1 4919 116 PANNEXIN-1 UP-REGULATION IN THE DORSAL ROOT GANGLION CONTRIBUTES TO NEUROPATHIC PAIN DEVELOPMENT. PANNEXIN-1 (PANX1) IS A LARGE-PORE MEMBRANE CHANNEL INVOLVED IN THE RELEASE OF ATP AND OTHER SIGNALING MEDIATORS. LITTLE IS KNOWN ABOUT THE EXPRESSION AND FUNCTIONAL ROLE OF PANX1 IN THE DORSAL ROOT GANGLION (DRG) IN THE DEVELOPMENT OF CHRONIC NEUROPATHIC PAIN. IN THIS STUDY, WE DETERMINED THE EPIGENETIC MECHANISM INVOLVED IN INCREASED PANX1 EXPRESSION IN THE DRG AFTER NERVE INJURY. SPINAL NERVE LIGATION IN RATS SIGNIFICANTLY INCREASED THE MRNA AND PROTEIN LEVELS OF PANX1 IN THE DRG BUT NOT IN THE SPINAL CORD. IMMUNOCYTOCHEMICAL LABELING SHOWED THAT PANX1 WAS PRIMARILY EXPRESSED IN A SUBSET OF MEDIUM AND LARGE DRG NEURONS IN CONTROL RATS AND THAT NERVE INJURY MARKEDLY INCREASED THE NUMBER OF PANX1-IMMUNOREACTIVE DRG NEURONS. NERVE INJURY SIGNIFICANTLY INCREASED THE ENRICHMENT OF TWO ACTIVATING HISTONE MARKS (H3K4ME2 AND H3K9AC) AND DECREASED THE OCCUPANCY OF TWO REPRESSIVE HISTONE MARKS (H3K9ME2 AND H3K27ME3) AROUND THE PROMOTER REGION OF PANX1 IN THE DRG. HOWEVER, NERVE INJURY HAD NO EFFECT ON THE DNA METHYLATION LEVEL AROUND THE PANX1 PROMOTER IN THE DRG. FURTHERMORE, INTRATHECAL INJECTION OF THE PANX1 BLOCKERS OR PANX1-SPECIFIC SIRNA SIGNIFICANTLY REDUCED PAIN HYPERSENSITIVITY INDUCED BY NERVE INJURY. IN ADDITION, SIRNA KNOCKDOWN OF PANX1 EXPRESSION IN A DRG CELL LINE SIGNIFICANTLY REDUCED CASPASE-1 RELEASE INDUCED BY NEURONAL DEPOLARIZATION. OUR FINDINGS SUGGEST THAT NERVE INJURY INCREASES PANX1 EXPRESSION LEVELS IN THE DRG THROUGH ALTERED HISTONE MODIFICATIONS. PANX1 UP-REGULATION CONTRIBUTES TO THE DEVELOPMENT OF NEUROPATHIC PAIN AND STIMULATION OF INFLAMMASOME SIGNALING.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2 3368  52 HISTONE METHYLTRANSFERASE G9A DIMINISHES EXPRESSION OF CANNABINOID CB(1) RECEPTORS IN PRIMARY SENSORY NEURONS IN NEUROPATHIC PAIN. TYPE 1 CANNABINOID RECEPTORS (CB(1)RS) ARE EXPRESSED IN THE DORSAL ROOT GANGLION (DRG) AND CONTRIBUTE TO THE ANALGESIC EFFECT OF CANNABINOIDS. HOWEVER, THE EPIGENETIC MECHANISM REGULATING THE EXPRESSION OF CB(1)RS IN NEUROPATHIC PAIN IS UNKNOWN. G9A (ENCODED BY THE EHMT2 GENE), A HISTONE 3 AT LYSINE 9 METHYLTRANSFERASE, IS A KEY CHROMATIN REGULATOR RESPONSIBLE FOR GENE SILENCING. IN THIS STUDY, WE DETERMINED G9A'S ROLE IN REGULATING CB(1)R EXPRESSION IN THE DRG AND IN CB(1)R-MEDIATED ANALGESIC EFFECTS IN AN ANIMAL MODEL OF NEUROPATHIC PAIN. WE SHOW THAT NERVE INJURY PROFOUNDLY REDUCED MRNA LEVELS OF CB(1)RS BUT INCREASED THE EXPRESSION OF CB(2) RECEPTORS IN THE RAT DRG. CHIP RESULTS INDICATED INCREASED ENRICHMENT OF HISTONE 3 AT LYSINE 9 DIMETHYLATION, A G9A-CATALYZED REPRESSIVE HISTONE MARK, AT THE PROMOTER REGIONS OF THE CB(1)R GENES. G9A INHIBITION IN NERVE-INJURED RATS NOT ONLY UP-REGULATED THE CB(1)R EXPRESSION LEVEL IN THE DRG BUT ALSO POTENTIATED THE ANALGESIC EFFECT OF A CB(1)R AGONIST ON NERVE INJURY-INDUCED PAIN HYPERSENSITIVITY. FURTHERMORE, IN MICE LACKING EHMT2 IN DRG NEURONS, NERVE INJURY FAILED TO REDUCE CB(1)R EXPRESSION IN THE DRG AND TO DECREASE THE ANALGESIC EFFECT OF THE CB(1)R AGONIST. MOREOVER, NERVE INJURY DIMINISHED THE INHIBITORY EFFECT OF THE CB(1)R AGONIST ON SYNAPTIC GLUTAMATE RELEASE FROM PRIMARY AFFERENT NERVES TO SPINAL CORD DORSAL HORN NEURONS IN WT MICE BUT NOT IN MICE LACKING EHMT2 IN DRG NEURONS. OUR FINDINGS REVEAL THAT NERVE INJURY DIMINISHES THE ANALGESIC EFFECT OF CB(1)R AGONISTS THROUGH G9A-MEDIATED CB(1)R DOWN-REGULATION IN PRIMARY SENSORY NEURONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3 5692  29 SILENCING OF LNCRNA PKIA-AS1 ATTENUATES SPINAL NERVE LIGATION-INDUCED NEUROPATHIC PAIN THROUGH EPIGENETIC DOWNREGULATION OF CDK6 EXPRESSION. NEUROPATHIC PAIN (NP) IS AMONG THE MOST INTRACTABLE COMORBIDITIES OF SPINAL CORD INJURY. DYSREGULATION OF NON-CODING RNAS HAS ALSO BEEN IMPLICATED IN THE DEVELOPMENT OF NEUROPATHIC PAIN. HERE, WE IDENTIFIED A NOVEL LNCRNA, PKIA-AS1, BY USING LNCRNA ARRAY ANALYSIS IN SPINAL CORD TISSUE OF SPINAL NERVE LIGATION (SNL) MODEL RATS, AND INVESTIGATED THE ROLE OF PKIA-AS1 IN SNL-MEDIATED NEUROPATHIC PAIN. WE OBSERVED THAT PKIA-AS1 WAS SIGNIFICANTLY UPREGULATED IN SNL MODEL RATS AND THAT PKIA-AS1 KNOCKDOWN ATTENUATED NEUROPATHIC PAIN PROGRESSION. ALTERNATIVELY, OVEREXPRESSION OF PKIA-AS1 WAS SUFFICIENT TO INDUCE NEUROPATHIC PAIN-LIKE SYMPTOMS IN UNINJURED RATS. WE ALSO FOUND THAT PKIA-AS1 MEDIATED SNL-INDUCED NEUROPATHIC PAIN BY DIRECTLY REGULATING THE EXPRESSION AND FUNCTION OF CDK6, WHICH IS ESSENTIAL FOR THE INITIATION AND MAINTENANCE OF NEUROINFLAMMATION AND NEUROPATHIC PAIN. THEREFORE, OUR STUDY IDENTIFIES PKIA-AS1 AS A NOVEL THERAPEUTIC TARGET FOR NEUROINFLAMMATION RELATED NEUROPATHIC PAIN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4 1318  41 DEMETHYLATION OF G-PROTEIN-COUPLED RECEPTOR 151 PROMOTER FACILITATES THE BINDING OF KRUPPEL-LIKE FACTOR 5 AND ENHANCES NEUROPATHIC PAIN AFTER NERVE INJURY IN MICE. G-PROTEIN-COUPLED RECEPTORS ARE CONSIDERED TO BE CELL-SURFACE SENSORS OF EXTRACELLULAR SIGNALS, THEREBY HAVING A CRUCIAL ROLE IN SIGNAL TRANSDUCTION AND BEING THE MOST FRUITFUL TARGETS FOR DRUG DISCOVERY. G-PROTEIN-COUPLED RECEPTOR 151 (GPR151) WAS REPORTED TO BE EXPRESSED SPECIFICALLY IN THE HABENULAR AREA. HERE WE REPORT THE EXPRESSION AND THE EPIGENETIC REGULATION OF GRP151 IN THE SPINAL CORD AFTER SPINAL NERVE LIGATION (SNL) AND THE CONTRIBUTION OF GPR151 TO NEUROPATHIC PAIN IN MALE MICE. SNL DRAMATICALLY INCREASED GPR151 EXPRESSION IN SPINAL NEURONS. GPR151 MUTATION OR SPINAL INHIBITION BY SHRNA ALLEVIATED SNL-INDUCED MECHANICAL ALLODYNIA AND HEAT HYPERALGESIA. INTERESTINGLY, THE CPG ISLAND IN THE GPR151 GENE PROMOTER REGION WAS DEMETHYLATED, THE EXPRESSION OF DNA METHYLTRANSFERASE 3B (DNMT3B) WAS DECREASED, AND THE BINDING OF DNMT3B WITH GPR151 PROMOTER WAS REDUCED AFTER SNL. OVEREXPRESSION OF DNMT3B IN THE SPINAL CORD DECREASED GPR151 EXPRESSION AND ATTENUATED SNL-INDUCED NEUROPATHIC PAIN. FURTHERMORE, KRUPPEL-LIKE FACTOR 5 (KLF5), A TRANSCRIPTIONAL FACTOR OF THE KLF FAMILY, WAS UPREGULATED IN SPINAL NEURONS, AND THE BINDING AFFINITY OF KLF5 WITH GPR151 PROMOTER WAS INCREASED AFTER SNL. INHIBITION OF KLF5 REDUCED GPR151 EXPRESSION AND ATTENUATED SNL-INDUCED PAIN HYPERSENSITIVITY. FURTHER MRNA MICROARRAY ANALYSIS REVEALED THAT MUTATION OF GPR151 REDUCED THE EXPRESSION OF A VARIETY OF PAIN-RELATED GENES IN RESPONSE TO SNL, ESPECIALLY MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) SIGNALING PATHWAY-ASSOCIATED GENES. THIS STUDY REVEALS THAT GPR151, INCREASED BY DNA DEMETHYLATION AND THE ENHANCED INTERACTION WITH KLF5, CONTRIBUTES TO THE MAINTENANCE OF NEUROPATHIC PAIN VIA INCREASING MAPK PATHWAY-RELATED GENE EXPRESSION.SIGNIFICANCE STATEMENT G-PROTEIN-COUPLED RECEPTORS (GPCRS) ARE TARGETS OF VARIOUS CLINICALLY APPROVED DRUGS. HERE WE REPORT THAT SNL INCREASED GPR151 EXPRESSION IN THE SPINAL CORD, AND MUTATION OR INHIBITION OF GPR151 ALLEVIATED SNL-INDUCED NEUROPATHIC PAIN. IN ADDITION, SNL DOWNREGULATED THE EXPRESSION OF DNMT3B, WHICH CAUSED DEMETHYLATION OF GPR151 GENE PROMOTER, FACILITATED THE BINDING OF TRANSCRIPTIONAL FACTOR KLF5 WITH THE GPR151 PROMOTER, AND FURTHER INCREASED GPR151 EXPRESSION IN SPINAL NEURONS. THE INCREASED GPR151 MAY CONTRIBUTE TO THE PATHOGENESIS OF NEUROPATHIC PAIN VIA ACTIVATING MAPK SIGNALING AND INCREASING PAIN-RELATED GENE EXPRESSION. OUR STUDY REVEALS AN EPIGENETIC MECHANISM UNDERLYING GPR151 EXPRESSION AND SUGGESTS THAT TARGETING GPR151 MAY OFFER A NEW STRATEGY FOR THE TREATMENT OF NEUROPATHIC PAIN.	2018	
                         
5 6664  33 UPREGULATION OF LNCRNA71132 IN THE SPINAL CORD REGULATES HYPERSENSITIVITY IN A RAT MODEL OF BONE CANCER PAIN. BONE CANCER PAIN (BCP) IS A PERVASIVE CLINICAL SYMPTOM WHICH IMPAIRS THE QUALITY LIFE. LONG NONCODING RNAS (LNCRNAS) ARE ENRICHED IN THE CENTRAL NERVOUS SYSTEM AND PLAY INDISPENSABLE ROLES IN NUMEROUS BIOLOGICAL PROCESSES, WHILE ITS REGULATORY FUNCTION IN NOCICEPTIVE INFORMATION PROCESSING REMAINS ELUSIVE. HERE, WE REPORTED THAT FUNCTIONAL MODULATORY ROLE OF ENSRNOT00000071132 (LNCRNA71132) IN THE BCP PROCESS AND SPONGING WITH MIR-143 AND ITS DOWNSTREAM GPR85-DEPENDENT SIGNALING CASCADE. SPINAL LNCRNA71132 WAS REMARKABLY INCREASED IN THE RAT MODEL OF BONE CANCER PAIN. THE KNOCKDOWN OF SPINAL LNCRNA71132 REVERTED BCP BEHAVIORS AND SPINAL C-FOS NEURONAL SENSITIZATION. OVEREXPRESSION OF SPINAL LNCRNA71132 IN NAIVE RAT GENERATED PAIN BEHAVIORS, WHICH WERE ACCOMPANIED BY INCREASED SPINAL C-FOS NEURONAL SENSITIZATION. FURTHERMORE, IT WAS FOUND THAT LNCRNA71132 PARTICIPATES IN THE MODULATION OF BCP BY INVERSELY REGULATING THE PROCESSING OF MIR-143-5P. IN ADDITION, AN INCREASE IN EXPRESSION OF SPINAL LNCRNA71132 RESULTED IN THE DECREASE IN EXPRESSION OF MIR-143 UNDER THE BCP STATE. FINALLY, IT WAS FOUND THAT MIR-143-5P REGULATES PAIN BEHAVIORS BY TARGETING GPR85. OVEREXPRESSION OF MIR-143-5P IN THE SPINAL CORD REVERTED THE NOCICEPTIVE BEHAVIORS TRIGGERED BY BCP, ACCOMPANIED BY A DECREASE IN EXPRESSION OF SPINAL GPR85 PROTEIN, BUT NO INFLUENCE ON EXPRESSION OF GPR85 MRNA. THE FINDINGS OF THIS STUDY INDICATE THAT LNCRNA71132 WORKS AS A MIRNA SPONGE IN MIR-143-5P-MEDIATED POSTTRANSCRIPTIONAL MODULATION OF GPR85 EXPRESSION IN BCP. THEREFORE, EPIGENETIC INTERVENTIONS AGAINST LNCRNA71132 MAY POTENTIALLY WORK AS NOVEL TREATMENT AVENUES IN TREATING NOCICEPTIVE HYPERSENSITIVITY TRIGGERED BY BONE CANCER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
6 1167  42 CONTRIBUTION OF DORSAL ROOT GANGLION OCTAMER TRANSCRIPTION FACTOR 1 TO NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY. NEUROPATHIC PAIN GENESIS IS RELATED TO GENE ALTERATIONS IN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY. TRANSCRIPTION FACTORS CONTROL GENE EXPRESSION. IN THIS STUDY, WE INVESTIGATED WHETHER OCTAMER TRANSCRIPTION FACTOR 1 (OCT1), A TRANSCRIPTION FACTOR, CONTRIBUTED TO NEUROPATHIC PAIN CAUSED BY CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE. CHRONIC CONSTRICTION INJURY PRODUCED A TIME-DEPENDENT INCREASE IN THE LEVEL OF OCT1 PROTEIN IN THE IPSILATERAL L4/5 DRG, BUT NOT IN THE SPINAL CORD. BLOCKING THIS INCREASE THROUGH MICROINJECTION OF OCT1 SIRNA INTO THE IPSILATERAL L4/5 DRG ATTENUATED THE INITIATION AND MAINTENANCE OF CCI-INDUCED MECHANICAL ALLODYNIA, HEAT HYPERALGESIA, AND COLD ALLODYNIA AND IMPROVED MORPHINE ANALGESIA AFTER CCI, WITHOUT AFFECTING BASAL RESPONSES TO ACUTE MECHANICAL, HEAT, AND COLD STIMULI AS WELL AS LOCOMOTOR FUNCTIONS. MIMICKING THIS INCREASE THROUGH MICROINJECTION OF RECOMBINANT ADENO-ASSOCIATED VIRUS 5 HARBORING FULL-LENGTH OCT1 INTO THE UNILATERAL L4/5 DRG LED TO MARKED MECHANICAL ALLODYNIA, HEAT HYPERALGESIA, AND COLD ALLODYNIA IN NAIVE RATS. MECHANISTICALLY, OCT1 PARTICIPATED IN CCI-INDUCED INCREASES IN DNMT3A MRNA AND ITS PROTEIN AND DNMT3A-MEDIATED DECREASES IN OPRM1 AND KCNA2 MRNAS AND THEIR PROTEINS IN THE INJURED DRG. THESE FINDINGS INDICATE THAT OCT1 MAY PARTICIPATE IN NEUROPATHIC PAIN AT LEAST IN PART BY TRANSCRIPTIONALLY ACTIVATING DNMT3A AND SUBSEQUENTLY EPIGENETIC SILENCING OF OPRM1 AND KCAN2 IN THE DRG. OCT1 MAY SERVE AS A POTENTIAL TARGET FOR THERAPEUTIC TREATMENTS AGAINST NEUROPATHIC PAIN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7 5354  48 RE1-SILENCING TRANSCRIPTION FACTOR CONTROLS THE ACUTE-TO-CHRONIC NEUROPATHIC PAIN TRANSITION AND CHRM2 RECEPTOR GENE EXPRESSION IN PRIMARY SENSORY NEURONS. NEUROPATHIC PAIN IS ASSOCIATED WITH PERSISTENT CHANGES IN GENE EXPRESSION IN PRIMARY SENSORY NEURONS, BUT THE UNDERLYING EPIGENETIC MECHANISMS THAT CAUSE THESE CHANGES REMAIN UNCLEAR. THE MUSCARINIC CHOLINERGIC RECEPTORS (MACHRS), PARTICULARLY THE M2 SUBTYPE (ENCODED BY THE CHOLINERGIC RECEPTOR MUSCARINIC 2 (CHRM2) GENE), ARE CRITICALLY INVOLVED IN THE REGULATION OF SPINAL NOCICEPTIVE TRANSMISSION. HOWEVER, LITTLE IS KNOWN ABOUT HOW CHRM2 EXPRESSION IS TRANSCRIPTIONALLY REGULATED. HERE WE SHOW THAT NERVE INJURY PERSISTENTLY INCREASED THE EXPRESSION OF RE1-SILENCING TRANSCRIPTION FACTOR (REST, ALSO KNOWN AS NEURON-RESTRICTIVE SILENCING FACTOR [NRSF]), A GENE-SILENCING TRANSCRIPTION FACTOR, IN THE DORSAL ROOT GANGLION (DRG). REMARKABLY, NERVE INJURY-INDUCED CHRONIC BUT NOT ACUTE PAIN HYPERSENSITIVITY WAS ATTENUATED IN MICE WITH REST KNOCKOUT IN DRG NEURONS. ALSO, SIRNA-MEDIATED REST KNOCKDOWN REVERSED NERVE INJURY-INDUCED CHRONIC PAIN HYPERSENSITIVITY IN RATS. NERVE INJURY PERSISTENTLY REDUCED CHRM2 EXPRESSION IN THE DRG AND DIMINISHED THE ANALGESIC EFFECT OF MUSCARINE. THE RE1 BINDING SITE ON THE CHRM2 PROMOTER IS REQUIRED FOR REST-MEDIATED CHRM2 REPRESSION, AND NERVE INJURY INCREASED THE ENRICHMENT OF REST IN THE CHRM2 PROMOTER IN THE DRG. FURTHERMORE, REST KNOCKDOWN OR GENETIC ABLATION IN DRG NEURONS NORMALIZED CHRM2 EXPRESSION AND AUGMENTED MUSCARINE'S ANALGESIC EFFECT ON NEUROPATHIC PAIN AND FULLY REVERSED THE NERVE INJURY-INDUCED REDUCTION IN THE INHIBITORY EFFECT OF MUSCARINE ON GLUTAMATERGIC INPUT TO SPINAL DORSAL HORN NEURONS. OUR FINDINGS INDICATE THAT NERVE INJURY-INDUCED REST UP-REGULATION IN DRG NEURONS PLAYS AN IMPORTANT ROLE IN THE ACUTE-TO-CHRONIC PAIN TRANSITION AND IS ESSENTIAL FOR THE TRANSCRIPTIONAL REPRESSION OF CHRM2 IN NEUROPATHIC PAIN.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8  532  36 ASTROCYTIC C-JUN N-TERMINAL KINASE-HISTONE DEACETYLASE-2 CASCADE CONTRIBUTES TO GLUTAMATE TRANSPORTER-1 DECREASE AND MECHANICAL ALLODYNIA FOLLOWING PERIPHERAL NERVE INJURY IN RATS. DECREASE OF GLUTAMATE TRANSPORTER-1 (GLT-1) IN THE SPINAL DORSAL HORN AFTER NERVE INJURY INDUCES ENHANCED EXCITATORY TRANSMISSION AND CAUSES PERSISTENT PAIN. HISTONE DEACETYLASES (HDACS)-CATALYZED DEACETYLATION MIGHT CONTRIBUTE TO THE DECREASE OF GLT-1, WHILE THE DETAILED MECHANISMS HAVE YET TO BE FULLY ELABORATED. SPINAL NERVE LIGATION (SNL) INDUCED SIGNIFICANT INCREASES OF HDAC2 AND DECREASES OF GLT-1 IN SPINAL ASTROCYTES. INTRATHECAL INFUSION OF THE HDAC2 INHIBITORS ATTENUATED THE DECREASE OF GLT-1 AND ENHANCED PHOSPHORYLATION OF GLUTAMATE RECEPTORS. GLT-1 AND PHOSPHORYLATED C-JUN N-TERMINAL KINASE (JNK) WERE HIGHLY COLOCALIZED IN THE SPINAL CORD, AND A LARGE NUMBER OF PJNK POSITIVE CELLS WERE HDAC2 POSITIVE. INTRATHECALLY INFUSION OF THE JNK INHIBITOR SP600125 SIGNIFICANTLY INHIBITED SNL-INDUCED UPREGULATION OF HDAC2. SNL-INDUCED HDAC2 UP-REGULATION COULD BE INHIBITED BY THE NEUTRALIZING ANTI-TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) BINDING PROTEIN ETANERCEPT OR THE MICROGLIAL INHIBITOR MINOCYCLINE. IN CULTURED ASTROCYTES, TNF-ALPHA INDUCED ENHANCED PHOSPHORYLATION OF JNK AND A SIGNIFICANT INCREASE OF HDAC2, AS WELL AS A REMARKABLE DECREASE OF GLT-1, WHICH COULD BE PREVENTED BY SP600125 OR THE HDAC2 SPECIFIC INHIBITOR CAY10683. OUR DATA SUGGEST THAT ASTROCYTIC JNK-HDAC2 CASCADE CONTRIBUTES TO GLT-1 DECREASE AND MECHANICAL ALLODYNIA FOLLOWING PERIPHERAL NERVE INJURY. NEUROIMMUNE ACTIVATION AFTER PERIPHERAL NERVE INJURY COULD INDUCE EPIGENETIC MODIFICATION CHANGES IN ASTROCYTES AND CONTRIBUTE TO CHRONIC PAIN MAINTENANCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9 6056  47 THE CYTIDINE N-ACETYLTRANSFERASE NAT10 PARTICIPATES IN PERIPHERAL NERVE INJURY-INDUCED NEUROPATHIC PAIN BY STABILIZING SYT9 EXPRESSION IN PRIMARY SENSORY NEURONS. RNA N4-ACETYLCYTIDINE (AC4C) MODIFICATION IS INCREASINGLY RECOGNIZED AS AN IMPORTANT LAYER OF GENE REGULATION; HOWEVER, THE INVOLVEMENT OF AC4C IN PAIN REGULATION HAS NOT BEEN STUDIED. HERE, WE REPORT THAT N-ACETYLTRANSFERASE 10 PROTEIN (NAT10; THE ONLY KNOWN AC4C "WRITER") CONTRIBUTES TO THE INDUCTION AND DEVELOPMENT OF NEUROPATHIC PAIN IN AN AC4C-DEPENDENT MANNER. PERIPHERAL NERVE INJURY INCREASES THE LEVELS OF NAT10 EXPRESSION AND OVERALL AC4C IN INJURED DORSAL ROOT GANGLIA (DRGS). THIS UPREGULATION IS TRIGGERED BY THE ACTIVATION OF UPSTREAM TRANSCRIPTION FACTOR 1 (USF1), A TRANSCRIPTION FACTOR THAT BINDS TO THE NAT10 PROMOTER. KNOCK-DOWN OR GENETIC DELETION OF NAT10 IN THE DRG ABOLISHES THE GAIN OF AC4C SITES IN SYT9 MRNA AND THE AUGMENTATION OF SYT9 PROTEIN, RESULTING IN A MARKED ANTINOCICEPTIVE EFFECT IN NERVE-INJURED MALE MICE. CONVERSELY, MIMICKING NAT10 UPREGULATION IN THE ABSENCE OF INJURY EVOKES THE ELEVATION OF SYT9 AC4C AND SYT9 PROTEIN AND INDUCES THE GENESIS OF NEUROPATHIC-PAIN-LIKE BEHAVIORS. THESE FINDINGS DEMONSTRATE THAT USF1-GOVERNED NAT10 REGULATES NEUROPATHIC PAIN BY TARGETING SYT9 AC4C IN PERIPHERAL NOCICEPTIVE SENSORY NEURONS. OUR FINDINGS ESTABLISH NAT10 AS A CRITICAL ENDOGENOUS INITIATOR OF NOCICEPTIVE BEHAVIOR AND A PROMISING NEW TARGET FOR TREATING NEUROPATHIC PAIN.SIGNIFICANCE STATEMENT THE CYTIDINE N4-ACETYLCYTIDINE (AC4C), A NEW EPIGENETIC RNA MODIFICATION, IS CRUCIAL FOR THE TRANSLATION AND STABILITY OF MRNA, BUT ITS ROLE FOR CHRONIC PAIN REMAINS UNCLEAR. HERE, WE DEMONSTRATE THAT N-ACETYLTRANSFERASE 10 (NAT10) ACTS AS AC4C N-ACETYLTRANSFERASE AND PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN. NAT10 WAS UPREGULATED VIA THE ACTIVATION OF THE TRANSCRIPTION FACTOR UPSTREAM TRANSCRIPTION FACTOR 1 (USF1) IN THE INJURED DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY. SINCE PHARMACOLOGICAL OR GENETIC DELETING NAT10 IN THE DRG ATTENUATED THE NERVE INJURY-INDUCED NOCICEPTIVE HYPERSENSITIVITIES PARTIALLY THROUGH SUPPRESSING SYT9 MRNA AC4C AND STABILIZING SYT9 PROTEIN LEVEL, NAT10 MAY SERVE AS AN EFFECTIVE AND NOVEL THERAPEUTIC TARGET FOR NEUROPATHIC PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10 2006  32 EPIGENETIC AUGMENTATION OF THE MACROPHAGE INFLAMMATORY PROTEIN 2/C-X-C CHEMOKINE RECEPTOR TYPE 2 AXIS THROUGH HISTONE H3 ACETYLATION IN INJURED PERIPHERAL NERVES ELICITS NEUROPATHIC PAIN. ALTHOUGH THERE IS GROWING EVIDENCE SHOWING THAT THE INVOLVEMENT OF CHEMOKINES IN THE PATHOGENESIS OF NEUROPATHIC PAIN IS ASSOCIATED WITH NEUROINFLAMMATION, THE DETAILS ARE UNCLEAR. WE INVESTIGATED THE C-X-C CHEMOKINE LIGAND TYPE 2 [MACROPHAGE INFLAMMATORY PROTEIN 2 (MIP-2)]/C-X-C CHEMOKINE RECEPTOR TYPE 2 (CXCR2) AXIS AND EPIGENETIC REGULATION OF THESE MOLECULES IN NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY. EXPRESSION OF MIP-2 AND CXCR2 WERE UP-REGULATED AND LOCALIZED ON ACCUMULATED NEUTROPHILS AND MACROPHAGES IN THE INJURED SCIATIC NERVE (SCN) AFTER PARTIAL SCIATIC NERVE LIGATION (PSL). PERINEURAL INJECTION OF MIP-2-NEUTRALIZING ANTIBODY (ANTI-MIP-2) OR THE CXCR2 ANTAGONIST N-(2-BROMOPHENYL)-N'-(2-HYDROXY-4-NITROPHENYL)UREA (SB225002) PREVENTED PSL-INDUCED TACTILE ALLODYNIA AND THERMAL HYPERALGESIA. PERINEURAL INJECTION OF RECOMBINANT MIP-2 ELICITED NEUROPATHIC PAIN-LIKE BEHAVIORS. ANTI-MIP-2 SUPPRESSED NEUTROPHIL ACCUMULATION IN THE SCN AFTER PSL. NEUTROPHIL DEPLETION BY INTRAPERITONEAL INJECTION OF LY6G ANTIBODY ATTENUATED PSL-INDUCED NEUROPATHIC PAIN. BOTH ANTI-MIP-2 AND SB225002 SUPPRESSED UP-REGULATION OF INFLAMMATORY CYTOKINES AND CHEMOKINES IN THE INJURED SCN. IN ADDITION, ACETYLATION OF HISTONE H3 [LYSINE (LYS9)-ACETYLATED HISTONE H3 (ACK9-H3)] ON THE PROMOTER REGION OF MIP-2 AND CXCR2 WAS INCREASED IN THE INJURED SCN AFTER PSL. EXPRESSION OF ACK9-H3 WAS OBSERVED IN THE NUCLEI OF NEUTROPHILS AND MACROPHAGES SURROUNDING THE EPINEURIUM. ADMINISTRATION OF THE HISTONE ACETYLTRANSFERASE INHIBITOR ANACARDIC ACID SUPPRESSED THE UP-REGULATION OF MIP-2 AND CXCR2 IN THE SCN AFTER PSL AND RESULTED IN THE PREVENTION OF PSL-INDUCED NEUROPATHIC PAIN. TAKEN TOGETHER, THESE RESULTS SHOW THAT AUGMENTATION OF THE MIP-2/CXCR2 AXIS BY HYPERACETYLATION OF HISTONE H3 ON THE PROMOTER REGION OF MIP-2 AND CXCR2 LOCATED IN THE INJURED PERIPHERAL NERVE ELICITS CHRONIC NEUROINFLAMMATION THROUGH NEUTROPHIL ACCUMULATION, LEADING TO NEUROPATHIC PAIN.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11 2450  32 EPIGENETIC SUPPRESSION OF LIVER X RECEPTOR BETA IN ANTERIOR CINGULATE CORTEX BY HDAC5 DRIVES CFA-INDUCED CHRONIC INFLAMMATORY PAIN. BACKGROUND: LIVER X RECEPTORS (LXRS), INCLUDING LXRALPHA AND LXRBETA, ARE KEY REGULATORS OF TRANSCRIPTIONAL PROGRAMS FOR BOTH CHOLESTEROL HOMEOSTASIS AND INFLAMMATION IN THE BRAIN. HERE, THE MODES OF ACTION OF LXRS AND THE EPIGENETIC MECHANISMS REGULATING LXRBETA EXPRESSION IN ANTERIOR CINGULATE CORTEX (ACC) OF CHRONIC INFLAMMATORY PAIN (CIP) ARE INVESTIGATED. METHODS: THE DEFICIT OF LXR ISOFORM AND ANALGESIC EFFECT OF LXR ACTIVATION BY GW3965 WERE EVALUATED USING THE MOUSE MODEL OF CIP INDUCED BY HINDPAW INJECTION OF COMPLETE FREUND'S ADJUVANT (CFA). THE MECHANISMS INVOLVED IN GW-MEDIATED ANALGESIC EFFECTS WERE ANALYZED WITH IMMUNOHISTOCHEMICAL METHODS, ELISA, CO-IMMUNOPRECIPITATION (CO-IP), WESTERN BLOT, AND ELECTROPHYSIOLOGICAL RECORDING. THE EPIGENETIC REGULATION OF LXRBETA EXPRESSION WAS INVESTIGATED BY CHROMATIN IMMUNOPRECIPITATION, QUANTITATIVE REAL-TIME PCR, AND SEQUENCING. RESULTS: WE REVEALED THAT CFA INSULT LED TO LXRBETA REDUCTION IN ACC, WHICH WAS ASSOCIATED WITH UPREGULATED EXPRESSION OF HISTONE DEACETYLASE 5 (HDAC5), AND KNOCKDOWN OF LXRBETA BY SHRNA LED TO THERMAL HYPERALGESIA. CO-IP SHOWED THAT LXRBETA INTERACTED WITH NF-KAPPAB P65 PHYSICALLY. LXRBETA ACTIVATION BY GW3965 EXERTED ANALGESIC EFFECTS BY INHIBITING THE NUCLEAR TRANSLOCATION OF NF-KAPPAB, REDUCING THE PHOSPHORYLATION OF MITOGEN-ACTIVATED PROTEIN KINASES (MAPKS) IN ACC, AND DECREASING THE PROMOTED INPUT-OUTPUT AND ENHANCED MEPSC FREQUENCY IN ACC NEURONS AFTER CFA EXPOSURE. IN VITRO EXPERIMENTS CONFIRMED THAT HDAC5 TRIGGERED HISTONE DEACETYLATION ON THE PROMOTER REGION OF LXRBETA, RESULTING IN DOWNREGULATION OF LXRBETA TRANSCRIPTION. CONCLUSION: THESE FINDINGS HIGHLIGHT AN EPIGENETIC MECHANISM UNDERLYING LXRBETA DEFICITS LINKED TO CIP, AND LXRBETA ACTIVATION MAY REPRESENT A POTENTIAL NOVEL TARGET FOR THE TREATMENT OF CIP WITH AN ALTERATION IN INFLAMMATION RESPONSES AND SYNAPTIC TRANSMISSION IN ACC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12 4637  35 NEURON-RESTRICTIVE SILENCER FACTOR CAUSES EPIGENETIC SILENCING OF KV4.3 GENE AFTER PERIPHERAL NERVE INJURY. PERIPHERAL NERVE INJURY CAUSES A VARIETY OF ALTERATIONS IN PAIN-RELATED GENE EXPRESSION IN PRIMARY AFFERENT, WHICH UNDERLIE THE NEURONAL PLASTICITY IN NEUROPATHIC PAIN. ONE OF THE CHARACTERISTIC ALTERATIONS IS A LONG-LASTING DOWNREGULATION OF VOLTAGE-GATED POTASSIUM (K(V)) CHANNEL, INCLUDING K(V)4.3, IN THE DORSAL ROOT GANGLION (DRG). THE PRESENT STUDY SHOWED THAT NERVE INJURY REDUCES THE MESSENGER RNA (MRNA) EXPRESSION LEVEL OF K(V)4.3 GENE, WHICH CONTAINS A CONSERVED NEURON-RESTRICTIVE SILENCER ELEMENT (NRSE), A BINDING SITE FOR NEURON-RESTRICTIVE SILENCER FACTOR (NRSF). MOREOVER, WE FOUND THAT INJURY CAUSES AN INCREASE IN DIRECT NRSF BINDING TO K(V)4.3-NRSE IN THE DRG, USING CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY. CHIP ASSAY FURTHER REVEALED THAT ACETYLATION OF HISTONE H4, BUT NOT H3, AT K(V)4.3-NRSE IS MARKEDLY REDUCED AT DAY 7 POST-INJURY. FINALLY, THE INJURY-INDUCED K(V)4.3 DOWNREGULATION WAS SIGNIFICANTLY BLOCKED BY ANTISENSE-KNOCKDOWN OF NRSF. TAKEN TOGETHER, THESE DATA SUGGEST THAT NERVE INJURY CAUSES AN EPIGENETIC SILENCING OF K(V)4.3 GENE MEDIATED THROUGH TRANSCRIPTIONAL SUPPRESSOR NRSF IN THE DRG.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13 6148  43 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	
                                                                                                                                                                                                                             
14 5838  32 STRIATAL SHATI/NAT8L-BDNF PATHWAYS DETERMINE THE SENSITIVITY TO SOCIAL DEFEAT STRESS IN MICE THROUGH EPIGENETIC REGULATION. THE GLOBAL NUMBER OF PATIENTS WITH DEPRESSION INCREASES IN CORRELATION TO EXPOSURE TO SOCIAL STRESS. CHRONIC STRESS DOES NOT TRIGGER DEPRESSION IN ALL INDIVIDUALS, AS SOME REMAIN RESILIENT. THE UNDERLYING MOLECULAR MECHANISMS THAT CONTRIBUTE TO STRESS SENSITIVITY HAVE BEEN POORLY UNDERSTOOD, ALTHOUGH REVEALING THE REGULATION OF STRESS SENSITIVITY COULD HELP DEVELOP TREATMENTS FOR DEPRESSION. WE PREVIOUSLY FOUND THAT STRIATAL SHATI/NAT8L, AN N-ACETYLTRANSFERASE, WAS INCREASED IN A DEPRESSION MOUSE MODEL. WE INVESTIGATED THE ROLES OF SHATI/NAT8L IN STRESS SENSITIVITY IN MICE AND FOUND THAT SHATI/NAT8L AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS IN THE DORSAL STRIATUM WERE INCREASED IN STRESS-SUSCEPTIBLE MICE BUT NOT IN RESILIENT MICE EXPOSED TO REPEATED SOCIAL DEFEAT STRESS (RSDS). KNOCKDOWN OF SHATI/NAT8L IN THE DORSAL STRIATUM INDUCED RESILIENCE TO RSDS. IN ADDITION, BLOCKADE OF BDNF SIGNALING IN THE DORSAL STRIATUM BY ANA-12, A BDNF-SPECIFIC RECEPTOR TROPOMYOSIN-RECEPTOR-KINASE B (TRKB) INHIBITOR, ALSO INDUCED RESILIENCE TO STRESS. SHATI/NAT8L IS CORRELATED WITH BDNF EXPRESSION AFTER RSDS, AND BDNF IS DOWNSTREAM OF SHATI/NAT8L PATHWAYS IN THE DORSAL STRIATUM; SHATI/NAT8L IS EPIGENETICALLY REGULATED BY BDNF VIA HISTONE ACETYLATION. OUR RESULTS DEMONSTRATE THAT STRIATAL SHATI/NAT8L-BDNF PATHWAYS DETERMINE STRESS SENSITIVITY THROUGH EPIGENETIC REGULATION. THE STRIATAL SHATI/NAT8L-BDNF PATHWAY COULD BE A NOVEL TARGET FOR TREATMENTS OF DEPRESSION AND COULD ESTABLISH A NOVEL THERAPEUTIC STRATEGY FOR DEPRESSION PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15 5401  42 REDUCTION OF SIRT1 EPIGENETICALLY UPREGULATES NALP1 EXPRESSION AND CONTRIBUTES TO NEUROPATHIC PAIN INDUCED BY CHEMOTHERAPEUTIC DRUG BORTEZOMIB. BACKGROUND: BORTEZOMIB IS A FREQUENTLY USED CHEMOTHERAPEUTIC DRUG FOR THE TREATMENT OF MULTIPLE MYELOMA AND OTHER NONSOLID MALIGNANCIES. ACCUMULATING EVIDENCE HAS DEMONSTRATED THAT BORTEZOMIB-INDUCED PERSISTENT PAIN SERVES AS THE MOST FREQUENT REASON FOR TREATMENT DISCONTINUATION. METHODS: THE VON FREY TEST WAS PERFORMED TO EVALUATE NEUROPATHIC PAIN BEHAVIOR, AND REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION, CHROMATIN IMMUNOPRECIPITATION, WESTERN BLOT, IMMUNOHISTOCHEMISTRY, AND SMALL INTERFERING RNA WERE PERFORMED TO EXPLORE THE MOLECULAR MECHANISMS IN ADULT MALE SPRAGUE-DAWLEY RATS. RESULTS: WE FOUND THAT APPLICATION OF BORTEZOMIB SIGNIFICANTLY INCREASED THE EXPRESSION OF NALP1 PROTEIN AND MRNA LEVELS IN SPINAL DORSAL HORN NEURONS, AND INTRATHECAL APPLICATION OF NALP1 SIRNA ATTENUATED THE BORTEZOMIB-INDUCED MECHANICAL ALLODYNIA. IN ADDITION, BORTEZOMIB ALSO DECREASED THE SIRT1 EXPRESSION, AND TREATMENT WITH SIRT1 ACTIVATOR RESVERATROL AMELIORATED THE NALP1 UPREGULATION AND MECHANICAL ALLODYNIA INDUCED BY BORTEZOMIB. MEANWHILE, KNOCKDOWN OF SIRT1 USING THE SIRT1 SIRNA INDUCED THE NALP1 UPREGULATION IN DORSAL HORN AND MECHANICAL ALLODYNIA IN NORMAL ANIMAL. THESE RESULTS SUGGESTED THAT REDUCTION OF SIRT1 INDUCED THE NALP1 UPREGULATION IN DORSAL HORN NEURONS, AND PARTICIPATED IN BORTEZOMIB-INDUCED MECHANICAL ALLODYNIA. IMPORTANTLY, WE FOUND THAT THE BINDING OF SIRT1 AND NALP1 PROMOTER REGION DID NOT CHANGE BEFORE AND AFTER BORTEZOMIB TREATMENT, BUT SIRT1 DOWNREGULATION INCREASED P-STAT3 EXPRESSION. FURTHERMORE, THE ACTIVATION OF STAT3 ENHANCED THE RECRUITMENT OF P-STAT3 TO THE NALP1 GENE PROMOTER, WHICH INCREASED THE ACETYLATION OF HISTONE H3 AND H4 IN NALP1 PROMOTER REGIONS AND EPIGENETICALLY UPREGULATED NALP1 EXPRESSION IN THE RODENTS WITH BORTEZOMIB TREATMENT. CONCLUSION: THESE FINDINGS SUGGESTED A NEW EPIGENETIC MECHANISM FOR NALP1 UPREGULATION INVOLVING SIRT1 REDUCTION AND SUBSEQUENT STAT3-MEDIATED HISTONE HYPERACETYLATION IN NALP1 PROMOTER REGION IN DORSAL HORN NEURONS, WHICH CONTRIBUTED TO THE BORTEZOMIB-INDUCED MECHANICAL ALLODYNIA.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16 2470  48 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	

17  685  35 BRAIN-DERIVED NEUROTROPHIC FACTOR INVOLVED EPIGENETIC REPRESSION OF UGT2B7 IN COLORECTAL CARCINOMA: A MECHANISM TO ALTER MORPHINE GLUCURONIDATION IN TUMOR. URIDINE DIPHOSPHATE-GLUCURONOSYLTRANSFERASE (UGT) 2B7, AS ONE OF SIGNIFICANT DRUG ENZYMES, IS RESPONSIBLE ON THE GLUCURONIDATION OF ABUNDANT ENDOBIOTICS OR XENOBIOTICS. WE HERE REPORT THAT IT IS MARKEDLY REPRESSED IN THE TUMOR TISSUES OF COLORECTAL CARCINOMA (CRC) PATIENTS. ACCORDINGLY, MORPHINE IN CRC CELLS WILL STIMULATE THE EXPRESSION OF ITS MAIN METABOLIC ENZYME, UGT2B7 DURING TOLERANCE GENERATION BY ACTIVATING THE POSITIVE SIGNALS IN HISTONE 3, ESPECIALLY FOR TRIMETHYLATED LYSINE 27 (H3K4ME3) AND ACETYLATED LYSINE 4 (H3K27AC). FURTHER STUDY REVEALS THAT BRAIN-DERIVED NEUTROPHILIC FACTOR (BDNF), A SECRETORY NEUROTROPHIN, ENRICHED IN CRC CAN INTERACT AND INHIBIT UGT2B7 BY PRIMARILY BLOCKING THE POSITIVE SIGNALS OF H3K4ME3 AS WELL AS ACTIVATING H3K27AC ON THE PROMOTER REGION OF UGT2B7. MEANWHILE, BDNF REPRESSION ATTRIBUTES TO THE SENSITIZATIONS OF MAIN CORE FACTORS IN POLY-COMB REPRESSIVE COMPLEX (PRC) 1 RATHER THAN PRC2 AS THE REASON OF THE DEPRESSION OF SUZ12 IN THE LATER COMPLEX. BESIDES THAT, THE PRODUCTIONS OF TWO MAIN MORPHINE GLUCURONIDES ARE BOTH INCREASED IN THE BDNF DEFICIENT OR TSA AND BIX-01294 TREATED MORPHINE TOLERANCE-LIKE HCT-116 CELLS. ON THE SAME CONDITION, ACTIVE METABOLITE, MORPHINE-6-GLUCURONIDE (M6G) WAS ACCUMULATED MORE THAN INACTIVE M3G. OUR FINDINGS IMPLY THAT ENZYMATIC ACTIVITY ENHANCEMENT AND SUBSTRATE REGIOSELECTIVE CATALYSIS ALTERATION OF UGT2B7 MAY RELEASE MORPHINE TOLERANCE UNDER THE CURE OF TUMOR-INDUCED PAIN.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18 1298  29 DECREASED NUCLEAR RECEPTOR ACTIVITY AND EPIGENETIC MODULATION ASSOCIATES WITH DOWN-REGULATION OF HEPATIC DRUG-METABOLIZING ENZYMES IN CHRONIC KIDNEY DISEASE. PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) REQUIRE MANY MEDICATIONS. CYP2C AND CYP3A DRUG-METABOLIZING ENZYMES PLAY A CRITICAL ROLE IN DETERMINING THE PHARMACOKINETICS OF THE MAJORITY OF PRESCRIBED MEDICATIONS. THESE ENZYMES ARE TRANSCRIPTIONALLY REGULATED BY THE NUCLEAR RECEPTORS PREGNANE X RECEPTOR (PXR) AND HEPATIC NUCLEAR FACTOR 4ALPHA (HNF-4ALPHA). EXPRESSION OF CYP2C AND CYP3A IS DECREASED IN CKD; HOWEVER, THE MECHANISMS BY WHICH THIS OCCURS IS UNKNOWN. WE INDUCED CKD IN RATS BY 5/6 NEPHRECTOMY AND USED CHROMATIN IMMUNOPRECIPITATION (CHIP) TO DETERMINE NUCLEAR RECEPTOR- AND EPIGENETIC ALTERATION-MEDIATED DIFFERENCES IN THE PROMOTER REGION OF THE CYP2C AND CYP3A GENES. RNA POLYMERASE II AND HNF-4ALPHA BINDING WAS DECREASED 76 AND 57% IN THE CYP2C11 PROMOTOR AND 71 AND 77% IN THE CYP3A2 PROMOTER, RESPECTIVELY (P<0.05). CHIP ALSO REVEALED A 57% DECREASE IN PXR BINDING TO THE CYP3A2 PROMOTER IN CKD RATS (P<0.05). THE DECREASE IN PXR AND HNF-4ALPHA BINDING WAS ACCOMPANIED BY DIMINISHED HISTONE 4 ACETYLATION IN THE CYP3A2 PROMOTER (48%) AND HISTONE 3 ACETYLATION IN THE CYP2C11 (77%) AND CYP3A2 (77%) PROMOTER LOCI FOR NUCLEAR RECEPTOR ACTIVATION (P<0.05). THIS STUDY SUGGESTS THAT DECREASED NUCLEAR RECEPTOR BINDING AND HISTONE ACETYLATION MAY CONTRIBUTE TO THE MECHANISM OF DRUG-METABOLIZING ENZYME DOWN-REGULATION AND ALTERED PHARMACOKINETICS IN CKD.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
19 5503  32 RGS9-2--CONTROLLED ADAPTATIONS IN THE STRIATUM DETERMINE THE ONSET OF ACTION AND EFFICACY OF ANTIDEPRESSANTS IN NEUROPATHIC PAIN STATES. THE STRIATAL PROTEIN REGULATOR OF G-PROTEIN SIGNALING 9-2 (RGS9-2) PLAYS A KEY MODULATORY ROLE IN OPIOID, MONOAMINE, AND OTHER G-PROTEIN-COUPLED RECEPTOR RESPONSES. HERE, WE USE THE MURINE SPARED-NERVE INJURY MODEL OF NEUROPATHIC PAIN TO INVESTIGATE THE MECHANISM BY WHICH RGS9-2 IN THE NUCLEUS ACCUMBENS (NAC), A BRAIN REGION INVOLVED IN MOOD, REWARD, AND MOTIVATION, MODULATES THE ACTIONS OF TRICYCLIC ANTIDEPRESSANTS (TCAS). PREVENTION OF RGS9-2 ACTION IN THE NAC INCREASES THE EFFICACY OF THE TCA DESIPRAMINE AND DRAMATICALLY ACCELERATES ITS ONSET OF ACTION. BY CONTROLLING THE ACTIVATION OF EFFECTOR MOLECULES BY G PROTEIN ALPHA AND BETAGAMMA SUBUNITS, RGS9-2 AFFECTS SEVERAL PROTEIN INTERACTIONS, PHOSPHOPROTEIN LEVELS, AND THE FUNCTION OF THE EPIGENETIC MODIFIER HISTONE DEACETYLASE 5, WHICH ARE IMPORTANT FOR TCA RESPONSIVENESS. FURTHERMORE, INFORMATION FROM RNA-SEQUENCING ANALYSIS REVEALS THAT RGS9-2 IN THE NAC AFFECTS THE EXPRESSION OF MANY GENES KNOWN TO BE INVOLVED IN NOCICEPTION, ANALGESIA, AND ANTIDEPRESSANT DRUG ACTIONS. OUR FINDINGS PROVIDE NOVEL INFORMATION ON NAC-SPECIFIC CELLULAR MECHANISMS THAT MEDIATE THE ACTIONS OF TCAS IN NEUROPATHIC PAIN STATES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20 2203  32 EPIGENETIC MODIFICATION OF SPINAL MIR-219 EXPRESSION REGULATES CHRONIC INFLAMMATION PAIN BY TARGETING CAMKIIGAMMA. EMERGING EVIDENCE HAS SHOWN THAT MIRNA-MEDIATED GENE EXPRESSION MODULATION CONTRIBUTES TO CHRONIC PAIN, BUT ITS FUNCTIONAL REGULATORY MECHANISM REMAINS UNKNOWN. HERE, WE FOUND THAT COMPLETE FREUND'S ADJUVANT (CFA)-INDUCED CHRONIC INFLAMMATION PAIN SIGNIFICANTLY REDUCED MIRNA-219 (MIR-219) EXPRESSION IN MICE SPINAL NEURONS. FURTHERMORE, THE EXPRESSION OF SPINAL CAMKIIGAMMA, AN EXPERIMENTALLY VALIDATED TARGET OF MIR-219, WAS INCREASED IN CFA MICE. OVEREXPRESSION OF SPINAL MIR-219 PREVENTED AND REVERSED THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA AND SPINAL NEURONAL SENSITIZATION INDUCED BY CFA. CONCURRENTLY, INCREASED EXPRESSION OF SPINAL CAMKIIGAMMA WAS REVERSED BY MIR-219 OVEREXPRESSION. DOWNREGULATION OF SPINAL MIR-219 IN NAIVE MICE INDUCED PAIN-RESPONSIVE BEHAVIORS AND INCREASED P-NMDAR1 EXPRESSION, WHICH COULD BE INHIBITED BY KNOCKDOWN OF CAMKIIGAMMA. BISULFITE SEQUENCING SHOWED THAT CFA INDUCED THE HYPERMETHYLATION OF CPG ISLANDS IN THE MIR-219 PROMOTER. TREATMENT WITH DEMETHYLATION AGENT 5'-AZA-2'-DEOXYCYTIDINE MARKEDLY ATTENUATED PAIN BEHAVIOR AND SPINAL NEURONAL SENSITIZATION, WHICH WAS ACCOMPANIED WITH THE INCREASE OF SPINAL MIR-219 AND DECREASE OF CAMKIIGAMMA EXPRESSION. TOGETHER, WE CONCLUDE THAT METHYLATION-MEDIATED EPIGENETIC MODIFICATION OF SPINAL MIR-219 EXPRESSION REGULATES CHRONIC INFLAMMATORY PAIN BY TARGETING CAMKIIGAMMA.	2014