1 3334 129 HISTONE DEACETYLASE INHIBITORS COUNTERACT CGRP SIGNALING AND PRONOCICEPTIVE SENSITIZATION IN A RAT MODEL OF MEDICATION OVERUSE HEADACHE. CHRONIC TRIPTAN EXPOSURE IN RODENTS RECAPITULATES MEDICATION OVERUSE HEADACHE (MOH), CAUSING CEPHALIC PAIN SENSITIZATION AND TRIGEMINAL GANGLION OVEREXPRESSION OF PRONOCICEPTIVE PROTEINS INCLUDING CGRP. BECAUSE OF THESE TRANSCRIPTIONAL DERANGEMENTS, AS WELL AS THE EMERGING ROLE OF EPIGENETICS IN CHRONIC PAIN, IN THE PRESENT STUDY, WE EVALUATED THE EFFECTS OF THE HISTONE DEACETYLASE INHIBITORS (HDACIS) PANOBINOSTAT AND GIVINOSTAT, IN RATS CHRONICALLY EXPOSED TO ELETRIPTAN FOR 1 MONTH. BOTH PANOBINOSTAT AND GIVINOSTAT COUNTERACTED OVEREXPRESSION OF GENES CODING FOR CGRP AND ITS RECEPTOR SUBUNIT RAMP1, HAVING NO EFFECTS ON CLR AND RCP RECEPTOR SUBUNITS IN THE TRIGEMINAL GANGLION (TG) OF ELETRIPTAN-EXPOSED RATS. WITHIN THE TRIGEMINAL NUCLEUS CAUDALIS (TNC), TRANSCRIPTS FOR THESE GENES WERE NEITHER UPREGULATED BY ELETRIPTAN NOR ALTERED BY CONCOMITANT TREATMENT WITH PANOBINOSTAT OR GIVINOSTAT. HDACIS COUNTERACTED HYPERSENSITIVITY TO CAPSAICIN-INDUCED VASODILATATION IN THE TRIGEMINAL TERRITORY, AS WELL AS PHOTOPHOBIC BEHAVIOR AND CEPHALIC ALLODYNIAIN ELETRIPTAN-EXPOSED RATS. ELETRIPTAN DID NOT AFFECT CGRP, CLR, AND RAMP1 EXPRESSION IN CULTURED TRIGEMINAL GANGLIA, WHEREAS BOTH INHIBITORS REDUCED TRANSCRIPTS FOR CLR AND RAMP-1. THE DRUGS, HOWEVER, INCREASED LUCIFERASE EXPRESSION DRIVEN BY CGRP PROMOTER IN CULTURED CELLS. OUR FINDINGS PROVIDE EVIDENCE FOR A KEY ROLE OF HDACS AND EPIGENETICS IN MOH PATHOGENESIS, HIGHLIGHTING THE THERAPEUTIC POTENTIAL OF HDAC INHIBITION IN THE PREVENTION OF MIGRAINE CHRONIFICATION. PERSPECTIVE: THE PRESENT STUDY HIGHLIGHTS A KEY EPIGENETIC ROLE OF HDAC IN THE RODENT MODEL OF MEDICATION OVERUSE HEADACHE, FURTHERING OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS RESPONSIBLE FOR PRONOCICEPTIVE SENSITIZATION DURING HEADACHE CHRONIFICATION. 2022 2 5597 30 ROLES OF MIR-432 AND CIRC_0000418 IN MEDIATING THE ANTI-DEPRESSANT ACTION OF ADAR1. ADENOSINE DEAMINASE ACTING ON RNA1 (ADAR1) IS A NEWLY DISCOVERED EPIGENETIC MOLECULE MARKER THAT IS SENSITIVE TO ENVIRONMENTAL STRESSORS. A RECENT STUDY HAS DEMONSTRATED THAT ADAR1 AFFECTS BDNF EXPRESSION VIA MIR-432 AND IS INVOLVED IN ANTIDEPRESSANT ACTION. HOWEVER, THE DETAILED MOLECULAR MECHANISM IS STILL UNCLEAR. WE HAVE UNCOVERED A NEW MOLECULAR MECHANISM SHOWING THE INVOLVEMENT OF MIR-432 AND CIRC_0000418 IN MEDIATING THE ANTIDEPRESSANT ACTION OF ADAR1. WE DEMONSTRATE THAT THE ADAR1 INDUCER (IFN-GAMMA) ALLEVIATES THE DEPRESSIVE-LIKE BEHAVIORS OF BALB/C MICE TREATED WITH CHRONIC UNPREDICTABLE STRESS (CUS) EXPOSURE. MOREOVER, BOTH IN VIVO AND IN VITRO STUDIES SHOW THAT ADAR1 DIFFERENTLY IMPACTS MIR-432 AND CIRC_0000418 EXPRESSIONS. FURTHERMORE, THE IN VITRO RESULTS DEMONSTRATE THAT CIRC_0000418 OPPOSITELY AFFECTS BDNF EXPRESSION. TOGETHER, OUR RESULTS INDICATE THAT ADAR1 AFFECTS CUS-INDUCED DEPRESSIVE-LIKE BEHAVIOR AND BDNF EXPRESSION BY ACTING ON MIR-432 AND CIRC_0000418. ELUCIDATION OF THIS NEW MOLECULAR MECHANISM WILL NOT ONLY PROVIDE INSIGHTS INTO FURTHER UNDERSTANDING THE IMPORTANT ROLE OF ADAR1 IN STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIOR BUT ALSO SUGGEST A POTENTIAL THERAPEUTIC STRATEGY FOR DEVELOPING NOVEL ANTI-DEPRESSIVE DRUGS. 2021 3 6215 23 THE INVOLVEMENT OF ADAR1 IN ANTIDEPRESSANT ACTION BY REGULATING BDNF VIA MIR-432. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS A BIOMARKER OF DEPRESSION. RECENT STUDIES HAVE FOUND ADENOSINE DEAMINASE ACTING ON RNA1 (ADAR1) IS A NOVEL TARGET BEING SENSITIVE TO STRESS AT EPIGENETIC LEVEL. THE EPIGENETIC REGULATION MECHANISM OF STRESS-RELATED DEPRESSION IS STILL UNCLEAR SO FAR. TO EXPLORE THE POTENTIAL REGULATING MECHANISM OF ADAR1 ON BDNF, OVER AND LOW EXPRESSION OF ADAR1 IN PC12 AND SH-SY5Y CELL LINES ARE PREPARED. IN THE MEANWHILE, CHRONIC UNPREDICTABLE STRESS (CUS) MICE ARE TREATED WITH ADAR1 INDUCER (INTERFERON-GAMMA, IFN-GAMMA). ADAR1 REGULATES BDNF EXPRESSION, WHICH IS PROVEN BY THAT OVER AND LOW EXPRESSIONS OF ADAR1 INCREASE AND DECREASE BDNF MRNA AND PROTEIN RESPECTIVELY IN VITRO. ADDITIONALLY, ADAR1 INDUCER ALLEVIATES THE DEPRESSIVE-LIKE BEHAVIOR OF CUS MICE BY RECOVERING THE DECREASED BDNF PROTEIN IN BRAIN AND SERUM. MOREOVER, OVER AND LOW EXPRESSIONS OF ADAR1 REDUCE AND ENHANCE MICRORNA-432 (MIR-432) EXPRESSION RESPECTIVELY IN VITRO. FURTHERLY, OVER AND LOW MIR-432 EXPRESSIONS LEAD TO DECREASED AND INCREASED BDNF AND ADAR1 MRNA, PROTEIN AND IMMUNOREACTIVITY RESPECTIVELY IN VITRO. THE ABOVE RESULTS DEMONSTRATE THAT ADAR1 IS INVOLVED IN ANTIDEPRESSANT ACTION BY REGULATING BDNF VIA MIR-432. THOSE NOVEL FINDINGS CAN PROVIDE A NEW IDEA FOR THE STUDY OF EPIGENETIC REGULATION MECHANISM, EARLY DIAGNOSIS, AND EFFECTIVE TREATMENT OF STRESS-RELATED DEPRESSION. 2021 4 3236 27 HEN EGG LYSOZYME ALLEVIATES STATIC MECHANICAL PAIN VIA NRF1-PARKIN-TACAN SIGNALING AXIS IN SENSORY NEURONS. MECHANICAL ALLODYNIA IMPINGES ON THE LIFE QUALITY OF PATIENTS. HEN EGG LYSOZYME (HEL) IS A SUBSTANCE EXTRACTED FROM EGGS THAT IS COMMONLY USED TO INHIBIT BACTERIAL ACTIVITY. THE ROLE OF HEL IN REGULATING AND TREATING PAIN IS UNCLEAR. HERE, WE FIND THAT HEL SELECTIVELY ATTENUATES STATIC MECHANICAL ALLODYNIA OF MICE INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA), SPINAL NERVE LIGATION (SNL) AND CHEMOTHERAPEUTIC AGENT. RNA-SEQ SCREENING REVEALS THAT CFA SIGNIFICANTLY REDUCES THE EXPRESSION OF PARKIN IN DORSAL ROOT GANGLION (DRG) NEURONS OF MICE, WHILE PRE-ADMINISTRATION OF HEL INCREASES THE EXPRESSION OF PARKIN AND REMITS THE STATIC MECHANICAL ALLODYNIA INDUCED BY PARKIN-SIRNA. MOREOVER, HEL INCREASES THE INTERACTION BETWEEN NUCLEAR RESPIRATORY FACTOR 1 (NRF1) AND HISTONE ACETYLTRANSFERASE P300 AND THEN ENHANCES THE NRF1 MEDIATED HISTONE ACETYLATION IN PRKN PROMOTER REGION IN DRGS OF MICE. FURTHER, PARKIN INTERACTS WITH MECHANOTRANSDUCING ION CHANNEL TACAN (TMEM120A) AND KNOCKDOWN OF PARKIN SIGNIFICANTLY INCREASES THE MEMBRANE TRAFFICKING OF TACAN IN SENSORY NEURONS OF MICE. WHILE PRE-ADMINISTRATION OF HEL INHIBITS THE INCREASED MEMBRANE TRAFFICKING OF TACAN IN SENSORY NEURONS OF MICE INDUCED BY PARKIN-SIRNA. IN ADDITION, PRE-GIVEN OF HEL ALSO SIGNIFICANTLY ATTENUATES THE STATIC MECHANICAL ALLODYNIA INDUCED BY OVEREXPRESSION OF TACAN IN MICE, AND THE EFFECT OF HEL CAN BE BLOCKED BY PARKIN-SIRNA. THIS INDICATES THAT HEL INCREASES THE EXPRESSION OF PARKIN THROUGH EPIGENETIC MECHANISMS AND THEN DECREASES TACAN MEMBRANE TRAFFICKING IN SENSORY NEURONS TO RELIEVE STATIC MECHANICAL HYPERSENSITIVITY. THEREFORE, WE REVEAL A NOVEL FUNCTION OF HEL, WHICH IS A POTENTIAL SUBSTANCE FOR THE TREATMENT OF STATIC MECHANICAL PAIN. 2022 5 3626 25 IN-SILICO DISCOVERY OF DUAL ACTIVE MOLECULE TO RESTORE SYNAPTIC WIRING AGAINST AUTISM SPECTRUM DISORDER VIA HDAC2 AND H3R INHIBITION. METAL-DEPENDENT HISTONE DEACETYLASES (HDACS) ARE ESSENTIAL EPIGENETIC REGULATORS; THEIR MOLECULAR AND PHARMACOLOGICAL ROLES IN MEDICALLY CRITICAL DISEASES SUCH AS NEUROPSYCHIATRIC DISORDERS, NEURODEGENERATION, AND CANCER ARE BEING STUDIED GLOBALLY. HDAC2'S DIFFERENTIAL EXPRESSION IN THE CENTRAL NERVOUS SYSTEM MAKES IT AN APPEALING THERAPEUTIC TARGET FOR CHRONIC NEUROLOGICAL DISEASES LIKE AUTISM SPECTRUM DISORDER. IN THIS STUDY, WE IDENTIFIED H3R INHIBITOR MOLECULES THAT ARE COMPUTATIONALLY EFFECTIVE AT BINDING TO THE HDAC2 METAL-COORDINATED BINDING SITE. THE STUDY HIGHLIGHTS THE IMPORTANCE OF PITOLISANT IN SCREENING THE POTENTIAL H3R INHIBITORS BY USING A HYBRID WORKFLOW OF LIGAND AND RECEPTOR-BASED DRUG DISCOVERY. THE SCREENED LEAD COMPOUNDS WITH PUBCHEM SIDS 103179850, 103185945, AND 103362074 SHOW VIABLE BINDING WITH HDAC2 IN SILICO. THE IMPORTANCE OF LIGAND CONTACTS WITH THE ZN2+ ION IN THE HDAC2 CATALYTIC SITE IS ALSO DISCUSSED AND INVESTIGATED FOR A SIGNIFICANT ROLE IN ENZYME INHIBITION. THE PROPOSED H3R INHIBITORS 103179850, 103185945, AND 103362074 ARE ESTIMATED AS DUAL-ACTIVE MOLECULES TO BLOCK THE HDAC2-MEDIATED DEACETYLATION OF THE EAAT2 GENE (SLC1A2) AND H3R-MEDIATED SYNAPTIC TRANSMISSION IRREGULARITY AND ARE, THEREFORE, OPEN FOR EXPERIMENTAL VALIDATION. 2022 6 6509 24 TRANSCRIPTION FACTOR RFX1 IS UBIQUITINATED BY E3 LIGASE STUB1 IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CAUSED BY COMPLEX INTERACTIONS BETWEEN GENES AND THE ENVIRONMENT. THE EXPRESSION LEVEL OF TRANSCRIPTION FACTOR REGULATORY FACTOR X 1 (RFX1) IS REDUCED IN T CELLS FROM SLE PATIENTS. RFX1 CAN REGULATE EPIGENETIC MODIFICATIONS OF CD70 AND CD11A AND PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT OF SLE. HOWEVER, THE MECHANISMS THAT MEDIATE REDUCTION OF RFX1 IN SLE ARE UNCLEAR. HERE, WE DEMONSTRATE THAT RFX1 PROTEIN EXPRESSION CAN BE TIGHTLY REGULATED BY POLYUBIQUITINATION-MEDIATED PROTEOSOMAL DEGRADATION VIA STIP1 HOMOLOGY AND U-BOX CONTAINING PROTEIN 1 (STUB1). THE E3 LIGASE STUB1 IS UPREGULATED IN CD4(+)T CELLS OF SLE PATIENTS COMPARED TO HEALTHY SUBJECTS. OVEREXPRESSION OF STUB1 IN CD4(+)T CELLS LEADS TO UPREGULATION OF LEVELS OF CD70 AND CD11A IN T CELLS. THE MODULATION OF STUB1 ACTIVITY MAY PROVIDE A NOVEL THERAPEUTIC APPROACH FOR SLE. 2016 7 2796 23 FBW7 MEDIATES SENESCENCE AND PULMONARY FIBROSIS THROUGH TELOMERE UNCAPPING. TISSUE STEM CELLS UNDERGO PREMATURE SENESCENCE UNDER STRESS, PROMOTING AGE-RELATED DISEASES; HOWEVER, THE ASSOCIATED MECHANISMS REMAIN UNCLEAR. HERE, WE REPORT THAT IN RESPONSE TO RADIATION, OXIDATIVE STRESS, OR BLEOMYCIN, THE E3 UBIQUITIN LIGASE FBW7 MEDIATES CELL SENESCENCE AND TISSUE FIBROSIS THROUGH TELOMERE UNCAPPING. FBW7 BINDING TO TELOMERE PROTECTION PROTEIN 1 (TPP1) FACILITATES TPP1 MULTISITE POLYUBIQUITINATION AND ACCELERATES DEGRADATION, TRIGGERING TELOMERE UNCAPPING AND DNA DAMAGE RESPONSE. OVEREXPRESSING TPP1 OR INHIBITING FBW7 BY GENETIC ABLATION, EPIGENETIC INTERFERENCE, OR PEPTIDOMIMETIC TELOMERE DYSFUNCTION INHIBITOR (TELODIN) REDUCES TELOMERE UNCAPPING AND SHORTENING, EXPANDING THE PULMONARY ALVEOLAR AEC2 STEM CELL POPULATION IN MICE. TELODIN, SYNTHESIZED FROM THE SEVENTH BETA STRAND BLADE OF FBW7 WD40 PROPELLER DOMAIN, INCREASES TPP1 STABILITY, LUNG RESPIRATORY FUNCTION, AND RESISTANCE TO SENESCENCE AND FIBROSIS IN ANIMALS CHRONICALLY EXPOSED TO ENVIRONMENTAL STRESS. OUR FINDINGS ELUCIDATE A PIVOTAL MECHANISM UNDERLYING STRESS-INDUCED PULMONARY EPITHELIAL STEM CELL SENESCENCE AND FIBROSIS, PROVIDING A FRAMEWORK FOR AGING-RELATED DISORDER INTERVENTIONS. 2020 8 5537 33 ROLE OF CALCITONIN GENE-RELATED PEPTIDE IN LIGHT-AVERSIVE BEHAVIOR: IMPLICATIONS FOR MIGRAINE. MIGRAINE IS A CHRONIC NEUROLOGICAL DISORDER CHARACTERIZED BY RECURRENT EPISODES OF SEVERE UNILATERAL THROBBING HEAD PAIN AND ASSOCIATED SYMPTOMS, SUCH AS PHOTOPHOBIA. OUR CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING MIGRAINE HAS BEEN HAMPERED BY LIMITATIONS IN ASCERTAINING MIGRAINE SYMPTOMS IN ANIMAL MODELS. CLINICAL STUDIES HAVE ESTABLISHED THE NEUROPEPTIDE CALCITONIN GENE-RELATED PEPTIDE (CGRP) AS A KEY PLAYER IN MIGRAINE. HERE, WE ESTABLISH A GENETIC MODEL OF PHOTOPHOBIA BY ENGINEERING INCREASED SENSITIVITY TO CGRP IN MICE. THESE TRANSGENIC MICE (NESTIN/HRAMP1) DISPLAY LIGHT-AVERSIVE BEHAVIOR THAT IS GREATLY ENHANCED BY INTRACEREBROVENTRICULAR INJECTION OF CGRP AND BLOCKED BY COADMINISTRATION OF THE CGRP RECEPTOR ANTAGONIST OLCEGEPANT. THIS BEHAVIOR APPEARS TO BE AN INDICATOR OF PHOTOPHOBIA AND CANNOT BE FULLY EXPLAINED BY GROSS ABNORMALITY OF OCULAR ANATOMY OR DIFFERENCES IN GENERAL ANXIETY OR MOTOR ACTIVITY. OUR FINDINGS DEMONSTRATE THAT A SINGLE GENE, RECEPTOR ACTIVITY-MODIFYING PROTEIN 1 (RAMP1), CAN BE A MODIFIER OF PHOTOPHOBIA AND, BY EXTENSION, SUGGEST THAT GENETIC OR EPIGENETIC MODULATION OF RAMP1 LEVELS MAY CONTRIBUTE TO MIGRAINE SUSCEPTIBILITY. MOREOVER, THEY VALIDATE CGRP HYPERSENSITIVE MICE AS A TOOL FOR EXPLORING THE NEUROBIOLOGY AND NOVEL THERAPIES FOR MIGRAINE AND OTHER DISORDERS INVOLVING PHOTOPHOBIA. 2009 9 6664 30 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 10 6056 32 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 11 2463 17 EPIGENETIC THERAPY REPROGRAMS HEREDITARY DISEASE. IN THIS ISSUE OF BLOOD, MAKARONA ET AL DEMONSTRATE THAT HISTONE DEACETYLASE (HDAC) INHIBITORS (HDACIS) IN GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD)-DEFICIENT CELLS REINSTATES ENZYME ACTIVITY BY BOOSTING GENE TRANSCRIPTION. THIS THERAPEUTIC APPROACH OPENS NEW AVENUES FOR PRECLINICAL AND CLINICAL STUDIES TO TREAT NOT ONLY CHRONIC NONSPHEROCYTIC HEMOLYTIC ANEMIA CAUSED BY SEVERE G6PD VARIANTS, BUT ALSO OTHER GENETIC DISEASES. 2014 12 4048 27 MAINTENANCE AND PHARMACOLOGIC TARGETING OF ROR1 PROTEIN LEVELS VIA UHRF1 IN T(1;19) PRE-B-ALL. EXPRESSION OF THE TRANSMEMBRANE PSEUDOKINASE ROR1 IS REQUIRED FOR SURVIVAL OF T(1;19)-PRE-B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T(1;19) PRE-B-ALL), CHRONIC LYMPHOCYTIC LEUKEMIA, AND MANY SOLID TUMORS. HOWEVER, TARGETING ROR1 WITH SMALL-MOLECULES HAS BEEN CHALLENGING DUE TO THE ABSENCE OF ROR1 KINASE ACTIVITY. TO IDENTIFY GENES THAT REGULATE ROR1 EXPRESSION AND MAY, THEREFORE, SERVE AS SURROGATE DRUG TARGETS, WE EMPLOYED AN SIRNA SCREENING APPROACH AND DETERMINED THAT THE EPIGENETIC REGULATOR AND E3 UBIQUITIN LIGASE, UHRF1, IS REQUIRED FOR T(1;19) PRE-B-ALL CELL VIABILITY IN A ROR1-DEPENDENT MANNER. UPON UHRF1 SILENCING, ROR1 PROTEIN IS REDUCED WITHOUT ALTERING ROR1 MRNA, AND ECTOPICALLY EXPRESSED UHRF1 IS SUFFICIENT TO INCREASE ROR1 LEVELS. ADDITIONALLY, PROTEASOME INHIBITION RESCUES LOSS OF ROR1 PROTEIN AFTER UHRF1 SILENCING, SUGGESTING A ROLE FOR THE PROTEASOME IN THE UHRF1-ROR1 AXIS. FINALLY, WE SHOW THAT ROR1-POSITIVE CELLS ARE TWICE AS SENSITIVE TO THE UHRF1-TARGETING DRUG, NAPHTHAZARIN, AND UNDERGO INCREASED APOPTOSIS COMPARED TO ROR1-NEGATIVE CELLS. NAPHTHAZARIN ELICITS REDUCED EXPRESSION OF UHRF1 AND ROR1, AND COMBINATION OF NAPHTHAZARIN WITH INHIBITORS OF PRE-B CELL RECEPTOR SIGNALING RESULTS IN FURTHER REDUCTION OF CELL SURVIVAL COMPARED WITH EITHER INHIBITOR ALONE. THEREFORE, OUR WORK REVEALS A MECHANISM BY WHICH UHRF1 STABILIZES ROR1, SUGGESTING A POTENTIAL TARGETING STRATEGY TO INHIBIT ROR1 IN T(1;19) PRE-B-ALL AND OTHER MALIGNANCIES. 2018 13 5838 31 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 14 1016 27 CIITA EXPRESSION IS REGULATED BY HISTONE DEACETYLASE ENZYMES AND HAS A ROLE IN ALPHA-SYNUCLEIN PRE-FORMED FIBRIL-INDUCED ANTIGEN PRESENTATION IN MURINE MICROGLIAL CELL LINE. AIM: PARKINSON'S DISEASE (PD) IS A CHRONIC NEURODEGENERATIVE DISORDER RELATED WITH SEVERAL GENETIC AND EPIGENETIC FACTORS. IN THE CONTEXT OF EPIGENETIC FACTORS, HISTONE ACETYLATION IS ONE OF THE MOST ASSOCIATED MECHANISMS WITH PARKINSON'S DISEASE PROGRESSION. THIS STUDY INVESTIGATES THE EFFECTS OF THE INCREASED HISTONE ACETYLATION ON ANTIGEN PRESENTATION IN MICROGLIAL CELLS WHICH WERE INDUCED BY PRE-FORMED FIBRILS OF ALPHA-SYNUCLEIN (PFF ALPHA-SYNUCLEIN). METHODS: PARKINSON'S DISEASE MODEL WAS CREATED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION TO THE BV-2 MICROGLIAL CELLS. BV-2 CELLS WERE CO-TREATED WITH CUDC-907 AND TMP-195 TO INCREASE HISTONE ACETYLATION IN THE PRESENCE OF ALPHA-SYNUCLEIN. ANTIGEN REPRESENTATION WAS EVALUATED BY DETERMINING EXPRESSION LEVELS OF MAJOR HISTOCOMPATIBILITY COMPLEX-II (MHC-II) AND CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX (CIITA). RESULTS: OUR RESULTS SHOWED THAT PFF ALPHA-SYNUCLEIN SIGNIFICANTLY INCREASED MHC-II EXPRESSION, AND THAT EFFECT WAS MOST SEVERE AT 6 H OF ADMINISTRATION OF ALPHA-SYNUCLEIN. INCREASING HISTONE ACETYLATION VIA CUDC-907 AND TMP-195 ENHANCED MHC-II LEVELS EXPRESSION, WHICH WAS MORE SEVERE IN CUDC-907. ADDITIONALLY, CIITA EXPRESSION LEVELS WERE SIGNIFICANTLY INCREASED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION AND INTENSIFIED WITH THE CO-TREATMENT OF CUDC-907 AND TMP-195. FURTHERMORE, PFF ALPHA-SYNUCLEIN CAUSED A TIME-DEPENDENT INCREASE IN THE IFN-GAMMA (IFN-?) AND INTERLEUKIN-16(IL-16) LEVELS, AND THAT INCREASE WAS POTENTIATED WITH CUDC-907 AND TMP-195. CONCLUSION: CHANGES IN MHC-II AND CIITA EXPRESSION INDICATE THAT HISTONE ACETYLATION INCREASES THE ANTIGEN PRESENTATION PROPERTIES OF MICROGLIAL CELLS AFTER PFF ALPHA-SYNUCLEIN OR HISTONE DEACETYLASE INHIBITOR (HDACI) ADMINISTRATION. OUR RESULTS SHOW THAT MICROGLIAL ANTIGEN PRESENTATION MIGHT HAVE AN ESSENTIAL ROLE IN THE PATHOLOGY OF PARKINSON'S DISEASE, AND ALPHA-SYNUCLEIN LIKELY TO PLAY A PRIMARY ROLE IN THIS MECHANISM. 2022 15 582 32 BEHAVIORAL AND PHYSIOLOGICAL EFFECTS OF ACUTE AND CHRONIC KAVA EXPOSURE IN ADULT ZEBRAFISH. KAVA KAVA (PIPER METHYSTICUM) IS A MEDICINAL PLANT CONTAINING KAVALACTONES THAT EXERT POTENT SEDATIVE, ANALGESIC AND ANTI-STRESS ACTION. HOWEVER, THEIR PHARMACOLOGICAL EFFECTS AND MOLECULAR TARGETS REMAIN POORLY UNDERSTOOD. THE ZEBRAFISH (DANIO RERIO) HAS RECENTLY EMERGED AS A POWERFUL NEW MODEL ORGANISM FOR NEUROSCIENCE RESEARCH AND DRUG DISCOVERY. HERE, WE EVALUATE THE EFFECTS OF ACUTE AND CHRONIC EXPOSURE TO KAVA AND KAVALACTONES ON ADULT ZEBRAFISH ANXIETY, AGGRESSION AND SOCIALITY, AS WELL AS ON THEIR NEUROCHEMICAL, NEUROENDOCRINE AND GENOMIC RESPONSES. SUPPORTING EVOLUTIONARILY CONSERVED MOLECULAR TARGETS, ACUTE KAVA AND KAVALACTONES EVOKED DOSE-DEPENDENT BEHAVIORAL INHIBITION, UPREGULATED BRAIN EXPRESSION OF EARLY PROTOONCOGENES C-FOS AND C-JUN, ELEVATED BRAIN MONOAMINES AND LOWERED WHOLE-BODY CORTISOL. CHRONIC 7-DAY KAVA EXPOSURE EVOKED SIMILAR BEHAVIORAL EFFECTS, DID NOT ALTER CORTISOL LEVELS, AND FAILED TO EVOKE WITHDRAWAL-LIKE STATES UPON DISCONTINUATION. HOWEVER, CHRONIC KAVA UPREGULATED SEVERAL MICROGLIAL (INOS, EGR-2, CD11B), ASTROCYTAL (C3, C4B, S100A), EPIGENETIC (NCOA-1) AND PRO-INFLAMMATORY (IL-1BETA, IL-6, TNFA) BIOMARKER GENES, DOWNREGULATED CD206 AND IL-4, AND DID NOT AFFECT MAJOR APOPTOTIC GENES IN THE BRAIN. COLLECTIVELY, THIS STUDY SUPPORTS ROBUST, EVOLUTIONARILY CONSERVED BEHAVIORAL AND PHYSIOLOGICAL EFFECTS OF KAVA AND KAVALACTONES IN ZEBRAFISH, IMPLICATES BRAIN MONOAMINES IN THEIR ACUTE EFFECTS, AND PROVIDES NOVEL IMPORTANT INSIGHTS INTO POTENTIAL ROLE OF NEUROGLIAL AND EPIGENETIC MECHANISMS IN LONG-TERM KAVA USE. 2020 16 854 38 CHONDROPROTECTIVE EFFECTS OF A HISTONE DEACETYLASE INHIBITOR, PANOBINOSTAT, ON PAIN BEHAVIOR AND CARTILAGE DEGRADATION IN ANTERIOR CRUCIATE LIGAMENT TRANSECTION-INDUCED EXPERIMENTAL OSTEOARTHRITIC RATS. OSTEOARTHRITIS (OA) IS THE MOST COMMON ARTICULAR DEGENERATIVE DISEASE CHARACTERIZED BY CHRONIC PAIN, JOINT INFLAMMATION, AND MOVEMENT LIMITATIONS, WHICH ARE SIGNIFICANTLY INFLUENCED BY ABERRANT EPIGENETIC MODIFICATIONS OF NUMEROUS OA-SUSCEPTIBLE GENES. RECENT STUDIES REVEALED THAT BOTH THE ABNORMAL ACTIVATION AND DIFFERENTIAL EXPRESSION OF HISTONE DEACETYLASES (HDACS) MIGHT CONTRIBUTE TO OA PATHOGENESIS. IN THIS STUDY, WE INVESTIGATED THE CHONDROPROTECTIVE EFFECTS OF A MARINE-DERIVED HDAC INHIBITOR, PANOBINOSTAT, ON ANTERIOR CRUCIATE LIGAMENT TRANSECTION (ACLT)-INDUCED EXPERIMENTAL OA RATS. THE INTRA-ARTICULAR ADMINISTRATION OF 2 OR 10 MICROG OF PANOBINOSTAT (EACH GROUP, N = 7) PER WEEK FROM THE 6TH TO 17TH WEEK ATTENUATES ACLT-INDUCED NOCICEPTIVE BEHAVIORS, INCLUDING SECONDARY MECHANICAL ALLODYNIA AND WEIGHT-BEARING DISTRIBUTION. HISTOPATHOLOGICAL AND MICROCOMPUTED TOMOGRAPHY ANALYSIS SHOWED THAT PANOBINOSTAT SIGNIFICANTLY PREVENTS CARTILAGE DEGENERATION AFTER ACLT. MOREOVER, INTRA-ARTICULAR PANOBINOSTAT EXERTS HYPERTROPHIC EFFECTS IN THE CHONDROCYTES OF ARTICULAR CARTILAGE BY REGULATING THE PROTEIN EXPRESSIONS OF HDAC4, HDAC6, HDAC7, RUNT-DOMAIN TRANSCRIPTION FACTOR-2, AND MATRIX METALLOPROTEINASE-13. THE STUDY INDICATED THAT HDACS MIGHT HAVE DIFFERENT MODULATIONS ON THE CHONDROCYTE PHENOTYPE IN THE EARLY STAGES OF OA DEVELOPMENT. THESE RESULTS PROVIDE NEW EVIDENCE THAT PANOBINOSTAT MAY BE A POTENTIAL THERAPEUTIC DRUG FOR OA. 2021 17 3598 15 IMPLICATIONS ON HYPNOTHERAPY: NEUROPLASTICITY, EPIGENETICS AND PAIN. WE PROVIDE A BRIEF REVIEW ABOUT THE SIGNIFICANCE OF HYPNOSIS WITH RESPECT TO APPLICATIONS AND PHYSIOLOGICAL PROCESSES IN HYPNOTHERAPY. OUR REVIEW CONCLUDES THAT HYPNOSIS IS A PROMISING METHOD TO MANAGE ACUTE AND CHRONIC PAIN. IN ADDITION, WE DISCUSS INDICATIONS POINTING TOWARD THE VIEW THAT HYPNOSIS CAN INDUCE CHANGES IN NEUROPLASTICITY POSSIBLY INVOLVING EPIGENETIC MECHANISMS. 2021 18 1679 25 DRUG RESISTANCE IN GIARDIA DUODENALIS. GIARDIA DUODENALIS IS A MICROAEROPHILIC PARASITE OF THE HUMAN GASTROINTESTINAL TRACT AND A MAJOR CONTRIBUTOR TO DIARRHEAL AND POST-INFECTIOUS CHRONIC GASTROINTESTINAL DISEASE WORLD-WIDE. TREATMENT OF G. DUODENALIS INFECTION CURRENTLY RELIES ON A SMALL NUMBER OF DRUG CLASSES. NITROHETEROCYCLICS, IN PARTICULAR METRONIDAZOLE, HAVE REPRESENTED THE FRONT LINE TREATMENT FOR THE LAST 40 YEARS. NITROHETEROCYCLIC-RESISTANT G. DUODENALIS HAVE BEEN ISOLATED FROM PATIENTS AND CREATED IN VITRO, PROMPTING CONSIDERABLE RESEARCH INTO THE BIOMOLECULAR MECHANISMS OF RESISTANCE. THESE COMPOUNDS ARE REDOX-ACTIVE AND ARE BELIEVED TO DAMAGE PROTEINS AND DNA AFTER BEING ACTIVATED BY OXIDOREDUCTASE ENZYMES IN METABOLICALLY ACTIVE CELLS. IN THIS REVIEW, WE EXPLORE THE MOLECULAR PHENOTYPES OF NITROHETEROCYCLIC-RESISTANT G. DUODENALIS DESCRIBED TO DATE IN THE CONTEXT OF THE PROTIST'S UNUSUAL GLYCOLYTIC AND ANTIOXIDANT SYSTEMS. WE PROPOSE THAT RESISTANCE MECHANISMS ARE LIKELY TO EXTEND WELL BEYOND CURRENTLY DESCRIBED RESISTANCE-ASSOCIATED ENZYMES (I.E., PYRUVATE FERREDOXIN OXIDOREDUCTASES AND NITROREDUCTASES), TO INCLUDE NAD(P)H- AND FLAVIN-GENERATING PATHWAYS, AND POSSIBLY REDOX-SENSITIVE EPIGENETIC REGULATION. MECHANISMS THAT ALLOW G. DUODENALIS TO TOLERATE OXIDATIVE STRESS MAY LEAD TO RESISTANCE AGAINST BOTH OXYGEN AND NITROHETEROCYCLICS, WITH IMPLICATIONS FOR CLINICAL CONTROL. THE PRESENT REVIEW HIGHLIGHTS THE POTENTIAL FOR SYSTEMS BIOLOGY TOOLS AND ADVANCED BIOINFORMATICS TO FURTHER INVESTIGATE THE MULTIFACETED MECHANISMS OF NITROHETEROCYCLIC RESISTANCE IN THIS IMPORTANT PATHOGEN. 2015 19 1401 23 DIETARY AND PHARMACOLOGICAL TREATMENT OF ABDOMINAL PAIN IN IBS. THIS REVIEW INTRODUCES THE PRINCIPLES OF VISCERAL SENSATION AND APPRAISES THE CURRENT APPROACHES TO MANAGEMENT OF VISCERAL PAIN IN FUNCTIONAL GI DISEASES, PRINCIPALLY IBS. THESE APPROACHES INCLUDE DIETARY MEASURES INCLUDING FIBRE SUPPLEMENTATION, LOW FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES AND POLYOLS DIET, AND PHARMACOLOGICAL APPROACHES SUCH AS ANTISPASMODICS, PEPPERMINT OIL, ANTIDEPRESSANTS (TRICYCLIC AGENTS, SELECTIVE SEROTONIN REUPTAKE INHIBITORS), 5-HT(3) RECEPTOR ANTAGONISTS (ALOSETRON, ONDANSETRON, RAMOSETRON), NON-ABSORBED ANTIBIOTIC (RIFAXIMIN), SECRETAGOGUES (LUBIPROSTONE, LINACLOTIDE), MU-OPIOID RECEPTOR (OR) AND KAPPA-OR AGONIST, DELTA-OR ANTAGONIST (ELUXADOLINE), HISTAMINE H1 RECEPTOR ANTAGONIST (EBASTINE), NEUROKININ-2 RECEPTOR ANTAGONIST (IBODUTANT) AND GABAERGIC AGENTS (GABAPENTIN AND PREGABALIN). EFFICACY AND SAFETY ARE DISCUSSED BASED ON PIVOTAL TRIALS OR PUBLISHED SYSTEMATIC REVIEWS AND META-ANALYSIS, EXPRESSING ORS OR RELATIVE RISKS AND THEIR 95% CIS. POTENTIAL NEW APPROACHES MAY BE BASED ON RECENT INSIGHTS ON MUCOSAL EXPRESSION OF GENES, AND MICRORNA AND EPIGENETIC MARKERS IN HUMAN BIOPSIES AND IN ANIMAL MODELS OF VISCERAL HYPERSENSITIVITY.THE OBJECTIVES OF THIS REVIEW ARE TO APPRAISE THE PHYSIOLOGY AND ANATOMY OF GUT SENSATION AND THE EFFICACY IN THE RELIEF OF VISCERAL PAIN (TYPICALLY IN IBS) OF SEVERAL CLASSES OF THERAPIES. THESE INCLUDE FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES AND POLYOLS (FODMAPS) AND DIFFERENT CLASSES OF MEDICATIONS (BOX 1). BOX 1CLASSES OF PHARMACOLOGICAL AGENTS FOR VISCERAL PAINANTIDEPRESSANTS (TRICYCLIC AGENTS, SELECTIVE SEROTONIN REUPTAKE INHIBITORS)PEPPERMINT OIL5-HT(3) RECEPTOR ANTAGONISTS (ALOSETRON, ONDANSETRON, RAMOSETRON)NON-ABSORBED ANTIBIOTIC (RIFAXIMIN)SECRETAGOGUES (LUBIPROSTONE, LINACLOTIDE)MU-OPIOID RECEPTOR (OR) AND KAPPA-OR AGONIST AND DELTA-OR ANTAGONIST (ELUXADOLINE)HISTAMINE H1 RECEPTOR ANTAGONIST (EBASTINE)NEUROKININ-2 RECEPTOR ANTAGONIST (IBODUTANT)GABAERGIC AGENTS (GABAPENTIN AND PREGABALIN). 2017 20 5780 25 SPINAL RNF20-MEDIATED HISTONE H2B MONOUBIQUITYLATION REGULATES MGLUR5 TRANSCRIPTION FOR NEUROPATHIC ALLODYNIA. TO DATE, HISTONE H2B MONOUBIQUITINATION (H2BUB), A MARK ASSOCIATED WITH TRANSCRIPTIONAL ELONGATION AND ONGOING TRANSCRIPTION, HAS NOT BEEN LINKED TO THE DEVELOPMENT OR MAINTENANCE OF NEUROPATHIC PAIN STATES. HERE, USING MALE SPRAGUE DAWLEY RATS, WE DEMONSTRATED SPINAL NERVE LIGATION (SNL) INDUCED BEHAVIORAL ALLODYNIA AND PROVOKED RING FINGER PROTEIN 20 (RNF20)-DEPENDENT H2BUB IN DORSAL HORN. MOREOVER, SNL PROVOKED RNF20-MEDIATED H2BUB PHOSPHORYLATED RNA POLYMERASE II (RNAPII) IN THE PROMOTER FRAGMENTS OF MGLUR5, THEREBY ENHANCING MGLUR5 TRANSCRIPTION/EXPRESSION IN THE DORSAL HORN. CONVERSELY, FOCAL KNOCKDOWN OF SPINAL RNF20 EXPRESSION REVERSED NOT ONLY SNL-INDUCED ALLODYNIA BUT ALSO RNF20/H2BUB/RNAPII PHOSPHORYLATION-ASSOCIATED SPINAL MGLUR5 TRANSCRIPTION/EXPRESSION. NOTABLY, TNF-ALPHA INJECTION INTO NAIVE RATS AND SPECIFIC NEUTRALIZING ANTIBODY INJECTION INTO SNL-INDUCED ALLODYNIA RATS REVEALED THAT TNF-ALPHA-ASSOCIATED ALLODYNIA INVOLVES THE RNF20/H2BUB/RNAPII TRANSCRIPTIONAL AXIS TO UPREGULATE MGLUR5 EXPRESSION IN THE DORSAL HORN. COLLECTIVELY, OUR FINDINGS INDICATED TNF-ALPHA INDUCES RNF20-DRIVED H2B MONOUBIQUITINATION, WHICH FACILITATES PHOSPHORYLATED RNAPII-DEPENDENT MGLUR5 TRANSCRIPTION IN THE DORSAL HORN FOR THE DEVELOPMENT OF NEUROPATHIC ALLODYNIA.SIGNIFICANCE STATEMENT HISTONE H2B MONOUBIQUITINATION (H2BUB), AN EPIGENETIC POST-TRANSLATIONAL MODIFICATION, POSITIVELY CORRELATED WITH GENE EXPRESSION. HERE, TNF-ALPHA PARTICIPATED IN NEUROPATHIC PAIN DEVELOPMENT BY ENHANCING RNF20-MEDIATED H2BUB, WHICH FACILITATES PHOSPHORYLATED RNAPII-DEPENDENT MGLUR5 TRANSCRIPTION IN DORSAL HORN. OUR FINDING POTENTIALLY IDENTIFIED NEUROPATHIC ALLODYNIA PATHOPHYSIOLOGICAL PROCESSES UNDERPINNING ABNORMAL NOCICEPTION PROCESSING AND OPENS A NEW AVENUE FOR THE DEVELOPMENT OF NOVEL ANALGESICS. 2018