1 6138 117 THE ETIOLOGICAL CHANGES OF ACETYLATION IN PERIPHERAL NERVE INJURY-INDUCED NEUROPATHIC HYPERSENSITIVITY. NEUROPATHIC PAIN IS A COMMON CHRONIC PAIN CONDITION WITH MECHANISMS FAR CLEARLY BEEN ELUCIDATED. MOUNTING PRECLINICAL AND CLINICAL STUDIES HAVE SHOWN NEUROPATHIC PAIN IS HIGHLY ASSOCIATED WITH HISTONE ACETYLATION MODIFICATION, WHICH FOLLOWS EXPRESSION REGULATION OF VARIOUS PAIN-RELATED MOLECULES SUCH AS MGLUR1/5, GLUTAMATE ASPARTATE TRANSPORTER, GLUTAMATE TRANSPORTER-1, GAD65, NA(V)1.8, KV4.3, MU-OPIOID RECEPTOR, BRAIN-DERIVED NEUROTROPHIC FACTOR, AND CERTAIN CHEMOKINES. AS TWO TYPES OF PIVOTAL ENZYMES INVOLVED IN HISTONE ACETYLATION, HISTONE DEACETYLASES INDUCE HISTONE DEACETYLATION TO SILENCE GENE EXPRESSION; IN CONTRAST, HISTONE ACETYL TRANSFERASES FACILITATE HISTONE ACETYLATION TO POTENTIATE GENE TRANSCRIPTION. ACCORDINGLY, UPREGULATION OR BLOCKADE OF ACETYLATION MAY BE A PROMISING INTERVENTION DIRECTION FOR NEUROPATHIC PAIN TREATMENT. IN FACT, NUMEROUS ANIMAL STUDIES HAVE SUGGESTED VARIOUS HISTONE DEACETYLASE INHIBITORS, SIRT (CLASS III HISTONE DEACETYLASES) ACTIVATORS, AND HISTONE ACETYL TRANSFERASES INHIBITORS ARE EFFECTIVE IN NEUROPATHIC PAIN TREATMENT VIA TARGETING SPECIFIC EPIGENETIC SITES. IN THIS REVIEW, WE SUMMARIZE THE CHARACTERISTICS OF THE MOLECULES AND MECHANISMS OF NEUROPATHY-RELATED ACETYLATION, AS WELL AS THE ACETYLATION UPREGULATION AND BLOCKADE FOR NEUROPATHIC PAIN THERAPY. FINALLY, WE WILL DISCUSS THE CURRENT DRUG ADVANCES FOCUSING ON NEUROPATHY-RELATED ACETYLATION ALONG WITH THE UNDERLYING TREATMENT MECHANISMS. 2018 2 3319 42 HISTONE ACETYLATION AND HISTONE DEACETYLATION IN NEUROPATHIC PAIN: AN UNRESOLVED PUZZLE? CHRONIC PAIN IS BROADLY CLASSIFIED INTO SOMATIC, VISCERAL OR NEUROPATHIC PAIN DEPENDING UPON THE LOCATION AND EXTENT OF PAIN PERCEPTION. EVIDENCES FROM DIFFERENT ANIMAL STUDIES SUGGEST THAT INFLAMMATORY OR NEUROPATHIC PAIN IS ASSOCIATED WITH ALTERED ACETYLATION AND DEACETYLATION OF HISTONE PROTEINS, WHICH RESULT IN ABNORMAL TRANSCRIPTION OF NOCICEPTIVE PROCESSING GENES. THERE HAVE BEEN A NUMBER OF STUDIES INDICATING THAT NERVE INJURY UP-REGULATES HISTONE DEACETYLASE ENZYMES, WHICH LEADS TO INCREASED HISTONE DEACETYLATION AND INDUCE CHRONIC PAIN. TREATMENT WITH HISTONE DEACETYLASE INHIBITORS RELIEVES PAIN BY NORMALIZING NERVE INJURY-INDUCED DOWN REGULATION OF METABOTROPIC GLUTAMATE RECEPTORS, GLUTAMATE TRANSPORTERS, GLUTAMIC ACID DECARBOXYLASE 65, NEURON RESTRICTIVE SILENCER FACTOR AND SERUM AND GLUCOCORTICOID INDUCIBLE KINASE 1. ON THE OTHER HAND, A FEW STUDIES REFER TO INCREASED EXPRESSION OF HISTONE ACETYLASE ENZYMES IN RESPONSE TO NERVE INJURY THAT PROMOTES HISTONE ACETYLATION LEADING TO PAIN INDUCTION. TREATMENT WITH HISTONE ACETYL TRANSFERASE INHIBITORS HAVE BEEN REPORTED TO RELIEVE CHRONIC PAIN BY BLOCKING THE UP-REGULATION OF CHEMOKINES AND CYCLOOXYGENASE-2, THE CRITICAL FACTORS ASSOCIATED WITH HISTONE ACETYLATION-INDUCED PAIN. THE PRESENT REVIEW DESCRIBES THE DUAL ROLE OF HISTONE ACETYLATION/DEACETYLATION IN DEVELOPMENT OR ATTENUATION OF NEUROPATHIC PAIN ALONG WITH THE UNDERLYING MECHANISMS. 2017 3 3619 23 IN VIVO ACUTE ON CHRONIC ETHANOL EFFECTS IN LIVER: A MOUSE MODEL EXHIBITING EXACERBATED INJURY, ALTERED METABOLIC AND EPIGENETIC RESPONSES. CHRONIC ALCOHOLICS WHO ALSO BINGE DRINK (I.E., ACUTE ON CHRONIC) ARE PRONE TO AN EXACERBATED LIVER INJURY BUT ITS MECHANISM IS NOT UNDERSTOOD. WE THEREFORE INVESTIGATED THE IN VIVO EFFECTS OF CHRONIC AND BINGE ETHANOL INGESTION AND COMPARED TO CHRONIC ETHANOL FOLLOWED BY THREE REPEAT BINGE ETHANOL ON THE LIVER OF MALE C57/BL6 MICE FED ETHANOL IN LIQUID DIET (4%) FOR FOUR WEEKS FOLLOWED BY BINGE ETHANOL (INTRAGASTRIC ADMINISTRATION, 3.5 G/KG BODY WEIGHT, THREE DOSES, 12H APART). CHRONIC FOLLOWED BY BINGE ETHANOL EXACERBATED FAT ACCUMULATION, NECROSIS, DECREASE IN HEPATIC SAM AND SAM:SAH RATIO, INCREASE IN ADENOSINE LEVELS, AND ELEVATED CYP2E1 LEVELS. HISTONE H3 LYSINE ACETYLATION (H3ACK9), DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10), AND PHOSPHORYLATED H2AX INCREASED AFTER BINGE WHEREAS PHOSPHORYLATION OF HISTONE H3 SER 10 (H3S10) AND H3 SER 28 (H3S28) INCREASED AFTER CHRONIC ETHANOL-BINGE. HISTONE H3 LYSINE 4 AND 9 DIMETHYLATION INCREASED WITH A MARKED DIMETHYLATION IN H3K9 IN CHRONIC ETHANOL BINGE GROUP. TRIMETHYLATED HISTONE H3 LEVELS DID NOT CHANGE. NUCLEAR LEVELS OF HISTONE ACETYL TRANSFERASE GCN5 AND HISTONE DEACETYLASE HDAC3 WERE ELEVATED WHEREAS PHOSPHO-CREB DECREASED IN A DISTINCTIVE MANNER. TAKEN TOGETHER, ACUTE ON CHRONIC ETHANOL INGESTION CAUSED AMPLIFICATION OF LIVER INJURY AND ELICITED CHARACTERISTIC PROFILES OF HISTONE MODIFICATIONS, METABOLIC ALTERATIONS, AND CHANGES IN NUCLEAR PROTEIN LEVELS. THESE FINDINGS DEMONSTRATE THAT CHRONIC ETHANOL EXPOSURE RENDERS LIVER MORE SUSCEPTIBLE TO REPEAT ACUTE/BINGE ETHANOL INDUCED ACCELERATION OF ALCOHOLIC LIVER DISEASE. 2015 4 3191 33 HDAC AND HAT INHIBITORS DIFFERENTLY AFFECT ANALGESIA MEDIATED BY GROUP II METABOTROPIC GLUTAMATE RECEPTORS. BACKGROUND: HISTONE DEACETYLASES (HDACS) AND HISTONE ACETYLTRANSFERASES (HATS) ARE KEY PLAYERS IN EPIGENETIC REGULATION OF GENE EXPRESSION. ANALGESIC ACTIVITY BY HDAC INHIBITORS HAS BEEN REPORTED IN DIFFERENT PAIN MODELS INCLUDING INFLAMMATORY AND NEUROPATHIC PAIN. THESE DRUGS INTERFERE WITH GENE EXPRESSION THROUGH DIFFERENT MECHANISMS INCLUDING CHROMATIN REMODELING AND/OR ACTIVATION OF TRANSCRIPTION FACTORS. AMONG OTHER TARGETS, HDAC INHIBITORS REGULATE METABOTROPIC GLUTAMATE RECEPTORS TYPE 2 (MGLU2) EXPRESSION IN CENTRAL AND PERIPHERAL CENTRAL NERVOUS SYSTEM. HOWEVER WHETHER INHIBITION OF HAT ACTIVITY ALSO REGULATES MGLU2 EXPRESSION HAS NOT BEEN REPORTED. FINDINGS: HERE WE REPORT THAT CURCUMIN (CUR), A NATURALLY OCCURRING COMPOUND ENDOWED WITH P300/CREB-BINDING PROTEIN HAT INHIBITORY ACTIVITY, IS ABLE TO INDUCE A DRASTIC DOWN-REGULATION OF THE MGLU2 RECEPTOR IN THE MOUSE SPINAL CORD AFTER SYSTEMIC ADMINISTRATION TOGETHER WITH A MARKED HYPOACETYLATION OF HISTONES H3 AND H4 IN DORSAL ROOT GANGLIA (DRG). FURTHERMORE, THE ANALGESIC ACTIVITY OF THE MGLU2/3 AGONIST, LY379268 IS LOST AFTER A 3-DAY TREATMENT WITH CUR. CONVERSELY THE ANALGESIC ACTIVITY OF LY379268 IS POTENTIATED IN MICE PRETREATED FOR 5 CONSECUTIVE DAYS WITH THE HDAC INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), KNOWN TO INDUCE MGLU2-UPREGULATION. CONCLUSIONS: OUR RESULTS DEMONSTRATE THAT SYSTEMICALLY INJECTED CUR IS ABLE TO INHIBIT H3 AND H4 ACETYLATION IN THE DRG AND TO DOWN-REGULATE MGLU2 RECEPTORS IN THE SPINAL CORD. WE ALSO DEMONSTRATE THAT LONG TERM MODIFICATION OF THE MGLU2 EXPRESSION AFFECTS THE ANALGESIC PROPERTIES OF THE ORTHOSTERIC MGLU2/3 AGONIST, LY379268. THESE DATA OPEN UP THE POSSIBILITY THAT EPIGENETIC MODULATORS MIGHT BE GIVEN IN COMBINATION WITH "TRADITIONAL" DRUGS IN A CONTEXT OF A MULTI TARGET APPROACH FOR A BETTER ANALGESIC EFFICACY. 2014 5 1105 39 COMBINED INHIBITION OF HISTONE DEACETYLASES AND BET FAMILY PROTEINS AS EPIGENETIC THERAPY FOR NERVE INJURY-INDUCED NEUROPATHIC PAIN. CURRENT TREATMENTS FOR NEUROPATHIC PAIN HAVE OFTEN MODERATE EFFICACY AND PRESENT UNWANTED EFFECTS SHOWING THE NEED TO DEVELOP EFFECTIVE THERAPIES. ACCUMULATING EVIDENCE SUGGESTS THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN CHRONIC PAIN AND THE ANALGESIC ACTIVITY OF HISTONE DEACETYLASES (HDACS) INHIBITORS IS DOCUMENTED. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT INTERACT WITH ACETYLATED LYSINE RESIDUES ON HISTONES, BUT LITTLE IS KNOWN ABOUT THEIR IMPLICATION IN NEUROPATHIC PAIN. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE EFFECT OF THE COMBINATION OF HDAC AND BET INHIBITORS IN THE SPARED NERVE INJURY (SNI) MODEL IN MICE. INTRANASAL ADMINISTRATION OF I-BET762 (BET INHIBITOR) OR SAHA (HDAC INHIBITOR) ATTENUATED THERMAL AND MECHANICAL HYPERSENSITIVITY AND THIS ANTIALLODYNIC ACTIVITY WAS IMPROVED BY CO-ADMINISTRATION OF BOTH DRUGS. SPINAL CORD SECTIONS OF SNI MICE SHOWED AN INCREASED EXPRESSION OF HDAC1 AND BRD4 PROTEINS AND COMBINATION PRODUCED A STRONGER REDUCTION COMPARED TO EACH EPIGENETIC AGENT ALONE. SAHA AND I-BET762, ADMINISTERED ALONE OR IN COMBINATION, COUNTERACTED THE SNI-INDUCED MICROGLIA ACTIVATION BY INHIBITING THE EXPRESSION OF IBA1, CD11B, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS), THE ACTIVATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION-1 (STAT1) WITH COMPARABLE EFFICACY. CONVERSELY, THE EPIGENETIC INHIBITORS SHOWED A MODEST EFFECT ON SPINAL PROINFLAMMATORY CYTOKINES CONTENT THAT WAS SIGNIFICANTLY POTENTIATED BY THEIR COMBINATION. PRESENT RESULTS INDICATE A KEY ROLE OF ACETYLATED HISTONES AND THEIR RECRUITMENT BY BET PROTEINS ON MICROGLIA-MEDIATED SPINAL NEUROINFLAMMATION. TARGETING NEUROPATHIC PAIN WITH THE COMBINATION OF HDAC AND BET INHIBITORS MAY REPRESENT A PROMISING NEW THERAPEUTIC OPTION. 2021 6 3721 35 INHIBITION OF CLASS II HISTONE DEACETYLASES IN THE SPINAL CORD ATTENUATES INFLAMMATORY HYPERALGESIA. BACKGROUND: SEVERAL CLASSES OF HISTONE DEACETYLASES (HDACS) ARE EXPRESSED IN THE SPINAL CORD THAT IS A CRITICAL STRUCTURE OF THE NOCICEPTIVE PATHWAY. HDAC-REGULATED HISTONE ACETYLATION IS AN IMPORTANT COMPONENT OF CHROMATIN REMODELING LEADING TO EPIGENETIC REGULATION OF GENE TRANSCRIPTION. TO UNDERSTAND THE ROLE OF HISTONE ACETYLATION IN EPIGENETIC REGULATION OF PATHOLOGICAL PAIN, WE HAVE STUDIED THE IMPACT OF DIFFERENT CLASSES OF HDACS IN THE SPINAL CORD ON INFLAMMATORY HYPERALGESIA INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA). RESULTS: WE INTRATHECALLY APPLIED INHIBITORS SPECIFIC TO DIFFERENT CLASSES OF HDACS AND EVALUATED THEIR IMPACT ON INFLAMMATORY HYPERALGESIA. PRE-INJECTED INHIBITORS TARGETING CLASS I AS WELL AS II (SAHA, TSA, LAQ824) OR IIA (VPA, 4-PB) HDACS SIGNIFICANTLY DELAYED THE THERMAL HYPERALGESIA INDUCED BY UNILATERAL CFA INJECTION IN THE HINDPAW. EXISTING HYPERALGESIA INDUCED BY CFA WAS ALSO ATTENUATED BY THE HDAC INHIBITORS (HDACIS). IN CONTRAST, THESE INHIBITORS DID NOT INTERFERE WITH THE THERMAL RESPONSE EITHER IN NAIVE ANIMALS, OR ON THE CONTRALATERAL SIDE OF INFLAMED ANIMALS. INTERESTINGLY, MS-275 THAT SPECIFICALLY INHIBITS CLASS I HDACS FAILED TO ALTER THE HYPERALGESIA ALTHOUGH IT INCREASED HISTONE 3 ACETYLATION IN THE SPINAL CORD AS SAHA DID. USING IMMUNOBLOT ANALYSIS, WE FURTHER FOUND THAT THE LEVELS OF CLASS IIA HDAC MEMBERS (HDAC4, 5, 7, 9) IN THE SPINAL DORSAL HORN WERE UPREGULATED FOLLOWING CFA INJECTION WHILE THOSE OF CLASS I HDAC MEMBERS (HDAC1, 2, 3) REMAINED STABLE OR WERE SLIGHTLY REDUCED. CONCLUSIONS: OUR DATA SUGGEST THAT ACTIVITY OF CLASS II HDACS IN THE SPINAL CORD IS CRITICAL TO THE INDUCTION AND MAINTENANCE OF INFLAMMATORY HYPERALGESIA INDUCED BY CFA, WHILE ACTIVITY OF CLASS I HDACS MAY BE UNNECESSARY. COMPARISON OF THE EFFECTS OF HDACIS SPECIFIC TO CLASS II AND IIA AS WELL AS THE EXPRESSION PATTERN OF DIFFERENT HDACS IN THE SPINAL CORD IN RESPONSE TO CFA SUGGESTS THAT THE MEMBERS OF CLASS IIA HDACS MAY BE POTENTIAL TARGETS FOR ATTENUATING PERSISTENT INFLAMMATORY PAIN. 2010 7 5293 26 PROTEASOMAL DEGRADATION OF THE HISTONE ACETYL TRANSFERASE P300 CONTRIBUTES TO BETA-CELL INJURY IN A DIABETES ENVIRONMENT. IN TYPE 2 DIABETES, AMYLOID OLIGOMERS, CHRONIC HYPERGLYCEMIA, LIPOTOXICITY, AND PRO-INFLAMMATORY CYTOKINES ARE DETRIMENTAL TO BETA-CELLS, CAUSING APOPTOSIS AND IMPAIRED INSULIN SECRETION. THE HISTONE ACETYL TRANSFERASE P300, INVOLVED IN REMODELING OF CHROMATIN STRUCTURE BY EPIGENETIC MECHANISMS, IS A KEY UBIQUITOUS ACTIVATOR OF THE TRANSCRIPTIONAL MACHINERY. IN THIS STUDY, WE REPORT THAT LOSS OF P300 ACETYL TRANSFERASE ACTIVITY AND EXPRESSION LEADS TO BETA-CELL APOPTOSIS, AND MOST IMPORTANTLY, THAT STRESS SITUATIONS KNOWN TO BE ASSOCIATED WITH DIABETES ALTER P300 LEVELS AND FUNCTIONAL INTEGRITY. WE FOUND THAT PROTEASOMAL DEGRADATION IS THE MECHANISM SUBSERVING P300 LOSS IN BETA-CELLS EXPOSED TO HYPERGLYCEMIA OR PRO-INFLAMMATORY CYTOKINES. WE ALSO REPORT THAT MELATONIN, A HORMONE PRODUCED IN THE PINEAL GLAND AND KNOWN TO PLAY KEY ROLES IN BETA-CELL HEALTH, PRESERVES P300 LEVELS ALTERED BY THESE TOXIC CONDITIONS. COLLECTIVELY, THESE DATA IMPLY AN IMPORTANT ROLE FOR P300 IN THE PATHOPHYSIOLOGY OF DIABETES. 2018 8 3202 33 HDAC2 REGULATES ATYPICAL ANTIPSYCHOTIC RESPONSES THROUGH THE MODULATION OF MGLU2 PROMOTER ACTIVITY. HISTONE DEACETYLASES (HDACS) COMPACT CHROMATIN STRUCTURE AND REPRESS GENE TRANSCRIPTION. IN SCHIZOPHRENIA, CLINICAL STUDIES DEMONSTRATE THAT HDAC INHIBITORS ARE EFFICACIOUS WHEN GIVEN IN COMBINATION WITH ATYPICAL ANTIPSYCHOTICS. HOWEVER, THE MOLECULAR MECHANISM THAT INTEGRATES A BETTER RESPONSE TO ANTIPSYCHOTICS WITH CHANGES IN CHROMATIN STRUCTURE REMAINS UNKNOWN. HERE WE FOUND THAT CHRONIC ATYPICAL ANTIPSYCHOTICS DOWNREGULATED THE TRANSCRIPTION OF METABOTROPIC GLUTAMATE 2 RECEPTOR (MGLU2, ALSO KNOWN AS GRM2), AN EFFECT THAT WAS ASSOCIATED WITH DECREASED HISTONE ACETYLATION AT ITS PROMOTER IN MOUSE AND HUMAN FRONTAL CORTEX. THIS EPIGENETIC CHANGE OCCURRED IN CONCERT WITH A SEROTONIN 5-HT(2A) RECEPTOR-DEPENDENT UPREGULATION AND INCREASED BINDING OF HDAC2 TO THE MGLU2 PROMOTER. VIRALLY MEDIATED OVEREXPRESSION OF HDAC2 IN FRONTAL CORTEX DECREASED MGLU2 TRANSCRIPTION AND ITS ELECTROPHYSIOLOGICAL PROPERTIES, THEREBY INCREASING PSYCHOSIS-LIKE BEHAVIOR. CONVERSELY, HDAC INHIBITORS PREVENTED THE REPRESSIVE HISTONE MODIFICATIONS INDUCED AT THE MGLU2 PROMOTER BY ATYPICAL ANTIPSYCHOTICS, AND AUGMENTED THEIR THERAPEUTIC-LIKE EFFECTS. THESE OBSERVATIONS SUPPORT THE VIEW OF HDAC2 AS A PROMISING NEW TARGET FOR SCHIZOPHRENIA TREATMENT. 2012 9 5999 27 THE ACETYLOME REGULATORS HDAC1 AND HDAC2 DIFFERENTLY MODULATE INTESTINAL EPITHELIAL CELL DEPENDENT HOMEOSTATIC RESPONSES IN EXPERIMENTAL COLITIS. HISTONE DEACETYLASES (HDAC) REMOVE ACETYL GROUPS FROM PROTEINS, INFLUENCING GLOBAL AND SPECIFIC GENE EXPRESSION. HDACS CONTROL INFLAMMATION, AS SHOWN BY HDAC INHIBITOR-DEPENDENT PROTECTION FROM DEXTRAN SULFATE SODIUM (DSS)-INDUCED MURINE COLITIS. ALTHOUGH TISSUE-SPECIFIC HDAC KNOCKOUTS SHOW REDUNDANT AND SPECIFIC FUNCTIONS, LITTLE IS KNOWN OF THEIR INTESTINAL EPITHELIAL CELL (IEC) ROLE. WE HAVE SHOWN PREVIOUSLY THAT DUAL HDAC1/HDAC2 IEC-SPECIFIC LOSS DISRUPTS CELL PROLIFERATION AND DETERMINATION, WITH DECREASED SECRETORY CELL NUMBERS AND ALTERED BARRIER FUNCTION. WE THUS INVESTIGATED HOW COMPOUND HDAC1/HDAC2 OR HDAC2 IEC-SPECIFIC DEFICIENCY ALTERS THE INFLAMMATORY RESPONSE. FLOXED HDAC1 AND HDAC2 AND VILLIN-CRE MICE WERE INTERBRED. COMPOUND HDAC1/HDAC2 IEC-DEFICIENT MICE SHOWED CHRONIC BASAL INFLAMMATION, WITH INCREASED BASAL DISEASE ACTIVITY INDEX (DAI) AND DEREGULATED REG GENE COLONIC EXPRESSION. DSS-TREATED DUAL HDAC1/HDAC2 IEC-DEFICIENT MICE DISPLAYED INCREASED DAI, HISTOLOGICAL SCORE, INTESTINAL PERMEABILITY, AND INFLAMMATORY GENE EXPRESSION. IN CONTRAST TO DOUBLE KNOCKOUTS, HDAC2 IEC-SPECIFIC LOSS DID NOT AFFECT IEC DETERMINATION AND GROWTH, NOR RESULT IN CHRONIC INFLAMMATION. HOWEVER, HDAC2 DISRUPTION PROTECTED AGAINST DSS COLITIS, AS SHOWN BY DECREASED DAI, INTESTINAL PERMEABILITY AND CASPASE-3 CLEAVAGE. HDAC2 IEC-SPECIFIC DEFICIENT MICE DISPLAYED INCREASED EXPRESSION OF IEC GENE SUBSETS, SUCH AS COLONIC ANTIMICROBIAL REG3B AND REG3G MRNAS, AND DECREASED EXPRESSION OF IMMUNE CELL FUNCTION-RELATED GENES. OUR DATA SHOW THAT HDAC1 AND HDAC2 ARE ESSENTIAL IEC HOMEOSTASIS REGULATORS. IEC-SPECIFIC HDAC1 AND HDAC2 MAY ACT AS EPIGENETIC SENSORS AND TRANSMITTERS OF ENVIRONMENTAL CUES AND REGULATE IEC-MEDIATED MUCOSAL HOMEOSTATIC AND INFLAMMATORY RESPONSES. DIFFERENT LEVELS OF IEC HDAC ACTIVITY MAY LEAD TO POSITIVE OR NEGATIVE OUTCOMES ON INTESTINAL HOMEOSTASIS DURING INFLAMMATION. 2014 10 2448 29 EPIGENETIC SUPPRESSION OF GAD65 EXPRESSION MEDIATES PERSISTENT PAIN. CHRONIC PAIN IS A COMMON NEUROLOGICAL DISEASE INVOLVING LASTING, MULTIFACETED MALADAPTATIONS RANGING FROM GENE MODULATION TO SYNAPTIC DYSFUNCTION AND EMOTIONAL DISORDERS. SUSTAINED PATHOLOGICAL STIMULI IN MANY DISEASES ALTER THE OUTPUT ACTIVITIES OF CERTAIN GENES THROUGH EPIGENETIC MODIFICATIONS, BUT IT IS UNCLEAR HOW EPIGENETIC MECHANISMS OPERATE IN THE DEVELOPMENT OF CHRONIC PAIN. WE SHOW HERE THAT IN THE RAT BRAINSTEM NUCLEUS RAPHE MAGNUS, WHICH IS IMPORTANT FOR CENTRAL MECHANISMS OF CHRONIC PAIN, PERSISTENT INFLAMMATORY AND NEUROPATHIC PAIN EPIGENETICALLY SUPPRESSES GAD2 (ENCODING GLUTAMIC ACID DECARBOXYLASE 65 (GAD65)) TRANSCRIPTION THROUGH HISTONE DEACETYLASE (HDAC)-MEDIATED HISTONE HYPOACETYLATION, RESULTING IN IMPAIRED GAMMA-AMINOBUTYRIC ACID (GABA) SYNAPTIC INHIBITION. GAD2 KNOCKOUT MICE SHOWED SENSITIZED PAIN BEHAVIOR AND IMPAIRED GABA SYNAPTIC FUNCTION IN THEIR BRAINSTEM NEURONS. IN WILD-TYPE BUT NOT GAD2 KNOCKOUT MICE, HDAC INHIBITORS STRONGLY INCREASED GAD65 ACTIVITY, RESTORED GABA SYNAPTIC FUNCTION AND RELIEVED SENSITIZED PAIN BEHAVIOR. THESE FINDINGS SUGGEST GAD65 AND HDACS AS POTENTIAL THERAPEUTIC TARGETS IN AN EPIGENETIC APPROACH TO THE TREATMENT OF CHRONIC PAIN. 2011 11 4906 37 P300 EXERTS AN EPIGENETIC ROLE IN CHRONIC NEUROPATHIC PAIN THROUGH ITS ACETYLTRANSFERASE ACTIVITY IN RATS FOLLOWING CHRONIC CONSTRICTION INJURY (CCI). BACKGROUND: NEUROPATHIC PAIN IS DETRIMENTAL TO HUMAN HEALTH; HOWEVER, ITS PATHOGENESIS STILL REMAINS LARGELY UNKNOWN. OVEREXPRESSION OF PAIN-ASSOCIATED GENES AND INCREASED NOCICEPTIVE SOMATO-SENSITIVITY ARE WELL OBSERVED IN NEUROPATHIC PAIN. THE IMPORTANCE OF EPIGENETIC MECHANISMS IN REGULATING THE EXPRESSION OF PRO- OR ANTI-NOCICEPTIVE GENES HAS BEEN REVEALED BY STUDIES RECENTLY, AND WE HYPOTHESIZE THAT THE TRANSCRIPTIONAL COACTIVATOR AND THE HISTONE ACETYLTRANSFERASE E1A BINDING PROTEIN P300 (P300), AS A PART OF THE EPIGENETIC MECHANISMS OF GENE REGULATION, MAY BE INVOLVED IN THE PATHOGENESIS OF NEUROPATHIC PAIN INDUCED BY CHRONIC CONSTRICTION INJURY (CCI). TO TEST THIS HYPOTHESIS, TWO DIFFERENT APPROACHES WERE USED IN THIS STUDY: (I) DOWN-REGULATING P300 WITH SPECIFIC SMALL HAIRPIN RNA (SHRNA) AND (II) CHEMICAL INHIBITION OF P300 ACETYLTRANSFERASE ACTIVITY BY A SMALL MOLECULE INHIBITOR, C646. RESULTS: USING THE CCI RAT MODEL, WE FOUND THAT THE P300 EXPRESSION WAS INCREASED IN THE LUMBAR SPINAL CORD ON DAY 14 AFTER CCI. THE TREATMENT WITH INTRATHECAL P300 SHRNA REVERSED CCI-INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA, AND SUPPRESSED THE EXPRESSION OF CYCLOOXYGENASE-2 (COX-2), A NEUROPATHIC PAIN-ASSOCIATED FACTOR. FURTHERMORE, C646, AN INHIBITOR OF P300 ACETYLTRANSFERASE, ALSO ATTENUATED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA, ACCOMPANIED BY A SUPPRESSED COX-2 EXPRESSION, IN THE SPINAL CORD. CONCLUSIONS: THE RESULTS SUGGEST THAT, THROUGH ITS ACETYLTRANSFERASE ACTIVITY IN THE SPINAL CORD AFTER CCI, P300 EPIGENETICALLY PLAYS AN IMPORTANT ROLE IN NEUROPATHIC PAIN. INHIBITING P300, USING INTERFERING RNA OR C646, MAY BE A PROMISING APPROACH TO THE DEVELOPMENT OF NEW NEUROPATHIC PAIN THERAPIES. 2012 12 1945 29 EPIGALLOCATECHIN-3-GALLATE, A HISTONE ACETYLTRANSFERASE INHIBITOR, INHIBITS EBV-INDUCED B LYMPHOCYTE TRANSFORMATION VIA SUPPRESSION OF RELA ACETYLATION. BECAUSE THE P300/CBP-MEDIATED HYPERACETYLATION OF RELA (P65) IS CRITICAL FOR NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) ACTIVATION, THE ATTENUATION OF P65 ACETYLATION IS A POTENTIAL MOLECULAR TARGET FOR THE PREVENTION OF CHRONIC INFLAMMATION. DURING OUR ONGOING SCREENING STUDY TO IDENTIFY NATURAL COMPOUNDS WITH HISTONE ACETYLTRANSFERASE INHIBITOR (HATI) ACTIVITY, WE IDENTIFIED EPIGALLOCATECHIN-3-GALLATE (EGCG) AS A NOVEL HATI WITH GLOBAL SPECIFICITY FOR THE MAJORITY OF HAT ENZYMES BUT WITH NO ACTIVITY TOWARD EPIGENETIC ENZYMES INCLUDING HDAC, SIRT1, AND HMTASE. AT A DOSE OF 100 MICROMOL/L, EGCG ABROGATES P300-INDUCED P65 ACETYLATION IN VITRO AND IN VIVO, INCREASES THE LEVEL OF CYTOSOLIC IKAPPABALPHA, AND SUPPRESSES TUMOR NECROSIS FACTOR ALPHA (TNFALPHA)-INDUCED NF-KAPPAB ACTIVATION. WE ALSO SHOWED THAT EGCG PREVENTS TNFALPHA-INDUCED P65 TRANSLOCATION TO THE NUCLEUS, CONFIRMING THAT HYPERACETYLATION IS CRITICAL FOR NF-KAPPAB TRANSLOCATION AS WELL AS ACTIVITY. FURTHERMORE, EGCG TREATMENT INHIBITED THE ACETYLATION OF P65 AND THE EXPRESSION OF NF-KAPPAB TARGET GENES IN RESPONSE TO DIVERSE STIMULI. FINALLY, EGCG REDUCED THE BINDING OF P300 TO THE PROMOTER REGION OF INTERLEUKIN-6 GENE WITH AN INCREASED RECRUITMENT OF HDAC3, WHICH HIGHLIGHTS THE IMPORTANCE OF THE BALANCE BETWEEN HATS AND HISTONE DEACETYLASES IN THE NF-KAPPAB-MEDIATED INFLAMMATORY SIGNALING PATHWAY. IMPORTANTLY, EGCG AT 50 MICROMOL/L DOSE COMPLETELY BLOCKS EBV INFECTION-INDUCED CYTOKINE EXPRESSION AND SUBSEQUENTLY THE EBV-INDUCED B LYMPHOCYTE TRANSFORMATION. THESE RESULTS SHOW THE CRUCIAL ROLE OF ACETYLATION IN THE DEVELOPMENT OF INFLAMMATORY-RELATED DISEASES. 2009 13 1339 29 DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION, AND STRUCTURAL CHARACTERIZATION OF POTENT HISTONE DEACETYLASE INHIBITORS BASED ON CYCLIC ALPHA/BETA-TETRAPEPTIDE ARCHITECTURES. HISTONE DEACETYLASES (HDACS) ARE A FAMILY OF ENZYMES FOUND IN BACTERIA, FUNGI, PLANTS, AND ANIMALS THAT PROFOUNDLY AFFECT CELLULAR FUNCTION BY CATALYZING THE REMOVAL OF ACETYL GROUPS FROM -N-ACETYLATED LYSINE RESIDUES OF VARIOUS PROTEIN SUBSTRATES INCLUDING HISTONES, TRANSCRIPTION FACTORS, ALPHA-TUBULIN, AND NUCLEAR IMPORTERS. ALTHOUGH THE PRECISE ROLES OF HDAC ISOFORMS IN CELLULAR FUNCTION ARE NOT YET COMPLETELY UNDERSTOOD, INHIBITION OF HDAC ACTIVITY HAS EMERGED AS A PROMISING APPROACH FOR REVERSING THE ABERRANT EPIGENETIC STATES ASSOCIATED WITH CANCER AND OTHER CHRONIC DISEASES. POTENT NEW ISOFORM-SELECTIVE HDAC INHIBITORS WOULD THEREFORE HELP EXPAND OUR UNDERSTANDING OF THE HDAC ENZYMES AND REPRESENT ATTRACTIVE LEAD COMPOUNDS FOR DRUG DESIGN, ESPECIALLY IF COMBINED WITH HIGH-RESOLUTION STRUCTURAL ANALYSES OF SUCH INHIBITORS TO SHED LIGHT ON THE THREE-DIMENSIONAL PHARMACOPHORIC FEATURES NECESSARY FOR THE FUTURE DESIGN OF MORE POTENT AND SELECTIVE COMPOUNDS. HERE WE PRESENT STRUCTURAL AND FUNCTIONAL ANALYSES OF A SERIES OF BETA-AMINO-ACID-CONTAINING HDAC INHIBITORS INSPIRED BY CYCLIC TETRAPEPTIDE NATURAL PRODUCTS. TO SURVEY A DIVERSE ENSEMBLE OF PHARMACOPHORIC CONFIGURATIONS, WE SYSTEMATICALLY VARIED THE POSITION OF THE BETA-AMINO ACID, AMINO ACID CHIRALITY, FUNCTIONALIZATION OF THE ZN(2+)-COORDINATING AMINO ACID SIDE CHAIN, AND ALKYLATION OF THE BACKBONE AMIDE NITROGEN ATOMS AROUND THE MACROCYCLE. IN MANY CASES, THE COMPOUNDS WERE A SINGLE CONFORMATION IN SOLUTION AND EXHIBITED POTENT ACTIVITIES AGAINST A NUMBER OF HDAC ISOFORMS AS WELL AS EFFECTIVE ANTIPROLIFERATIVE AND CYTOTOXIC ACTIVITIES AGAINST HUMAN TUMOR CELLS. HIGH-RESOLUTION NMR SOLUTION STRUCTURES WERE DETERMINED FOR A SELECTION OF THE INHIBITORS, PROVIDING A USEFUL MEANS OF CORRELATING DETAILED STRUCTURAL INFORMATION WITH POTENCY. THE STRUCTURE-BASED APPROACH DESCRIBED HERE IS EXPECTED TO FURNISH VALUABLE INSIGHTS TOWARD THE FUTURE DESIGN OF MORE SELECTIVE HDAC INHIBITORS. 2009 14 3869 27 JNK1 REGULATES HISTONE ACETYLATION IN TRIGEMINAL NEURONS FOLLOWING CHEMICAL STIMULATION. TRIGEMINAL NERVE FIBERS IN NASAL AND ORAL CAVITIES ARE SENSITIVE TO VARIOUS ENVIRONMENTAL HAZARDOUS STIMULI, WHICH TRIGGER MANY NEUROTOXIC PROBLEMS SUCH AS CHRONIC MIGRAINE HEADACHE AND TRIGEMINAL IRRITATED DISORDERS. HOWEVER, THE ROLE OF JNK KINASE CASCADE AND ITS EPIGENETIC MODULATION OF HISTONE REMODELING IN TRIGEMINAL GANGLION (TG) NEURONS ACTIVATED BY ENVIRONMENTAL NEUROTOXINS REMAINS UNKNOWN. HERE WE INVESTIGATED THE ROLE OF JNK/C-JUN CASCADE IN THE REGULATION OF ACETYLATION OF H3 HISTONE IN TG NEURONS FOLLOWING IN VITRO STIMULATION BY A NEURO-INFLAMMATORY AGENT, MUSTARD OIL (MO). WE FOUND THAT MO STIMULATION ELICITED JNK/C-JUN PATHWAY SIGNIFICANTLY BY ENHANCING PHOSPHO-JNK1, PHOSPHO-C-JUN EXPRESSION, AND C-JUN ACTIVITY, WHICH WERE CORRELATED WITH AN ELEVATED ACETYLATED H3 HISTONE IN TG NEURONS. HOWEVER, INCREASES IN PHOSPHO-C-JUN AND C-JUN ACTIVITY WERE SIGNIFICANTLY BLOCKED BY A JNK INHIBITOR, SP600125. WE ALSO FOUND THAT ALTERED H3 HISTONE REMODELING, ASSESSED BY H3 ACETYLATION IN TRIGGERED TG NEURONS, WAS REDUCED BY SP600125. THE STUDY SUGGESTS THAT THE ACTIVATED JNK SIGNALING IN REGULATION OF HISTONE REMODELING MAY CONTRIBUTE TO NEURO-EPIGENTIC CHANGES IN PERIPHERAL SENSORY NEURONS FOLLOWING ENVIRONMENTAL NEUROTOXIC EXPOSURE. 2008 15 2249 35 EPIGENETIC MODULATION OF MGLU2 RECEPTORS BY HISTONE DEACETYLASE INHIBITORS IN THE TREATMENT OF INFLAMMATORY PAIN. KNOWING THAT EXPRESSION OF METABOTROPIC GLUTAMATE 2 (MGLU2) RECEPTORS IN THE DORSAL ROOT GANGLIA IS REGULATED BY ACETYLATION MECHANISMS, WE EXAMINED THE EFFECT OF TWO SELECTIVE AND CHEMICALLY UNRELATED HISTONE DEACETYLASE (HDAC) INHIBITORS, N-(2-AMINOPHENYL)-4-[N-(PYRIDINE-3-YLMETHOXY-CARBONYL)AMINOMETHYL]BENZAMIDE (MS-275) AND SUBEROYLANILIDE HYDROAMIC ACID (SAHA), IN A MOUSE MODEL OF PERSISTENT INFLAMMATORY PAIN. ALTHOUGH A SINGLE SUBCUTANEOUS INJECTION OF MS-275 (3 MG/KG) OR SAHA (5-50 MG/KG) WAS INEFFECTIVE, A 5-DAY TREATMENT WITH EITHER OF THE TWO HDAC INHIBITORS SUBSTANTIALLY REDUCED THE NOCICEPTIVE RESPONSE IN THE SECOND PHASE OF THE FORMALIN TEST, WHICH REFLECTS THE DEVELOPMENT OF CENTRAL SENSITIZATION IN THE DORSAL HORN OF THE SPINAL CORD. ANALGESIA WAS ABROGATED BY A SINGLE INJECTION OF THE MGLU2/3 RECEPTOR ANTAGONIST (ALPHAS)-ALPHA-AMINO-ALPHA-[(1S,2S)-2-CARBOXYCYCLOPROPYL]-9H-XANTINE-9-PROPANOIC ACID (LY341495; 1 MG/KG, I.P.), WHICH WAS INACTIVE PER SE. BOTH MS-275 AND SAHA UP-REGULATED THE EXPRESSION OF MGLU2 RECEPTORS IN THE DORSAL ROOT GANGLION (DRG) AND SPINAL CORD UNDER CONDITIONS IN WHICH THEY CAUSED ANALGESIA, WITHOUT CHANGING THE EXPRESSION OF MGLU1A, MGLU4, OR MGLU5 RECEPTORS. INDUCTION OF DRG MGLU2 RECEPTORS IN RESPONSE TO SAHA WAS ASSOCIATED WITH INCREASED ACETYLATION OF P65/RELA ON LYSINE 310, A PROCESS THAT ENHANCES THE TRANSCRIPTIONAL ACTIVITY OF P65/RELA AT NUCLEAR FACTOR-KAPPAB-REGULATED GENES. TRANSCRIPTION OF THE MGLU2 RECEPTOR GENE IS KNOWN TO BE ACTIVATED BY P65/RELA IN DRG NEURONS. WE CONCLUDE THAT HDAC INHIBITION PRODUCES ANALGESIA BY UP-REGULATING MGLU2 RECEPTOR EXPRESSION IN THE DRG, AN EFFECT THAT RESULTS FROM THE AMPLIFICATION OF NF-KAPPAB TRANSCRIPTIONAL ACTIVITY. THESE DATA PROVIDE THE FIRST EVIDENCE THAT HDAC INHIBITORS CAUSE ANALGESIA AND SUGGEST THAT HDACS ARE POTENTIAL TARGETS FOR THE EPIGENETIC TREATMENT OF PAIN. 2009 16 687 36 BRAINSTEM BRAIN-DERIVED NEUROTROPHIC FACTOR SIGNALING IS REQUIRED FOR HISTONE DEACETYLASE INHIBITOR-INDUCED PAIN RELIEF. OUR PREVIOUS STUDY DEMONSTRATED THAT PERSISTENT PAIN CAN EPIGENETICALLY SUPPRESS THE TRANSCRIPTION OF GAD2 [ENCODING GLUTAMIC ACID DECARBOXYLASE 65 (GAD65)] AND CONSEQUENTLY IMPAIR THE INHIBITORY FUNCTION OF GABAERGIC SYNAPSES IN CENTRAL PAIN-MODULATING NEURONS. THIS CONTRIBUTES TO THE DEVELOPMENT OF PERSISTENT PAIN SENSITIZATION. HISTONE DEACETYLASE (HDAC) INHIBITORS INCREASED GAD65 ACTIVITY CONSIDERABLY, RESTORED GABA SYNAPTIC FUNCTION, AND RENDERED SENSITIZED PAIN BEHAVIOR LESS PRONOUNCED. HOWEVER, THE MOLECULAR MECHANISMS BY WHICH HDAC REGULATES GABAERGIC TRANSMISSION THROUGH GAD65 UNDER PAIN CONDITIONS ARE UNKNOWN. THIS WORK SHOWED THAT HDAC INHIBITOR-INDUCED INCREASES IN COLOCALIZATION OF GAD65 AND SYNAPTIC PROTEIN SYNAPSIN I ON THE PRESYNAPTIC AXON TERMINALS OF THE NUCLEUS RAPHE MAGNUS (NRM) WERE BLOCKED BY A TRKB RECEPTOR ANTAGONIST K252A [(9S,10R,12R)-2,3,9,10,11,12-HEXAHYDRO-10-HYDROXY-9-METHYL-1-OXO-9,12-EPOXY-1H-DIINDOLO[1,2,3-FG:3',2',1'-KL]PYRROLO[3,4-I][1,6]BENZODIAZOCINE-10-CARBOXYLIC ACID METHYL ESTER], INDICATING THAT BDNF-TRKB SIGNALING MAY BE REQUIRED IN GAD65 MODULATION OF GABA SYNAPTIC FUNCTION. AT THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROMOTER, HDAC INHIBITORS INDUCED SIGNIFICANT INCREASES IN H3 HYPERACETYLATION, CONSISTENT WITH THE INCREASE IN BDNF MRNA AND TOTAL PROTEINS. ALTHOUGH EXOGENOUS BDNF FACILITATED GABA MINIATURE INHIBITORY POSTSYNAPTIC CURRENTS AND GAD65 ACCUMULATION IN NRM NEURONAL SYNAPSES IN NORMAL RATS, IT FAILED TO DO SO IN ANIMALS SUBJECTED TO PERSISTENT INFLAMMATION. IN ADDITION, BLOCKADE OF THE TRKB RECEPTOR WITH K252A HAS NO EFFECT ON MINIATURE INHIBITORY POSTSYNAPTIC CURRENTS AND SYNAPTIC GAD65 ACCUMULATION UNDER NORMAL CONDITIONS. IN ADDITION, THE ANALGESIC EFFECTS OF HDAC INHIBITORS ON BEHAVIOR WERE BLOCKED BY NRM INFUSION OF K252A. THESE FINDINGS SUGGEST THAT BDNF-TRKB SIGNALING IS REQUIRED FOR DRUGS THAT REVERSE THE EPIGENETIC EFFECTS OF CHRONIC PAIN AT THE GENE LEVEL, SUCH AS HDAC INHIBITORS. 2015 17 5937 38 TARGETING HISTONE DEACETYLASE ACTIVITY IN RHEUMATOID ARTHRITIS AND ASTHMA AS PROTOTYPES OF INFLAMMATORY DISEASE: SHOULD WE KEEP OUR HATS ON? CELLULAR ACTIVATION, PROLIFERATION AND SURVIVAL IN CHRONIC INFLAMMATORY DISEASES IS REGULATED NOT ONLY BY ENGAGEMENT OF SIGNAL TRANS-DUCTION PATHWAYS THAT MODULATE TRANSCRIPTION FACTORS REQUIRED FOR THESE PROCESSES, BUT ALSO BY EPIGENETIC REGULATION OF TRANSCRIPTION FACTOR ACCESS TO GENE PROMOTER REGIONS. HISTONE ACETYL TRANSFERASES COORDINATE THE RECRUITMENT AND ACTIVATION OF TRANSCRIPTION FACTORS WITH CONFORMATIONAL CHANGES IN HISTONES THAT ALLOW GENE PROMOTER EXPOSURE. HISTONE DEACETYLASES (HDACS) COUNTERACT HISTONE ACETYL TRANSFERASE ACTIVITY THROUGH THE TARGETING OF BOTH HISTONES AS WELL AS NONHISTONE SIGNAL TRANSDUCTION PROTEINS IMPORTANT IN INFLAMMATION. NUMEROUS STUDIES HAVE INDICATED THAT DEPRESSED HDAC ACTIVITY IN PATIENTS WITH INFLAMMATORY AIRWAY DISEASES MAY CONTRIBUTE TO LOCAL PROINFLAMMATORY CYTOKINE PRODUCTION AND DIMINISH PATIENT RESPONSES TO CORTICOSTEROID TREATMENT. RECENT OBSERVATIONS THAT HDAC ACTIVITY IS DEPRESSED IN RHEUMATOID ARTHRITIS PATIENT SYNOVIAL TISSUE HAVE PREDICTED THAT STRATEGIES RESTORING HDAC FUNCTION MAY BE THERAPEUTIC IN THIS DISEASE AS WELL. PHARMACOLOGICAL INHIBITORS OF HDAC ACTIVITY, HOWEVER, HAVE DEMONSTRATED POTENT THERAPEUTIC EFFECTS IN ANIMAL MODELS OF ARTHRITIS AND OTHER CHRONIC INFLAMMATORY DISEASES. IN THE PRESENT REVIEW WE ASSESS AND RECONCILE THESE OUTWARDLY PARADOXICAL STUDY RESULTS TO PROVIDE A WORKING MODEL FOR HOW ALTERATIONS IN HDAC ACTIVITY MAY CONTRIBUTE TO PATHOLOGY IN RHEUMATOID ARTHRITIS, AND HIGHLIGHT KEY QUESTIONS TO BE ANSWERED IN THE PRECLINICAL EVALUATION OF COMPOUNDS MODULATING THESE ENZYMES. 2008 18 2120 24 EPIGENETIC HISTONE MODIFICATIONS IN A CLINICALLY RELEVANT RAT MODEL OF CHRONIC ETHANOL-BINGE-MEDIATED LIVER INJURY. PURPOSE: ETHANOL BINGE AUGMENTS LIVER INJURY AFTER CHRONIC ETHANOL CONSUMPTION IN HUMANS, BUT THE MECHANISM BEHIND THE ENHANCED LIVER INJURY BY ETHANOL BINGE IS NOT KNOWN. IN THIS STUDY WE USED A CLINICALLY RELEVANT RAT MODEL IN WHICH LIVER INJURY IS AMPLIFIED BY BINGE AFTER CHRONIC ETHANOL TREATMENT AND INVESTIGATED THE IMPORTANCE OF HISTONE MODIFICATIONS. METHODS: EIGHT-WEEK-OLD SPRAGUE-DAWLEY RATS WERE FED ETHANOL IN A LIQUID DIET FOR 4 WEEKS. CONTROL RATS WERE FED AN ISOCALORIC LIQUID DIET. THIS WAS FOLLOWED BY THREE BINGE ADMINISTRATIONS OF ETHANOL (INTRAGASTRIC 5 G/KG BODY WEIGHT, 12 H APART). IN THE CONTROL, ETHANOL WAS REPLACED BY WATER. FOUR HOURS AFTER THE LAST BINGE ADMINISTRATION, LIVER SAMPLES WERE ANALYZED FOR HISTONE MODIFICATIONS AND PARAMETERS OF LIVER INJURY. RESULTS: CHRONIC ETHANOL ADMINISTRATION ALONE CAUSED AN INCREASE IN HISTONE H3 SER10 AND SER28 (H3S10 OR S28) PHOSPHORYLATION, AND BINGE ETHANOL REDUCED THEIR LEVELS. LEVELS OF DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10) INCREASED AFTER ACUTE BINGE ETHANOL AND REMAINED SAME AFTER CHRONIC ETHANOL BINGE. IN CONTRAST, HISTONE H3 LYSINE-9 ACETYLATION (H3ACK9) WAS NOT INCREASED AFTER CHRONIC ETHANOL BUT INCREASED SIGNIFICANTLY AFTER ACUTE BINGE AND CHRONIC ETHANOL BINGE. INCREASE IN HISTONE ACETYLATION WAS ACCOMPANIED BY INCREASED PHOSPHO-ERK1/2 IN THE NUCLEAR EXTRACTS. INCREASED ACETYLATION AFTER CHRONIC ETHANOL BINGE WAS ALSO ACCOMPANIED BY INCREASED PROTEIN LEVELS OF GCN5 HISTONE ACETYL TRANSFERASE AND A MODEST INCREASE IN HDAC3 IN THE NUCLEUS. HISTONE LYSINE-9 DIMETHYLATION WAS SIGNIFICANTLY INCREASED AFTER CHRONIC ETHANOL BINGE. CHRONIC ETHANOL BINGE ALSO RESULTED IN A DECREASE IN THE SAM:SAH RATIO WITH A RELATIVE DECREASE OF SAM LEVELS AND A CORRESPONDING INCREASE IN SAH LEVELS. CONCLUSIONS: ETHANOL BINGE AFTER CHRONIC ETHANOL ALTERED THE PROFILE OF SITE-SPECIFIC HISTONE MODIFICATIONS AND MAY UNDERLIE THE MECHANISM OF AUGMENTED LIVER INJURY BY CHRONIC-ETHANOL-BINGE-TREATED RATS. 2014 19 3832 24 INVOLVEMENT OF SPINAL SIRT1 IN DEVELOPMENT OF CHRONIC CONSTRICTION INJURY INDUCED NEUROPATHIC PAIN IN RATS. IT IS KNOWN THAT THE EPIGENETIC PROCESS OF HISTONE ACETYLATION IS INVOLVED IN THE NEUROPATHIC PAIN. THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER SIRTUIN TYPE 1 (SIRT1), AN NAD(+) DEPENDENT DEACETYLASE, AFFECTED ALLODYNIA AND HYPERALGESIA IN NEUROPATHIC PAIN. THE NEUROPATHIC PAIN MODEL WAS ESTABLISHED BY LIGATURE OF THE RIGHT SCIATIC NERVE TO INDUCE CHRONIC CONSTRICTION INJURY (CCI) IN RATS. HISTONE ACETYLTRANSFERASE (HAT) ACTIVITY WAS INCREASED AND, AND HISTONE DEACETYLASE (HDAC) ACTIVITY WAS DECLINED IN TISSUE OF THE SPINAL DORSA HORN IN CCI RATES BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA). THE PERSISTENT HYPERALGESIA AND ALLODYNIA CAUSED BY CCI WERE ASSOCIATED WITH DOWNREGULATION OF SIRT1 AND UPREGULATION OF ACETYLATED-H3 (AC-H3) IN TISSUE OF THE SPINAL CORD BY WESTERN BLOT ASSAY, WHICH WAS REVERSED AFTER INTRATHECAL INJECTION OF SIRT1 AGONIST SRT1720. SRT1720 TREATMENT ACHIEVED ANALGESIC THROUGH INHIBITING THE ACETYLATION OF NUCLEAR FACTOR KAPPA B (NF-KAPPAB) AND BLOCKING THE RELEASES OF THE INFLAMMATORY FACTORS INCLUDING TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) AND INTERLEUKIN (IL)-6 BY MEANS OF WESTERN BLOT AND REAL-TIME QUANTITATIVE PCR (RT-PCR), RESPECTIVELY. TAKEN TOGETHER, THESE DATA SUGGEST THAT SIRT1 IN THE SPINAL CORD PLAYS AN IMPORTANT ROLE IN THE NEUROPATHIC PAIN IN THE RAT MODEL. 2018 20 2353 26 EPIGENETIC REGULATION OF OPIOID-INDUCED HYPERALGESIA, DEPENDENCE, AND TOLERANCE IN MICE. REPEATED ADMINISTRATION OF OPIOIDS SUCH AS MORPHINE INDUCES PERSISTENT BEHAVIORAL CHANGES INCLUDING OPIOID-INDUCED HYPERALGESIA (OIH), TOLERANCE, AND PHYSICAL DEPENDENCE. IN THE CURRENT WORK WE EXPLORED HOW THE BALANCE OF HISTONE ACETYLTRANSFERASE (HAT) VERSUS HISTONE DEACETYLASE (HDAC) MIGHT REGULATE THESE MORPHINE-INDUCED CHANGES. NOCICEPTIVE THRESHOLDS, ANALGESIA, AND PHYSICAL DEPENDENCE WERE ASSESSED DURING AND FOR A PERIOD OF SEVERAL WEEKS AFTER MORPHINE EXPOSURE. TO PROBE THE ROLES OF HISTONE ACETYLATION, THE HAT INHIBITOR CURCUMIN OR A SELECTIVE HDAC INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) WAS ADMINISTERED DAILY TO GROUPS OF ANIMALS. HISTONE ACETYLATION IN SPINAL CORD WAS ASSESSED BY WESTERN BLOT AND IMMUNOHISTOCHEMISTRY. CONCURRENT ADMINISTRATION OF CURCUMIN WITH MORPHINE FOR 4 DAYS SIGNIFICANTLY REDUCED DEVELOPMENT OF OPIOID-INDUCED MECHANICAL ALLODYNIA, THERMAL HYPERALGESIA, TOLERANCE, AND PHYSICAL DEPENDENCE. CONVERSELY, THE HDAC INHIBITOR SAHA ENHANCED THESE RESPONSES. INTERESTINGLY, SAHA TREATMENT AFTER THE TERMINATION OF OPIOID ADMINISTRATION SUSTAINED THESE BEHAVIORAL CHANGES FOR AT LEAST 4 WEEKS. HISTONE H3 ACETYLATION IN THE DORSAL HORN OF THE SPINAL CORD WAS INCREASED AFTER CHRONIC MORPHINE TREATMENT, BUT H4 ACETYLATION WAS UNCHANGED. MOREOVER, WE OBSERVED A DECREASE IN HDAC ACTIVITY IN THE SPINAL CORDS OF MORPHINE-TREATED MICE WHILE OVERALL HAT ACTIVITY WAS UNCHANGED, SUGGESTING A SHIFT TOWARD A STATE OF ENHANCED HISTONE ACETYLATION. PERSPECTIVE: THE CURRENT STUDY INDICATES THAT EPIGENETIC MECHANISMS PLAY A CRUCIAL ROLE IN OPIOID-INDUCED LONG-LASTING NEUROPLASTICITY. THESE RESULTS PROVIDE NEW SIGHT INTO UNDERSTANDING THE MECHANISMS OF OPIOID-INDUCED NEUROPLASTICITY AND SUGGEST NEW STRATEGIES TO LIMIT OPIOID ABUSE POTENTIAL AND INCREASE THE VALUE OF THESE DRUGS AS ANALGESICS. 2013