORY NEURONS AFTER PERIPHERAL NERVE INJURY: IMPLICATIONS IN THE DEVELOPMENT OF NEUROPATHIC PAIN. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS KNOWN TO BE UP-REGULATED IN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY, AND TO CONTRIBUTE TO NEUROPATHIC PAIN. HERE, WE FOUND THAT THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA AT DAY 7 POST-INJURY WERE INHIBITED ONLY WHEN ANTI-BDNF ANTIBODY WAS INTRATHECALLY ADMINISTRATED AT DAY 2 POST-INJURY. CONSISTENT WITH BEHAVIORAL RESULTS, WESTERN BLOT ANALYSIS SHOWED THAT THE EXPRESSION LEVELS OF BDNF PROTEIN IN THE SPINAL DORSAL HORN WERE MARKEDLY INDUCED DURING EARLY STAGE POST-INJURY. MOREOVER, THE MAXIMAL INCREASE IN BDNF MRNA EXPRESSION IN THE DRG WAS OBSERVED AT DAY 1 POST-INJURY, AND SIGNIFICANTLY ELEVATED LEVELS WERE SUSTAINED FOR AT LEAST 14 DAYS. FOUR OF FIVE BDNF MRNA TRANSCRIPTS WERE UP-REGULATED AFTER NERVE INJURY, AND THE MOST INDUCIBLE TRANSCRIPT WAS EXON I. USING A CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY, WE FOUND THAT NERVE INJURY PROMOTES HISTONE H3 AND H4 ACETYLATION, TRANSCRIPTIONALLY ACTIVE MODIFICATIONS, AT BDNF PROMOTER I AT DAY 1 POST-INJURY, AND THE LEVELS OF HISTONE ACETYLATION REMAIN ELEVATED FOR AT LEAST 7 DAYS. TAKEN TOGETHER, OUR FINDINGS SUGGEST THAT AN INITIAL INCREASE IN BDNF EXON I EXPRESSION CONTROLLED BY EPIGENETIC MECHANISMS MIGHT HAVE A CRUCIAL ROLE IN THE DEVELOPMENT OF NEUROPATHIC PAIN.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20  2477  25 EPIGENETIC UPREGULATION OF CDK5 IN THE DORSAL HORN CONTRIBUTES TO NEUROPATHIC PAIN IN RATS. NUMEROUS REPORTS HAVE SHOWN THAT CYCLIN-DEPENDENT KINASE 5 (CDK5), A PROLINE-DIRECTED SERINE/THREONINE KINASE, CRITICALLY CONTRIBUTES TO THE INDUCTION AND MAINTENANCE OF CHRONIC PAIN INDUCED BY PERIPHERAL INFLAMMATION AND NERVE INJURY. RECENT EVIDENCE HAS ALSO SUGGESTED THE CRITICAL ROLE OF AN EPIGENETIC MECHANISM IN THE SETTING OF CHRONIC PAIN. THE PRESENT STUDY AIMS TO ELUCIDATE THE CYCLIC AMP RESPONSE ELEMENT-BINDING PROTEIN (CREB)-MEDIATED UPREGULATION OF CDK5 AND ITS FUNCTIONAL SIGNIFICANCE IN RATS WITH NEUROPATHIC PAIN INDUCED BY CHRONIC CONSTRICTION INJURY (CCI) IN THE SCIATIC NERVE. SIGNIFICANTLY INCREASED EXPRESSION OF CDK5 WAS OBSERVED IN THE DORSAL HORN OF RATS WITH CCI, AND INTRATHECAL DELIVERY OF CDK5 INHIBITOR ROSCOVITINE SIGNIFICANTLY ATTENUATED THE MECHANICAL ALLODYNIA IN THESE RATS. PHOSPHORYLATION OF CREB AND ITS OCCUPANCY IN THE CDK5 PROMOTER REGION WAS ALSO INCREASED IN THE DORSAL HORN, WHICH LED TO INCREASED HISTONE H4 ACETYLATION IN THE CDK5 PROMOTER REGION AND THE UPREGULATED TRANSCRIPTION OF CDK5. INHIBITION OF CREB ACTIVITY ATTENUATED THE UPREGULATION OF CDK5 AND ALLEVIATED THE MECHANICAL ALLODYNIA IN RATS WITH CCI. THESE RESULTS DEMONSTRATED A CREB-MEDIATED EPIGENETIC UPREGULATION OF CDK5 IN THE DORSAL HORN, WHICH CRITICALLY CONTRIBUTED TO THE MAINTENANCE OF PAINFUL BEHAVIOR IN THE RATS WITH NEUROPATHIC PAIN.	2014