1 2476 126 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
2 2470  47 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	

3 2785  38 EZH2 REGULATES SPINAL NEUROINFLAMMATION IN RATS WITH NEUROPATHIC PAIN. ALTERATION IN GENE EXPRESSION ALONG THE PAIN SIGNALING PATHWAY IS A KEY MECHANISM CONTRIBUTING TO THE GENESIS OF NEUROPATHIC PAIN. ACCUMULATING STUDIES HAVE SHOWN THAT EPIGENETIC REGULATION PLAYS A CRUCIAL ROLE IN NOCICEPTIVE PROCESS IN THE SPINAL DORSAL HORN. IN THIS PRESENT STUDY, WE INVESTIGATED THE ROLE OF ENHANCER OF ZESTE HOMOLOG-2 (EZH2), A SUBUNIT OF THE POLYCOMB REPRESSIVE COMPLEX 2, IN THE SPINAL DORSAL HORN IN THE GENESIS OF NEUROPATHIC PAIN IN RATS INDUCED BY PARTIAL SCIATIC NERVE LIGATION. EZH2 IS A HISTONE METHYLTRANSFERASE, WHICH CATALYZES THE METHYLATION OF HISTONE H3 ON K27 (H3K27), RESULTING IN GENE SILENCING. WE FOUND THAT LEVELS OF EZH2 AND TRI-METHYLATED H3K27 (H3K27TM) IN THE SPINAL DORSAL HORN WERE INCREASED IN RATS WITH NEUROPATHIC PAIN ON DAY 3 AND DAY 10 POST NERVE INJURIES. EZH2 WAS PREDOMINANTLY EXPRESSED IN NEURONS IN THE SPINAL DORSAL HORN UNDER NORMAL CONDITIONS. THE NUMBER OF NEURONS WITH EZH2 EXPRESSION WAS INCREASED AFTER NERVE INJURY. MORE STRIKINGLY, NERVE INJURY DRASTICALLY INCREASED THE NUMBER OF MICROGLIA WITH EZH2 EXPRESSION BY MORE THAN SEVENFOLD. INTRATHECAL INJECTION OF THE EZH2 INHIBITOR ATTENUATED THE DEVELOPMENT AND MAINTENANCE OF MECHANICAL AND THERMAL HYPERALGESIA IN RATS WITH NERVE INJURY. SUCH ANALGESIC EFFECTS WERE CONCURRENTLY ASSOCIATED WITH THE REDUCED LEVELS OF EZH2, H3K27TM, IBA1, GFAP, TNF-ALPHA, IL-1BETA, AND MCP-1 IN THE SPINAL DORSAL HORN IN RATS WITH NERVE INJURY. OUR RESULTS HIGHLY SUGGEST THAT TARGETING THE EZH2 SIGNALING PATHWAY COULD BE AN EFFECTIVE APPROACH FOR THE MANAGEMENT OF NEUROPATHIC PAIN.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4 6148  32 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	
                                                                                                                                                                                                                             
5 5851  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6 6172  39 THE HDAC1/C-JUN COMPLEX IS ESSENTIAL IN THE PROMOTION OF NERVE INJURY-INDUCED NEUROPATHIC PAIN THROUGH JNK SIGNALING. HISTONE DEACETYLASE INHIBITORS (HDACIS) INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION AND ARE KNOWN TO HAVE ANALGESIC PROPERTIES IN MODELS OF CHRONIC INFLAMMATORY PAIN. ADMINISTRATION OF A SELECTIVE HDAC1 INHIBITOR (LG325) IN SNI-SUBJECTED MICE SIGNIFICANTLY ATTENUATED BEHAVIOR RELATED TO INJURY-INDUCED PAIN. UNDERSTANDING THE HDAC1 PATHWAY IN EPIGENETIC REGULATION OF PATHOLOGICAL PAIN IS OF GREAT MEDICAL RELEVANCE. SPARED NERVE INJURY (SNI) MICE SHOWED A SIGNIFICANT INCREASE IN THE HDAC1 PROTEIN LEVELS WITHIN SPINAL CORD IN COINCIDENCE WITH THE NOCICEPTIVE PHENOTYPE AT 1 AND 3 WEEKS AFTER NERVE INJURY. NO VARIATION IN HDAC3, DNMT3A, ACH3, MBD3 AND MECP2 LEVELS WAS DETECTED. INCREASED EXPRESSION OF HDAC1 IS ACCOMPANIED BY ACTIVATION OF THE JNK-C-JUN SIGNALING PATHWAY. A ROBUST SPINAL JNK-1 OVERPHOSPHORYLATION WAS OBSERVED POST NERVE-INJURY ALONG WITH A SELECTIVE JNK-DEPENDENT INCREASE IN P-C-JUN AND HDAC1 PROTEIN LEVELS. CO-IMMUNOPRECIPITATION EXPERIMENTS SHOWED THE PRESENCE OF A HETERODIMERIC COMPLEX BETWEEN HDAC1 AND C-JUN IN SNI MICE INDICATING THAT THESE TRANSCRIPTION FACTORS CAN ACT TOGETHER TO REGULATE TRANSCRIPTION THROUGH HETERODIMERIZATION. STIMULATION OF C-JUN PHOSPHORYLATION WAS PREVENTED BY THE SELECTIVE HDAC1 INHIBITOR LG325. WE FOUND THAT HDAC1 WAS ASSOCIATED WITH C-JUN IN NUCLEI OF SPINAL DORSAL HORN ASTROCYTES EXPRESSING JNK. ON THE OTHER HAND, THE PRESENCE OF HDAC1 AND C-JUN INTERACTION WAS NOT DETECTED IN CONTROL MICE. THESE FINDINGS PROVIDE NEW INSIGHTS INTO THE MECHANISMS UNDERLYING THE ANTI-NOCICEPTIVE ACTIVITY OF HDAC INHIBITORS. TAKEN TOGETHER, THESE DATA SUPPORT A ROLE FOR HISTONE DEACETYLASE IN THE EMERGENCE OF NEUROPATHIC PAIN.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7  717  48 CALCITONIN GENE-RELATED PEPTIDE REGULATES SPINAL MICROGLIAL ACTIVATION THROUGH THE HISTONE H3 LYSINE 27 TRIMETHYLATION VIA ENHANCER OF ZESTE HOMOLOG-2 IN RATS WITH NEUROPATHIC PAIN. BACKGROUND: CALCITONIN GENE-RELATED PEPTIDE (CGRP) AS A MEDIATOR OF MICROGLIAL ACTIVATION AT THE TRANSCRIPTIONAL LEVEL MAY FACILITATE NOCICEPTIVE SIGNALING. TRIMETHYLATION OF H3 LYSINE 27 (H3K27ME3) BY ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS AN EPIGENETIC MARK THAT REGULATES INFLAMMATORY-RELATED GENE EXPRESSION AFTER PERIPHERAL NERVE INJURY. IN THIS STUDY, WE EXPLORED THE RELATIONSHIP BETWEEN CGRP AND H3K27ME3 IN MICROGLIAL ACTIVATION AFTER NERVE INJURY, AND ELUCIDATED THE UNDERLYING MECHANISMS IN THE PATHOGENESIS OF CHRONIC NEUROPATHIC PAIN. METHODS: MICROGLIAL CELLS (BV2) WERE TREATED WITH CGRP AND DIFFERENTIALLY ENRICHMENTS OF H3K27ME3 ON GENE PROMOTERS WERE EXAMINED USING CHIP-SEQ. A CHRONIC CONSTRICTION INJURY (CCI) RAT MODEL WAS USED TO EVALUATE THE ROLE OF CGRP ON MICROGLIAL ACTIVATION AND EZH2/H3K27ME3 SIGNALING IN CCI-INDUCED NEUROPATHIC PAIN. RESULTS: OVEREXPRESSIONS OF EZH2 AND H3K27ME3 WERE CONFIRMED IN SPINAL MICROGLIA OF CCI RATS BY IMMUNOFLUORESCENCE. CGRP TREATMENT INDUCED THE INCREASED OF H3K27ME3 EXPRESSION IN THE SPINAL DORSAL HORN AND CULTURED MICROGLIAL CELLS (BV2) THROUGH EZH2. CHIP-SEQ DATA INDICATED THAT CGRP SIGNIFICANTLY ALTERED H3K27ME3 ENRICHMENTS ON GENE PROMOTERS IN MICROGLIA FOLLOWING CGRP TREATMENT, INCLUDING 173 GAINING H3K27ME3 AND 75 LOSING THIS MARK, WHICH MOSTLY ENRICHED IN REGULATION OF CELL GROWTH, PHAGOSOME, AND INFLAMMATION. QRT-PCR VERIFIED EXPRESSIONS OF REPRESENTATIVE CANDIDATE GENES (TRAF3IP2, BCL2L11, ITGAM, DAB2, NLRP12, WNT3, ADAM10) AND REAL-TIME CELL ANALYSIS (RTCA) VERIFIED MICROGLIAL PROLIFERATION. ADDITIONALLY, CGRP TREATMENT AND CCI INCREASED EXPRESSIONS OF ITGAM, ADAM10, MCP-1, AND CX3CR1, KEY MEDIATORS OF MICROGLIAL ACTIVATION IN SPINAL DORSAL HORN AND CULTURED MICROGLIAL CELLS. SUCH INCREASED EFFECTS INDUCED BY CCI WERE SUPPRESSED BY CGRP ANTAGONIST AND EZH2 INHIBITOR, WHICH WERE CONCURRENTLY ASSOCIATED WITH THE ATTENUATED MECHANICAL AND THERMAL HYPERALGESIA IN CCI RATS. CONCLUSION: OUR FINDINGS HIGHLY INDICATE THAT CGRP IS IMPLICATED IN THE GENESIS OF NEUROPATHIC PAIN THROUGH REGULATING MICROGLIAL ACTIVATION VIA EZH2-MEDIATED H3K27ME3 IN THE SPINAL DORSAL HORN.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                          
8 6429  40 THE UPREGULATION OF NLRP3 INFLAMMASOME IN DORSAL ROOT GANGLION BY TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 2 (TET2) CONTRIBUTED TO DIABETIC NEUROPATHIC PAIN IN MICE. BACKGROUND: THE NUCLEOTIDE OLIGOMERIZATION DOMAIN (NOD)-LIKE RECEPTOR FAMILY PYRIN DOMAIN CONTAINING 3 (NLRP3) IN DORSAL ROOT GANGLION (DRG) CONTRIBUTES TO PAIN HYPERSENSITIVITY IN MULTIPLE NEUROPATHIC PAIN MODELS, BUT THE FUNCTION OF THE NLRP3 IN DIABETIC NEUROPATHIC PAIN (DNP) AND THE REGULATION MECHANISM ARE STILL LARGELY UNKNOWN. EPIGENETIC REGULATION PLAYS A VITAL ROLE IN THE CONTROLLING OF GENE EXPRESSION. TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 2 (TET2) IS A DNA DEMETHYLASE THAT CONTRIBUTES TO TRANSCRIPTIONAL ACTIVATION. TET2 IS ALSO INVOLVED IN HIGH GLUCOSE (HG)-INDUCED PATHOLOGY. METHODS: DNP WAS INDUCED IN MICE VIA THE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN (STZ) FOR FIVE CONSECUTIVE DAYS AND THE MECHANICAL THRESHOLD WAS EVALUATED IN STZ-DIABETIC MICE BY USING VON FREY HAIRS. THE EXPRESSION LEVEL OF THE NLRP3 PATHWAY AND TET2 IN DRG WERE DETERMINED THROUGH MOLECULAR BIOLOGY EXPERIMENTS. THE REGULATION OF THE NLRP3 PATHWAY BY TET2 WAS EXAMINED IN IN VITRO AND IN VIVO CONDITIONS. RESULTS: IN THE PRESENT RESEARCH, WE FIRST ESTABLISHED THE DNP MODEL AND FOUND THAT NLRP3 PATHWAY WAS ACTIVATED IN DRG. THE TREATMENT OF NLRP3 INHIBITOR MCC950 ALLEVIATED THE MECHANICAL ALLODYNIA OF DNP MICE. THEN WE REVEALED THAT IN STZ-DIABETIC MICE DRG, THE GENOMIC DNA WAS DEMETHYLATED, AND THE EXPRESSION OF DNA DEMETHYLASE TET2 WAS INCREASED EVIDENTLY. USING RNA-SEQUENCING ANALYSIS, WE FOUND THAT THE EXPRESSION OF TXNIP, A GENE THAT ENCODES A THIOREDOXIN-INTERACTING PROTEIN (TXNIP) WHICH MEDIATES NLRP3 ACTIVATION, WAS ELEVATED IN THE DRG AFTER STZ TREATMENT. IN ADDITION, KNOCKING DOWN OF TET2 EXPRESSION IN DRG USING TET2-SIRNA SUPPRESSED THE MRNA EXPRESSION OF TXNIP AND SUBSEQUENTLY INHIBITED THE EXPRESSION/ACTIVATION OF NLRP3 INFLAMMASOME IN VITRO AND IN VIVO AS WELL AS RELIEVED THE PAIN SENSITIVITY OF DNP ANIMALS. CONCLUSION: THE RESULTS SUGGESTED THAT THE UPREGULATION OF THE TXNIP/NLRP3 PATHWAY BY TET2 IN DRG WAS INVOLVED IN THE PAIN HYPERSENSITIVITY OF THE DNP MODEL.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9 2783  37 EZH2 METHYLTRANSFERASE REGULATES NEUROINFLAMMATION AND NEUROPATHIC PAIN. RECENT STUDIES BY US AND OTHERS HAVE SHOWN THAT ENHANCER OF ZESTE HOMOLOG-2 (EZH2), A HISTONE METHYLTRANSFERASE, IN GLIAL CELLS REGULATES THE GENESIS OF NEUROPATHIC PAIN BY MODULATING THE PRODUCTION OF PROINFLAMMATORY CYTOKINES AND CHEMOKINES. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES IN THIS RESEARCH AREA. EZH2 IS A SUBUNIT OF POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), WHICH PRIMARILY SERVES AS A HISTONE METHYLTRANSFERASE TO CATALYZE METHYLATION OF HISTONE 3 ON LYSINE 27 (H3K27), ULTIMATELY RESULTING IN TRANSCRIPTIONAL REPRESSION. ANIMALS WITH NEUROPATHIC PAIN EXHIBIT INCREASED EZH2 ACTIVITY AND NEUROINFLAMMATION OF THE INJURED NERVE, SPINAL CORD, AND ANTERIOR CINGULATE CORTEX. INHIBITION OF EZH2 WITH DZNEP OR GSK-126 AMELIORATES NEUROINFLAMMATION AND NEUROPATHIC PAIN. EZH2 PROTEIN EXPRESSION INCREASES UPON ACTIVATION OF TOLL-LIKE RECEPTOR 4 AND CALCITONIN GENE-RELATED PEPTIDE RECEPTORS, DOWNREGULATION OF MIR-124-3P AND MIR-378 MICRORNAS, OR UPREGULATION OF LNCENC1 AND MALAT1 LONG NONCODING RNAS. GENES SUPPRESSED BY EZH2 INCLUDE SUPPRESSOR OF CYTOKINE SIGNALING 3 (SOCS3), NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE-2 FACTOR (NRF2), MIR-29B-3P, MIR-146A-5P, AND BRAIN-SPECIFIC ANGIOGENESIS INHIBITOR 1 (BAI1). PRO-INFLAMMATORY MEDIATORS FACILITATE NEURONAL ACTIVATION ALONG PAIN-SIGNALING PATHWAYS BY SENSITIZING NOCICEPTORS IN THE PERIPHERY, AS WELL AS ENHANCING EXCITATORY SYNAPTIC ACTIVITIES AND SUPPRESSING INHIBITORY SYNAPTIC ACTIVITIES IN THE CNS. THESE STUDIES COLLECTIVELY REVEAL THAT EZH2 IS IMPLICATED IN SIGNALING PATHWAYS KNOWN TO BE KEY PLAYERS IN THE PROCESS OF NEUROINFLAMMATION AND GENESIS OF NEUROPATHIC PAIN. THEREFORE, TARGETING THE EZH2 SIGNALING PATHWAY MAY OPEN A NEW AVENUE TO MITIGATE NEUROINFLAMMATION AND NEUROPATHIC PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10  710  30 C-TERMINAL DOMAIN SMALL PHOSPHATASE 1 (CTDSP1) REGULATES GROWTH FACTOR EXPRESSION AND AXONAL REGENERATION IN PERIPHERAL NERVE TISSUE. PERIPHERAL NERVE INJURY (PNI) REPRESENTS A MAJOR CLINICAL AND ECONOMIC BURDEN. DESPITE THE ABILITY OF PERIPHERAL NEURONS TO REGENERATE THEIR AXONS AFTER AN INJURY, PATIENTS ARE OFTEN LEFT WITH MOTOR AND/OR SENSORY DISABILITY AND MAY DEVELOP CHRONIC PAIN. SUCCESSFUL REGENERATION AND TARGET ORGAN REINNERVATION REQUIRE COMPREHENSIVE TRANSCRIPTIONAL CHANGES IN BOTH INJURED NEURONS AND SUPPORT CELLS LOCATED AT THE SITE OF INJURY. THE EXPRESSION OF MOST OF THE GENES REQUIRED FOR AXON GROWTH AND GUIDANCE AND FOR SYNAPSIS FORMATION IS REPRESSED BY A SINGLE MASTER TRANSCRIPTIONAL REGULATOR, THE REPRESSOR ELEMENT 1 SILENCING TRANSCRIPTION FACTOR (REST). SUSTAINED INCREASE OF REST LEVELS AFTER INJURY INHIBITS AXON REGENERATION AND LEADS TO CHRONIC PAIN. AS TARGETING OF TRANSCRIPTION FACTORS IS CHALLENGING, WE TESTED WHETHER MODULATION OF REST ACTIVITY COULD BE ACHIEVED THROUGH KNOCKDOWN OF CARBOXY-TERMINAL DOMAIN SMALL PHOSPHATASE 1 (CTDSP1), THE ENZYME THAT STABILIZES REST BY PREVENTING ITS TARGETING TO THE PROTEASOME. TO TEST WHETHER KNOCKDOWN OF CTDSP1 PROMOTES NEUROTROPHIC FACTOR EXPRESSION IN BOTH SUPPORT CELLS LOCATED AT THE SITE OF INJURY AND IN PERIPHERAL NEURONS, WE TRANSFECTED MESENCHYMAL PROGENITOR CELLS (MPCS), A TYPE OF SUPPORT CELLS THAT ARE PRESENT AT HIGH CONCENTRATIONS AT THE SITE OF INJURY, AND DORSAL ROOT GANGLION (DRG) NEURONS WITH REST OR CTDSP1 SPECIFIC SIRNA. WE QUANTIFIED NEUROTROPHIC FACTOR EXPRESSION BY RT-QPCR AND WESTERN BLOT, AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) RELEASE IN THE CELL CULTURE MEDIUM BY ELISA, AND WE MEASURED NEURITE OUTGROWTH OF DRG NEURONS IN CULTURE. OUR RESULTS SHOW THAT CTDSP1 KNOCKDOWN PROMOTES NEUROTROPHIC FACTOR EXPRESSION IN BOTH DRG NEURONS AND THE SUPPORT CELLS MPCS, AND PROMOTES DRG NEURON REGENERATION. THERAPEUTICS TARGETING CTDSP1 ACTIVITY MAY, THEREFORE, REPRESENT A NOVEL EPIGENETIC STRATEGY TO PROMOTE PERIPHERAL NERVE REGENERATION AFTER PNI BY PROMOTING THE REGENERATIVE PROGRAM REPRESSED BY INJURY-INDUCED INCREASED LEVELS OF REST IN BOTH NEURONS AND SUPPORT CELLS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11  804  34 CENTRAL ENDOTHELIN-1 CONFERS ANALGESIA BY TRIGGERING SPINAL NEURONAL HISTONE DEACETYLASE 5 (HDAC5) NUCLEAR EXCLUSION IN PERIPHERAL NEUROPATHIC PAIN IN MICE. THE RATIONALE OF SPINAL ADMINISTRATION OF ENDOTHELIN-1(ET-1) MEDIATED ANTI-NOCICEPTIVE EFFECT HAS NOT BEEN ELUCIDATED. ET-1 IS REPORTED TO PROMOTE NUCLEAR EFFLUXION OF HISTONE DEACETYLASE 5 (HDAC5) IN MYOCYTES, AND SPINAL HDAC5 IS IMPLICATED IN MODULATION OF PAIN PROCESSING. IN THIS STUDY, WE AIMED TO INVESTIGATE WHETHER CENTRAL ET-1 PLAYS AN ANTI-NOCICEPTIVE ROLE BY FACILITATING SPINAL HDAC5 NUCLEAR SHUTTLING UNDER NEUROPATHIC PAIN. HERE, WE DEMONSTRATE THAT UPREGULATING SPINAL ET-1 ATTENUATED THE NOCICEPTION INDUCED BY PARTIAL SCIATIC NERVE LIGATION SURGERY AND THIS ANALGESIC EFFECT MEDIATED BY ET-1 WAS ATTENUATED BY INTRATHECAL INJECTION OF ENDOTHELIN A RECEPTOR SELECTIVE INHIBITOR (BQ123) OR BY BLOCKING THE EXPORTATION OF NUCLEAR HDAC5 BY ADENO-ASSOCIATED VIRUSES TARGETING NEURONAL HDAC5 (AVV-HDAC5 S259/498A MUTANT). NOTABLY, ET-1 ADMINISTRATION INCREASED SPINAL GLUTAMATE ACID DECARBOXYLASES (GAD65/67) EXPRESSION VIA INITIATING HDAC5 NUCLEAR EXPORTATION AND INCREASED THE ACETYLATION OF HISTONE 3 AT LYSINE 9 (ACETYL-H3K9) IN THE PROMOTOR REGIONS OF SPINAL GAD1 AND GAD2 GENES. THIS WAS REVERSED BY BLOCKING ENDOTHELIN A RECEPTOR FUNCTION OR BY INHIBITING THE SPINAL NEURONAL NUCLEAR EXPORTATION OF HDAC5. THEREFORE, INDUCING SPINAL GABAERGIC NEURONAL HDAC5 NUCLEAR EXPORTATION MAY BE A NOVEL THERAPEUTIC APPROACH FOR MANAGING NEUROPATHIC PAIN. PERSPECTIVE: NEUROPATHIC PAIN IS INTRACTABLE IN A CLINICAL SETTING, AND EPIGENETIC REGULATION IS CONSIDERED TO CONTRIBUTE TO THIS PROCESSING. CHARACTERIZING THE ANTI-NOCICEPTIVE EFFECT OF ET-1 AND INVESTIGATING THE ASSOCIATED EPIGENETIC MECHANISMS IN ANIMAL MODELS MAY LEAD TO THE DEVELOPMENT OF NEW THERAPEUTIC STRATEGIES AND TARGETS FOR TREATING NEUROPATHIC PAIN.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12 4742  33 NOVEL HISTONE MODIFICATIONS IN MICROGLIA DERIVED FROM A MOUSE MODEL OF CHRONIC PAIN. AS THE RESIDENT IMMUNE CELLS IN THE CENTRAL NERVOUS SYSTEM, MICROGLIA PLAY AN IMPORTANT ROLE IN THE MAINTENANCE OF ITS HOMEOSTASIS. DYSREGULATION OF MICROGLIA HAS BEEN ASSOCIATED WITH THE DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, THE RELEVANT MOLECULAR PATHWAYS REMAIN POORLY DEFINED. IN THIS STUDY, WE USED A MASS SPECTROMETRY-BASED PROTEOMIC APPROACH TO SCREEN POTENTIAL CHANGES OF HISTONE PROTEIN MODIFICATIONS IN MICROGLIA ISOLATED FROM THE BRAIN OF CONTROL AND CISPLATIN-INDUCED NEUROPATHIC PAIN ADULT C57BL/6J MALE MICE. WE IDENTIFIED SEVERAL NOVEL MICROGLIAL HISTONE MODIFICATIONS ASSOCIATED WITH PAIN, INCLUDING STATISTICALLY SIGNIFICANTLY DECREASED HISTONE H3.1 LYSINE 27 MONO-METHYLATION (H3.1K27ME1, 54.8% OF CONTROL) AND H3 LYSINE 56 TRI-METHYLATION (7.5% OF CONTROL), AS WELL AS A TREND SUGGESTING INCREASED H3 TYROSINE 41 NITRATION. WE FURTHER INVESTIGATED THE FUNCTIONAL ROLE OF H3.1K27ME1 AND FOUND THAT TREATMENT OF CULTURED MICROGLIAL CELLS FOR 4 CONSECUTIVE DAYS WITH 1-10 MUM OF NCDM-64, A POTENT AND SELECTIVE INHIBITOR OF LYSINE DEMETHYLASE 7A, AN ENZYME RESPONSIBLE FOR THE DEMETHYLATION OF H3K27ME1, DOSE-DEPENDENTLY ELEVATED ITS LEVELS WITH A GREATER THAN A TWO-FOLD INCREASE OBSERVED AT 10 MUM COMPARED TO VEHICLE-TREATED CONTROL CELLS. MOREOVER, PRETREATMENT OF MICE WITH NCDM-64 (10 OR 25 MG/KG/DAY, I.P.) PRIOR TO CISPLATIN TREATMENT PREVENTED THE DEVELOPMENT OF NEUROPATHIC PAIN IN MICE. THE IDENTIFICATION OF SPECIFIC CHROMATIN MARKS IN MICROGLIA ASSOCIATED WITH CHRONIC PAIN MAY YIELD CRITICAL INSIGHT INTO THE CONTRIBUTION OF MICROGLIA TO THE DEVELOPMENT AND MAINTENANCE OF PAIN, AND OPENS NEW AVENUES FOR THE DEVELOPMENT OF NOVEL NONOPIOID THERAPEUTICS FOR THE EFFECTIVE MANAGEMENT OF CHRONIC PAIN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13 5401  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  532  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15 5781  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17 2203  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18  743  28 CANNABINOID TYPE 2 RECEPTOR SYSTEM MODULATES PACLITAXEL-INDUCED MICROGLIAL DYSREGULATION AND CENTRAL SENSITIZATION IN RATS. PACLITAXEL INDUCES MICROGLIAL ACTIVATION AND PRODUCTION OF PROINFLAMMATORY MEDIATORS IN THE DORSAL HORN, WHICH CONTRIBUTE TO THE DEVELOPMENT AND MAINTENANCE OF CENTRAL SENSITIZATION AND PAIN BEHAVIOR. MDA7, 1-([3-BENZYL-3-METHYL-2,3-DIHYDRO-1-BENZOFURAN-6-YL]CARBONYL) PIPERIDINE, IS A NOVEL HIGHLY SELECTIVE CANNABINOID TYPE 2 (CB2) AGONIST. WE TESTED THE HYPOTHESIS THAT ACTIVATION OF CB2 RECEPTOR BY MDA7 MODULATES MICROGLIAL DYSREGULATION, SUPPRESSES THE OVEREXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IN MICROGLIA IN THE DORSAL HORN, AND ATTENUATES THE CENTRAL SENSITIZATION AND PAIN BEHAVIOR INDUCED BY PACLITAXEL. FOR 4 CONSECUTICE DAYS, GROUPS OF RATS RANDOMLY RECEIVED SALINE OR 1.0 MG/KG OF PACLITAXEL DAILY INTRAPERITONEALLY FOR A TOTAL CUMULATIVE DOSE OF 4 MG/KG. MDA7 15 MG/KG INTRAPERITONEALLY OR VEHICLE WERE ADMINISTERED 15 MIN BEFORE ADMINISTERING PACLITAXEL FOR 4 DAYS AND THEN CONTINUED FOR ANOTHER 10 DAYS. BEHAVIORAL AND MOLECULAR STUDIES WERE PERFORMED. PACLITAXEL INDUCED THE EXPRESSION OF CB2 RECEPTORS AND PRODUCTION OF INTERLEUKIN (IL)-6 IN MICROGLIA IN THE DORSAL HORN. MDA7 ATTENUATED THE EXPRESSION OF IL-6 AND PROMOTED THE EXPRESSION OF IL-10. PACLITAXEL INDUCED EPIGENETIC UPREGULATION OF IRF8 AND P2X PURINOCEPTOR 4 (P2X4) IN MICROGLIA AND SUBSEQUENTLY INCREASED THE EXPRESSION OF ALPHA ISOFORM OF CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II (CAMKIIALPHA), TRANSCRIPTIONAL FACTORS P-CREB AND DELTAFOSB, LEADING TO THE OVERPRODUCTION OF BDNF IN MICROGLIA. PACLITAXEL ALSO UPREGULATED THE EXPRESSION OF GLUTAMATE RECEPTOR SUBUNITS GLUR1 AND NR2B, DECREASED THE EXPRESSION OF K(+)-CL(-) COTRANSPORTER, AND INDUCED MECHANICAL ALLODYNIA IN RATS. ALL OF THE AFOREMENTIONED MOLECULAR CHANGES WERE ATTENUATED BY MDA7. OUR DATA SHOW THAT MDA7 ATTENUATED PACLITAXEL-INDUCED MOLECULAR AND BEHAVIORAL CHANGES IN RATS. PERSPECTIVE: THIS STUDY PROVIDES EVIDENCE THAT PACLITAXEL INDUCED MICROGLIA DYSREGULATION AND EPIGENETICALLY UPREGULATED THE MICROGLIAL EXPRESSION OF BDNF, WHICH LED TO SENSITIZATION OF DORSAL HORN NEURONS AND MECHANICAL ALLODYNIA IN RATS. THE CB2 AGONIST MDA7 ALLEVIATED THESE PATHOLOGICAL PROCESSES. MDA7 REPRESENTS AN INNOVATIVE THERAPEUTIC APPROACH FOR TREATMENT OF CHEMOTHERAPY-INDUCED NEUROPATHY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                             
19 2068  29 EPIGENETIC CONTROL OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 BY HDAC-MEDIATED RECRUITMENT OF P300. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS ARE THE MOST WIDELY USED MEDICINE TO TREAT PAIN AND INFLAMMATION, AND TO INHIBIT PLATELET FUNCTION. UNDERSTANDING THE EXPRESSION REGULATION OF ENZYMES OF THE PROSTANOID PATHWAY IS OF GREAT MEDICAL RELEVANCE. HISTONE ACETYLATION CRUCIALLY CONTROLS GENE EXPRESSION. WE SET OUT TO IDENTIFY THE IMPACT OF HISTONE DEACETYLASES (HDACS) ON THE GENERATION OF PROSTANOIDS AND EXAMINE THE CONSEQUENCES ON VASCULAR FUNCTION. HDAC INHIBITION (HDACI) WITH THE PAN-HDAC INHIBITOR, VORINOSTAT, ATTENUATED PROSTAGLANDIN (PG)E(2) GENERATION IN THE MURINE VASCULATURE AND IN HUMAN VASCULAR SMOOTH MUSCLE CELLS. IN LINE WITH THIS, THE EXPRESSION OF THE KEY ENZYME FOR PGE(2) SYNTHESIS, MICROSOMAL PGE SYNTHASE-1 (PTGES1), WAS REDUCED BY HDACI. ACCORDINGLY, THE RELAXATION TO ARACHIDONIC ACID WAS DECREASED AFTER EX VIVO INCUBATION OF MURINE VESSELS WITH HDACI. TO IDENTIFY THE UNDERLYING MECHANISM, CHROMATIN IMMUNOPRECIPITATION (CHIP) AND CHIP-SEQUENCING ANALYSIS WERE PERFORMED. THESE RESULTS SUGGEST THAT HDACS ARE INVOLVED IN THE RECRUITMENT OF THE TRANSCRIPTIONAL ACTIVATOR P300 TO THE PTGES1 GENE AND THAT HDACI PREVENTED THIS EFFECT. IN LINE WITH THE ACETYLTRANSFERASE ACTIVITY OF P300, H3K27 ACETYLATION WAS REDUCED AFTER HDACI AND RESULTED IN THE FORMATION OF HETEROCHROMATIN IN THE PTGES1 GENE. IN CONCLUSION, HDAC ACTIVITY MAINTAINS PTGES1 EXPRESSION BY RECRUITING P300 TO ITS GENE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20 5954  38 TBI-INDUCED NOCICEPTIVE SENSITIZATION IS REGULATED BY HISTONE ACETYLATION. CHRONIC PAIN AFTER TRAUMATIC BRAIN INJURY (TBI) IS VERY COMMON, BUT THE MECHANISMS LINKING TBI TO PAIN AND THE PAIN-RELATED INTERACTIONS OF TBI WITH PERIPHERAL INJURIES ARE POORLY UNDERSTOOD. IN THESE STUDIES WE PURSUED THE HYPOTHESIS THAT TBI PAIN SENSITIZATION IS ASSOCIATED WITH HISTONE ACETYLATION IN THE RAT LATERAL FLUID PERCUSSION MODEL. SOME ANIMALS RECEIVED HINDPAW INCISIONS IN ADDITION TO TBI TO MIMIC POLYTRAUMA. NEUROPATHOLOGICAL ANALYSIS OF BRAIN TISSUE FROM SHAM AND TBI ANIMALS REVEALED EVIDENCE OF BLEEDING, BREAKDOWN OF THE BLOOD BRAIN BARRIER, IN THE CORTEX, HIPPOCAMPUS, THALAMUS AND OTHER STRUCTURES RELATED TO PAIN SIGNAL PROCESSING. MECHANICAL ALLODYNIA WAS MEASURED IN THESE ANIMALS FOR UP TO EIGHT WEEKS POST-INJURY. INHIBITORS OF HISTONE ACETYLTRANSFERASE (HAT) AND HISTONE DEACETYLASE (HDAC) WERE USED TO PROBE THE ROLE OF HISTONE ACETYLATION IN SUCH PAIN PROCESSING. WE FOLLOWED SERUM MARKERS INCLUDING GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP), NEURON-SPECIFIC ENOLASE 2 (NSE) MYELIN BASIC PROTEIN (MBP) AND S100BETA TO GAUGE TBI INJURY SEVERITY. OUR RESULTS SHOWED THAT TBI CAUSED MECHANICAL ALLODYNIA IN THE HINDPAWS OF THE RATS LASTING SEVERAL WEEKS. HINDPAWS CONTRALATERAL TO TBI SHOWED MORE RAPID AND PROFOUND SENSITIZATION THAN IPSILATERAL HINDPAWS. THE INHIBITION OF HAT USING CURCUMIN 50 MG/KG S.C REDUCED MECHANICAL SENSITIZATION WHILE THE HDAC INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID 50 MG/KG I.P. PROLONGED SENSITIZATION IN THE TBI RATS. IMMUNOHISTOCHEMICAL ANALYSES OF SPINAL CORD TISSUE LOCALIZED CHANGES IN THE LEVEL OF ACETYLATION OF THE H3K9 HISTONE MARK TO DORSAL HORN NEURONS. TAKEN TOGETHER, THESE FINDINGS DEMONSTRATE THAT TBI INDUCES SUSTAINED NOCICEPTIVE SENSITIZATION, AND CHANGES IN SPINAL NEURONAL HISTONE PROTEINS MAY PLAY AN IMPORTANT ROLE.	2017