1 1689 155 DUAL HDAC/BRD4 INHIBITORS RELIEVES NEUROPATHIC PAIN BY ATTENUATING INFLAMMATORY RESPONSE IN MICROGLIA AFTER SPARED NERVE INJURY. DESPITE THE EFFORT ON DEVELOPING NEW TREATMENTS, THERAPY FOR NEUROPATHIC PAIN IS STILL A CLINICAL CHALLENGE AND COMBINATION THERAPY REGIMES OF TWO OR MORE DRUGS ARE OFTEN NEEDED TO IMPROVE EFFICACY. ACCUMULATING EVIDENCE SHOWS AN ALTERED EXPRESSION AND ACTIVITY OF HISTONE ACETYLATION ENZYMES IN CHRONIC PAIN CONDITIONS AND RESTORATION OF THESE ABERRANT EPIGENETIC MODIFICATIONS PROMOTES PAIN-RELIEVING ACTIVITY. RECENT STUDIES SHOWED A SYNERGISTIC ACTIVITY IN NEUROPATHIC PAIN MODELS BY COMBINATION OF HISTONE DEACETYLASES (HDACS) AND BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) INHIBITORS. ON THESE PREMISES, THE PRESENT STUDY INVESTIGATED THE PHARMACOLOGICAL PROFILE OF NEW DUAL HDAC/BRD4 INHIBITORS, NAMED SUM52 AND SUM35, IN THE SPARED NERVE INJURY (SNI) MODEL IN MICE AS INNOVATIVE STRATEGY TO SIMULTANEOUSLY INHIBIT HDACS AND BETS. INTRANASAL ADMINISTRATION OF SUM52 AND SUM35 ATTENUATED THERMAL AND MECHANICAL HYPERSENSITIVITY IN THE ABSENCE OF LOCOMOTOR SIDE EFFECTS. BOTH DUAL INHIBITORS SHOWED A PREFERENTIAL INTERACTION WITH BRD4-BD2 DOMAIN, AND SUM52 RESULTED THE MOST ACTIVE COMPOUND. SUM52 REDUCED MICROGLIA-MEDIATED SPINAL NEUROINFLAMMATION IN SPINAL CORD SECTIONS OF SNI MICE AS SHOWED BY REDUCTION OF IBA1 IMMUNOSTAINING, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) EXPRESSION, P65 NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 MAPK OVER-PHOSPHORYLATION. A ROBUST DECREASE OF THE SPINAL PROINFLAMMATORY CYTOKINES CONTENT (IL-6, IL-1SS) WAS ALSO OBSERVED AFTER SUM52 TREATMENT. PRESENT RESULTS, SHOWING THE PAIN-RELIEVING ACTIVITY OF HDAC/BRD4 DUAL INHIBITORS, INDICATE THAT THE SIMULTANEOUS MODULATION OF BET AND HDAC ACTIVITY BY A SINGLE MOLECULE ACTING AS MULTI-TARGET AGENT MIGHT REPRESENT A PROMISE FOR NEUROPATHIC PAIN RELIEF.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2 4861  33 ORGANIC ANION TRANSPORTER 1 IS AN HDAC4-REGULATED MEDIATOR OF NOCICEPTIVE HYPERSENSITIVITY IN MICE. PERSISTENT PAIN IS SUSTAINED BY MALADAPTIVE CHANGES IN GENE TRANSCRIPTION RESULTING IN ALTERED FUNCTION OF THE RELEVANT CIRCUITS; THERAPIES ARE STILL UNSATISFACTORY. THE EPIGENETIC MECHANISMS AND AFFECTED GENES LINKING NOCICEPTIVE ACTIVITY TO TRANSCRIPTIONAL CHANGES AND PATHOLOGICAL SENSITIVITY ARE UNCLEAR. HERE, WE FOUND THAT, AMONG SEVERAL HISTONE DEACETYLASES (HDACS), SYNAPTIC ACTIVITY SPECIFICALLY AFFECTS HDAC4 IN MURINE SPINAL CORD DORSAL HORN NEURONS. NOXIOUS STIMULI THAT INDUCE LONG-LASTING INFLAMMATORY HYPERSENSITIVITY CAUSE NUCLEAR EXPORT AND INACTIVATION OF HDAC4. THE DEVELOPMENT OF INFLAMMATION-ASSOCIATED MECHANICAL HYPERSENSITIVITY, BUT NEITHER ACUTE NOR BASAL SENSITIVITY, IS IMPAIRED BY THE EXPRESSION OF A CONSTITUTIVELY NUCLEAR LOCALIZED HDAC4 MUTANT. NEXT GENERATION RNA-SEQUENCING REVEALED AN HDAC4-REGULATED GENE PROGRAM COMPRISING MEDIATORS OF SENSITIZATION INCLUDING THE ORGANIC ANION TRANSPORTER OAT1, KNOWN FOR ITS RENAL TRANSPORT FUNCTION. USING PHARMACOLOGICAL AND MOLECULAR TOOLS TO MODULATE OAT1 ACTIVITY OR EXPRESSION, WE CAUSALLY LINK OAT1 TO PERSISTENT INFLAMMATORY HYPERSENSITIVITY IN MICE. THUS, HDAC4 IS A KEY EPIGENETIC REGULATOR THAT TRANSLATES NOCICEPTIVE ACTIVITY INTO SENSITIZATION BY REGULATING OAT1, WHICH IS A POTENTIAL TARGET FOR PAIN-RELIEVING THERAPIES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3 5474  39 RESTORATION OF HISTONE ACETYLATION AMELIORATES DISEASE AND METABOLIC ABNORMALITIES IN A FUS MOUSE MODEL. DYSREGULATION OF EPIGENETIC MECHANISMS IS EMERGING AS A CENTRAL EVENT IN NEURODEGENERATIVE DISORDERS, INCLUDING AMYOTROPHIC LATERAL SCLEROSIS (ALS). IN MANY MODELS OF NEURODEGENERATION, GLOBAL HISTONE ACETYLATION IS DECREASED IN THE AFFECTED NEURONAL TISSUES. HISTONE ACETYLATION IS CONTROLLED BY THE ANTAGONISTIC ACTIONS OF TWO PROTEIN FAMILIES -THE HISTONE ACETYLTRANSFERASES (HATS) AND THE HISTONE DEACETYLASES (HDACS). DRUGS INHIBITING HDAC ACTIVITY ARE ALREADY USED IN THE CLINIC AS ANTI-CANCER AGENTS. THE AIM OF THIS STUDY WAS TO EXPLORE THE THERAPEUTIC POTENTIAL OF HDAC INHIBITION IN THE CONTEXT OF ALS. WE DISCOVERED THAT TRANSGENIC MICE OVEREXPRESSING WILD-TYPE FUS ("TG FUS+/+"), WHICH RECAPITULATE MANY ASPECTS OF HUMAN ALS, SHOWED REDUCED GLOBAL HISTONE ACETYLATION AND ALTERATIONS IN METABOLIC GENE EXPRESSION, RESULTING IN A DYSREGULATED METABOLIC HOMEOSTASIS. CHRONIC TREATMENT OF TG FUS+/+ MICE WITH ACY-738, A POTENT HDAC INHIBITOR THAT CAN CROSS THE BLOOD-BRAIN BARRIER, AMELIORATED THE MOTOR PHENOTYPE AND SUBSTANTIALLY EXTENDED THE LIFE SPAN OF THE TG FUS+/+ MICE. AT THE MOLECULAR LEVEL, ACY-738 RESTORED GLOBAL HISTONE ACETYLATION AND METABOLIC GENE EXPRESSION, THEREBY RE-ESTABLISHING METABOLITE LEVELS IN THE SPINAL CORD. TAKEN TOGETHER, OUR FINDINGS LINK EPIGENETIC ALTERATIONS TO METABOLIC DYSREGULATION IN ALS PATHOLOGY, AND HIGHLIGHT ACY-738 AS A POTENTIAL THERAPEUTIC STRATEGY TO TREAT THIS DEVASTATING DISEASE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4 2470  42 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	

5  889  29 CHRONIC DIETARY ADMINISTRATION OF VALPROIC ACID PROTECTS NEURONS OF THE RAT NUCLEUS BASALIS MAGNOCELLULARIS FROM IBOTENIC ACID NEUROTOXICITY. VALPROIC ACID (VPA) HAS BEEN USED FOR MANY YEARS AS A DRUG OF CHOICE FOR EPILEPSY AND MOOD DISORDERS. RECENTLY, EVIDENCE HAS BEEN PROPOSED FOR A WIDE SPECTRUM OF ACTIONS OF THIS DRUG, INCLUDING ANTITUMORAL AND NEUROPROTECTIVE PROPERTIES. VALPROIC ACID-MEDIATED NEUROPROTECTION IN VIVO HAS BEEN SO FAR DEMONSTRATED IN A LIMITED NUMBER OF EXPERIMENTAL MODELS. IN THIS STUDY, WE HAVE TESTED THE NEUROPROTECTIVE POTENTIAL OF CHRONIC (4 + 1 WEEKS) DIETARY ADMINISTRATION OF VPA ON DEGENERATION OF CHOLINERGIC AND GABAERGIC NEURONS OF THE RAT NUCLEUS BASALIS MAGNOCELLULARIS (NBM), INJECTED WITH THE EXCITOTOXIN, IBOTENIC ACID (IBO), AN ANIMAL MODELS THAT IS RELEVANT FOR ALZHEIMER'S DISEASE-LIKE NEURODEGENERATION. WE SHOW THAT VPA TREATMENT SIGNIFICANTLY PROTECTS BOTH CHOLINERGIC AND GABAERGIC NEURONS PRESENT IN THE INJECTED AREA FROM THE EXCITOTOXIC INSULT. A SIGNIFICANT LEVEL OF NEUROPROTECTION, IN PARTICULAR, IS EXERTED TOWARDS THE CHOLINERGIC NEURONS OF THE NBM PROJECTING TO THE CORTEX, AS DEMONSTRATED BY THE SUBSTANTIALLY HIGHER LEVELS OF CHOLINERGIC MARKERS MAINTAINED IN THE TARGET CORTICAL AREA OF VPA-TREATED RATS AFTER IBO INJECTION IN THE NBM. WE FURTHER SHOW THAT CHRONIC VPA ADMINISTRATION RESULTS IN INCREASED ACETYLATION OF HISTONE H3 IN BRAIN, CONSISTENT WITH THE HISTONE DEACETYLASE INHIBITORY ACTION OF VPA AND PUTATIVELY LINKED TO A NEUROPROTECTIVE ACTION OF THE DRUG MEDIATED AT THE EPIGENETIC LEVEL.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6 4499  27 MORPHINE WITHDRAWAL PRODUCES ERK-DEPENDENT AND ERK-INDEPENDENT EPIGENETIC MARKS IN NEURONS OF THE NUCLEUS ACCUMBENS AND LATERAL SEPTUM. EPIGENETIC CHANGES SUCH AS COVALENT MODIFICATIONS OF HISTONE PROTEINS REPRESENT COMPLEX MOLECULAR SIGNATURES THAT PROVIDE A CELLULAR MEMORY OF PREVIOUSLY EXPERIENCED STIMULI WITHOUT IRREVERSIBLE CHANGES OF THE GENETIC CODE. IN THIS STUDY WE SHOW THAT NEW GENE EXPRESSION INDUCED IN VIVO BY MORPHINE WITHDRAWAL OCCURS WITH CONCOMITANT EPIGENETIC MODIFICATIONS IN BRAIN REGIONS CRITICALLY INVOLVED IN DRUG-DEPENDENT BEHAVIORS. WE FOUND THAT NALOXONE-PRECIPITATED WITHDRAWAL, BUT NOT CHRONIC MORPHINE ADMINISTRATION, CAUSED A STRONG INDUCTION OF PHOSPHO-HISTONE H3 IMMUNOREACTIVITY IN THE NUCLEUS ACCUMBENS (NAC) SHELL/CORE AND IN THE LATERAL SEPTUM (LS), A CHANGE THAT WAS ACCOMPANIED BY AUGMENTED H3 ACETYLATION (LYS14) IN NEURONS OF THE NAC SHELL. MORPHINE WITHDRAWAL INDUCED THE PHOSPHORYLATION OF THE EPIGENETIC FACTOR METHYL-CPG-BINDING PROTEIN 2 (MECP2) IN SER421 BOTH IN THE LS AND THE NAC SHELL. THESE EPIGENETIC CHANGES WERE ACCOMPANIED BY THE ACTIVATION OF MEMBERS OF THE ERK PATHWAY AS WELL AS INCREASED EXPRESSION OF THE IMMEDIATE EARLY GENES (IEG) C-FOS AND ACTIVITY-REGULATED CYTOSKELETON-ASSOCIATED PROTEIN (ARC/ARG3.1). USING A PHARMACOLOGICAL APPROACH, WE FOUND THAT H3 PHOSPHORYLATION AND IEG EXPRESSION WERE PARTIALLY DEPENDENT ON ERK ACTIVATION, WHILE MECP2 PHOSPHORYLATION WAS FULLY ERK-INDEPENDENT. THESE FINDINGS PROVIDE NEW IMPORTANT INFORMATION ON THE ROLE OF THE ERK PATHWAY IN THE REGULATION OF EPIGENETIC MARKS AND GENE EXPRESSION THAT MAY CONCUR TO REGULATE IN VIVO THE CELLULAR CHANGES UNDERLYING THE ONSET OF THE OPIOID WITHDRAWAL SYNDROME.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  804  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8 5347  32 RARBETA AGONIST DRUG (C286) DEMONSTRATES EFFICACY IN A PRE-CLINICAL NEUROPATHIC PAIN MODEL RESTORING MULTIPLE PATHWAYS VIA DNA REPAIR MECHANISMS. NEUROPATHIC PAIN (NP) IS ASSOCIATED WITH PROFOUND GENE EXPRESSION ALTERATIONS WITHIN THE NOCICEPTIVE SYSTEM. DNA MECHANISMS, SUCH AS EPIGENETIC REMODELING AND REPAIR PATHWAYS HAVE BEEN IMPLICATED IN NP. HERE WE HAVE USED A RAT MODEL OF PERIPHERAL NERVE INJURY TO STUDY THE EFFECT OF A RECENTLY DEVELOPED RARBETA AGONIST, C286, CURRENTLY UNDER CLINICAL RESEARCH, IN NP. A 4-WEEK TREATMENT INITIATED 2 DAYS AFTER THE INJURY NORMALIZED PAIN SENSATION. GENOME-WIDE AND PATHWAY ENRICHMENT ANALYSIS SHOWED THAT MULTIPLE MECHANISMS PERSISTENTLY ALTERED IN THE SPINAL CORD WERE RESTORED TO PREINJURY LEVELS BY THE AGONIST. CONCOMITANT UPREGULATION OF DNA REPAIR PROTEINS, ATM AND BRCA1, THE LATTER BEING REQUIRED FOR C286-MEDIATED PAIN MODULATION, SUGGESTS THAT EARLY DNA REPAIR MAY BE IMPORTANT TO PREVENT PHENOTYPIC EPIGENETIC IMPRINTS IN NP. THUS, C286 IS A PROMISING DRUG CANDIDATE FOR NEUROPATHIC PAIN AND DNA REPAIR MECHANISMS MAY BE USEFUL THERAPEUTIC TARGETS TO EXPLORE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9 6148  33 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	
                                                                                                                                                                                                                             
10 5503  26 RGS9-2--CONTROLLED ADAPTATIONS IN THE STRIATUM DETERMINE THE ONSET OF ACTION AND EFFICACY OF ANTIDEPRESSANTS IN NEUROPATHIC PAIN STATES. THE STRIATAL PROTEIN REGULATOR OF G-PROTEIN SIGNALING 9-2 (RGS9-2) PLAYS A KEY MODULATORY ROLE IN OPIOID, MONOAMINE, AND OTHER G-PROTEIN-COUPLED RECEPTOR RESPONSES. HERE, WE USE THE MURINE SPARED-NERVE INJURY MODEL OF NEUROPATHIC PAIN TO INVESTIGATE THE MECHANISM BY WHICH RGS9-2 IN THE NUCLEUS ACCUMBENS (NAC), A BRAIN REGION INVOLVED IN MOOD, REWARD, AND MOTIVATION, MODULATES THE ACTIONS OF TRICYCLIC ANTIDEPRESSANTS (TCAS). PREVENTION OF RGS9-2 ACTION IN THE NAC INCREASES THE EFFICACY OF THE TCA DESIPRAMINE AND DRAMATICALLY ACCELERATES ITS ONSET OF ACTION. BY CONTROLLING THE ACTIVATION OF EFFECTOR MOLECULES BY G PROTEIN ALPHA AND BETAGAMMA SUBUNITS, RGS9-2 AFFECTS SEVERAL PROTEIN INTERACTIONS, PHOSPHOPROTEIN LEVELS, AND THE FUNCTION OF THE EPIGENETIC MODIFIER HISTONE DEACETYLASE 5, WHICH ARE IMPORTANT FOR TCA RESPONSIVENESS. FURTHERMORE, INFORMATION FROM RNA-SEQUENCING ANALYSIS REVEALS THAT RGS9-2 IN THE NAC AFFECTS THE EXPRESSION OF MANY GENES KNOWN TO BE INVOLVED IN NOCICEPTION, ANALGESIA, AND ANTIDEPRESSANT DRUG ACTIONS. OUR FINDINGS PROVIDE NOVEL INFORMATION ON NAC-SPECIFIC CELLULAR MECHANISMS THAT MEDIATE THE ACTIONS OF TCAS IN NEUROPATHIC PAIN STATES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11 6000  35 THE ACTIVATION OF HISTONE DEACETYLASES 4 PREVENTED ENDOTHELIAL DYSFUNCTION: A CRUCIAL MECHANISM OF HUANGQIGUIZHIWUWU DECOCTION IN IMPROVING MICROCIRCULATION DYSFUNCTION IN DIABETES. ETHNOPHARMACOLOGICAL RELEVANCE: THE REGULATION OF EPIGENETIC FACTORS IS CONSIDERED A CRUCIAL TARGET FOR SOLVING COMPLEX CHRONIC DISEASES SUCH AS CARDIO-CEREBROVASCULAR DISEASES. HUANGQIGUIZHIWUWU DECOCTION (HGWWD), A CLASSIC CHINESE PRESCRIPTION, IS MAINLY USED TO TREAT VARIOUS VASCULAR DISEASES. ALTHOUGH OUR PREVIOUS STUDIES REPORTED THAT HGWWD COULD EFFECTIVELY PREVENT VASCULAR DYSFUNCTION IN DIABETIC RODENT MODELS, THE PRECISE MECHANISM IS STILL ELUSIVE. AIM OF THE STUDY: IN THIS STUDY, WE INVESTIGATED THE EPIGENETIC MECHANISMS OF MODULATING THE DAMAGE OF VASCULAR ENDOTHELIAL CELLS IN DIABETES BY HGWWD. METHODS: WE FIRST ANALYZED COMMON ACTIVE COMPONENTS OF HGWWD BY USING HPLC-Q-TOF-MS/MS ANALYSIS, AND PREDICTED THE ISOFORMS OF HISTONE DEACETYLASE (HDAC) THAT CAN POTENTIALLY COMBINE THE ABOVE ACTIVE COMPONENTS BY SYSTEMS PHARMACOLOGY. NEXT, WE SCREENED THE INVOLVEMENT OF SPECIFIC HDAC ISOFORMS IN THE PROTECTIVE EFFECT OF HGWWD ON VASCULAR INJURY BY USING PHARMACOLOGICAL BLOCKADE COMBINED WITH THE EVALUATION OF VASCULAR FUNCTION IN VIVO AND IN VITRO. RESULTS: FIRSTLY, HDAC1, HDAC2, HDAC3, HDAC4, HDAC6, HDAC7, SIRT2, AND SIRT3 HAVE BEEN IMPLICATED WITH THE POSSIBILITY OF BINDING TO THE THIRTY-ONE COMMON ACTIVE COMPONENTS IN HGWWD. FURTHERMORE, THE PROTECTIVE EFFECT OF HGWWD IS REVERSED BY BOTH TSA (HDAC INHIBITOR) AND MC1568 (CLASS II HDAC INHIBITOR) ON VASCULAR IMPAIRMENT ACCOMPANIED BY REDUCED AORTIC HDAC ACTIVITY IN STZ MICE. FINALLY, INHIBITION OF HDAC4 BLOCKED THE PROTECTIVE EFFECT OF HGWWD ON MICROVASCULAR AND ENDOTHELIAL DYSFUNCTION IN DIABETIC MICE. CONCLUSIONS: THESE RESULTS PROVE THE KEY ROLE OF HDAC4 IN DIABETES-INDUCED MICROVASCULAR DYSFUNCTION AND UNDERLYING EPIGENETIC MECHANISMS FOR THE PROTECTIVE EFFECT OF HGWWD IN DIABETES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12  984  31 CHRONIC PSYCHOLOGICAL STRESS ALTERS GENE EXPRESSION IN RAT COLON EPITHELIAL CELLS PROMOTING CHROMATIN REMODELING, BARRIER DYSFUNCTION AND INFLAMMATION. CHRONIC STRESS IS COMMONLY ASSOCIATED WITH ENHANCED ABDOMINAL PAIN (VISCERAL HYPERSENSITIVITY), BUT THE CELLULAR MECHANISMS UNDERLYING HOW CHRONIC STRESS INDUCES VISCERAL HYPERSENSITIVITY ARE POORLY UNDERSTOOD. IN THIS STUDY, WE EXAMINED CHANGES IN GENE EXPRESSION IN COLON EPITHELIAL CELLS FROM A RAT MODEL USING RNA-SEQUENCING TO EXAMINE STRESS-INDUCED CHANGES TO THE TRANSCRIPTOME. FOLLOWING CHRONIC STRESS, THE MOST SIGNIFICANTLY UP-REGULATED GENES INCLUDED ATG16L1, COQ10B, DCAF13, NAT2, PTBP2, RRAS2, SPINK4 AND DOWN-REGULATED GENES INCLUDING ABAT, CITED2, CNNM2, DAB2IP, PLEKHM1, SCD2, AND TAB2. THE PRIMARY ALTERED BIOLOGICAL PROCESSES REVEALED BY NETWORK ENRICHMENT ANALYSIS WERE INFLAMMATION/IMMUNE RESPONSE, TISSUE MORPHOGENESIS AND DEVELOPMENT, AND NUCLEOSOME/CHROMATIN ASSEMBLY. THE MOST SIGNIFICANTLY DOWN-REGULATED PROCESS WAS THE DIGESTIVE SYSTEM DEVELOPMENT/FUNCTION, WHEREAS THE MOST SIGNIFICANTLY UP-REGULATED PROCESSES WERE INFLAMMATORY RESPONSE, ORGANISMAL INJURY, AND CHROMATIN REMODELING MEDIATED BY H3K9 METHYLATION. FURTHERMORE, A SUBPOPULATION OF STRESSED RATS DEMONSTRATED VERY SIGNIFICANTLY ALTERED GENE EXPRESSION AND TRANSCRIPT ISOFORMS, ENRICHED FOR THE DIFFERENTIAL EXPRESSION OF GENES INVOLVED IN THE INFLAMMATORY RESPONSE, INCLUDING UPREGULATION OF CYTOKINE AND CHEMOKINE RECEPTOR GENE EXPRESSION COUPLED WITH DOWNREGULATION OF EPITHELIAL ADHERENS AND TIGHT JUNCTION MRNAS. IN SUMMARY, THESE FINDINGS SUPPORT THAT CHRONIC STRESS IS ASSOCIATED WITH INCREASED LEVELS OF CYTOKINES AND CHEMOKINES, THEIR DOWNSTREAM SIGNALING PATHWAYS COUPLED TO DYSREGULATION OF INTESTINAL CELL DEVELOPMENT AND FUNCTION. EPIGENETIC REGULATION OF CHROMATIN REMODELING LIKELY PLAYS A PROMINENT ROLE IN THIS PROCESS. RESULTS ALSO SUGGEST THAT SUPER ENHANCERS PLAY A PRIMARY ROLE IN CHRONIC STRESS-ASSOCIATED INTESTINAL BARRIER DYSFUNCTION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13 2246  29 EPIGENETIC MODULATION OF INFLAMMATION AND SYNAPTIC PLASTICITY PROMOTES RESILIENCE AGAINST STRESS IN MICE. MAJOR DEPRESSIVE DISORDER IS ASSOCIATED WITH ABNORMALITIES IN THE BRAIN AND THE IMMUNE SYSTEM. CHRONIC STRESS IN ANIMALS SHOWED THAT EPIGENETIC AND INFLAMMATORY MECHANISMS PLAY IMPORTANT ROLES IN MEDIATING RESILIENCE AND SUSCEPTIBILITY TO DEPRESSION. HERE, THROUGH A HIGH-THROUGHPUT SCREENING, WE IDENTIFY TWO PHYTOCHEMICALS, DIHYDROCAFFEIC ACID (DHCA) AND MALVIDIN-3'-O-GLUCOSIDE (MAL-GLUC) THAT ARE EFFECTIVE IN PROMOTING RESILIENCE AGAINST STRESS BY MODULATING BRAIN SYNAPTIC PLASTICITY AND PERIPHERAL INFLAMMATION. DHCA/MAL-GLUC ALSO SIGNIFICANTLY REDUCES DEPRESSION-LIKE PHENOTYPES IN A MOUSE MODEL OF INCREASED SYSTEMIC INFLAMMATION INDUCED BY TRANSPLANTATION OF HEMATOPOIETIC PROGENITOR CELLS FROM STRESS-SUSCEPTIBLE MICE. DHCA REDUCES PRO-INFLAMMATORY INTERLEUKIN 6 (IL-6) GENERATIONS BY INHIBITING DNA METHYLATION AT THE CPG-RICH IL-6 SEQUENCES INTRONS 1 AND 3, WHILE MAL-GLUC MODULATES SYNAPTIC PLASTICITY BY INCREASING HISTONE ACETYLATION OF THE REGULATORY SEQUENCES OF THE RAC1 GENE. PERIPHERAL INFLAMMATION AND SYNAPTIC MALADAPTATION ARE IN LINE WITH NEWLY HYPOTHESIZED CLINICAL INTERVENTION TARGETS FOR DEPRESSION THAT ARE NOT ADDRESSED BY CURRENTLY AVAILABLE ANTIDEPRESSANTS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  532  28 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 5713  39 SIRT2 INHIBITION REVERSES ANHEDONIA IN THE VGLUT1+/- DEPRESSION MODEL. SOME HISTONE DEACETYLASE (HDACS) ENZYMES HAVE BEEN PROPOSED AS EPIGENETIC TARGETS INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION AND ANTIDEPRESSANT-LIKE ACTION. AMONG THEM, WE HAVE RECENTLY IDENTIFIED SIRT2, A CLASS III NAD(+)-DEPENDENT HDAC, AS BEING OPPOSITELY REGULATED BY STRESS AND ANTIDEPRESSANTS. MOREOVER, SIRT2 INHIBITION HAS SHOWN ANTIANHEDONIC-LIKE ACTION IN THE CHRONIC MILD STRESS MODEL OF DEPRESSION. HERE WE HAVE EXTENDED THE STUDY USING AN ALTERNATIVE MODEL OF DEPRESSION BASED IN A GENETIC MANIPULATION OF GLUTAMATE FUNCTION. SPECIFICALLY, MICE HETEROZYGOUS FOR THE VESICULAR GLUTAMATE TRANSPORTER 1 (VGLUT1+/-) WERE USED. FIRSTLY, MRNA EXPRESSION OF THE DIFFERENT MEMBERS OF THE HDAC SUPERFAMILY IN THE PREFRONTAL CORTEX (PFC) OF VGLUT1+/- MICE AND WT LITTERMATES WERE STUDIED BY RT-PCR. SECONDLY, THE EFFECT OF REPEATED TREATMENT WITH THE SELECTIVE SIRT2 INHIBITOR 33I AND THE ANTIDEPRESSANT IMIPRAMINE ON ANHEDONIC BEHAVIOUR OF VGLUT1+/- MICE WAS STUDIED BY WEEKLY MONITORING OF SUCROSE INTAKE. FURTHER, THE INTERACTION OF 33I TOWARDS SPECIFIC MONOAMINERGIC TARGETS SUCH AS SEROTONIN OR NORADRENALINE TRANSPORTERS AS WELL AS THE MONOAMINOOXIDASE ENZYME WAS STUDIED. THE MRNA OCCURANCE OF THE DIFFERENT MEMBERS OF HDAC SUPERFAMILY WAS NOT ALTERED IN THE PFC OF VGLUT1+/- MICE. WHILE REPEATED IMIPRAMINE SHOWED AN ANTI-ANHEDONIC ACTION IN BOTH VGLUT1+/- AND WT, THE SELECTIVE SIRT2 INHIBITOR 33I FULLY REVERSED ANHEDONIA OF VGLUT1+/-. FURTHER, 33I SHOWED NO INTERACTION WITH THE ABOVE MENTIONED MONOAMINERGIC MOLECULAR TARGETS. THESE RESULTS CONFIRM THAT SIRT2 INHIBITION IS ABLE TO REVERSE ANHEDONIA IN DIFFERENT ANIMAL MODELS AND HIGHLIGHT THE NEED TO FURTHER INVESTIGATE THE ROLE OF SIRT2 INHIBITORS AS NEW ANTIDEPRESSANT AGENTS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16 6586  40 TUBASTATIN, A SELECTIVE HISTONE DEACETYLASE 6 INHIBITOR SHOWS ANTI-INFLAMMATORY AND ANTI-RHEUMATIC EFFECTS. EPIGENETIC MODIFICATIONS REPRESENT A PROMISING NEW APPROACH TO MODULATE CELL FUNCTIONS AS OBSERVED IN AUTOIMMUNE DISEASES. EMERGING EVIDENCE SUGGESTS THE UTILITY OF HDAC INHIBITORS IN THE TREATMENT OF CHRONIC IMMUNE AND INFLAMMATORY DISORDERS. HOWEVER, CLASS AND ISOFORM SELECTIVE INHIBITION OF HDAC IS CURRENTLY FAVORED AS IT LIMITS THE TOXICITY THAT HAS BEEN OBSERVED WITH PAN-HDAC INHIBITORS. HDAC6, A MEMBER OF THE HDAC FAMILY, WHOSE MAJOR SUBSTRATE IS ALPHA-TUBULIN, IS BEING INCREASINGLY IMPLICATED IN THE PATHOGENESIS OF INFLAMMATORY DISORDERS. THE PRESENT STUDY WAS CARRIED OUT TO STUDY THE POTENTIAL ANTI-INFLAMMATORY AND ANTI-RHEUMATIC EFFECTS OF HDAC6 SELECTIVE INHIBITOR TUBASTATIN. TUBASTATIN, A POTENT HUMAN HDAC6 INHIBITOR WITH AN IC50 OF 11 NM SHOWED SIGNIFICANT INHIBITION OF TNF-ALPHA AND IL-6 IN LPS STIMULATED HUMAN THP-1 MACROPHAGES WITH AN IC50 OF 272 NM AND 712 NM RESPECTIVELY. ADDITIONALLY, TUBASTATIN INHIBITED NITRIC OXIDE (NO) SECRETION IN MURINE RAW 264.7 MACROPHAGES DOSE DEPENDENTLY WITH AN IC50 OF 4.2 MUM AND INDUCED ALPHA-TUBULIN HYPERACETYLATION CORRESPONDING TO HDAC6 INHIBITION IN THP-1 CELLS WITHOUT AFFECTING THE CELL VIABILITY. TUBASTATIN SHOWED SIGNIFICANT INHIBITION OF PAW VOLUME AT 30 MG/KG I.P. IN A FREUND'S COMPLETE ADJUVANT (FCA) INDUCED ANIMAL MODEL OF INFLAMMATION. THE DISEASE MODIFYING ACTIVITY OF TUBASTATIN WAS ALSO EVIDENT IN COLLAGEN INDUCED ARTHRITIS DBA1 MOUSE MODEL AT 30 MG/KG I.P. THE SIGNIFICANT ATTENUATION OF CLINICAL SCORES (~70%) BY TUBASTATIN WAS CONFIRMED HISTOPATHOLOGICALLY AND WAS FOUND COMPARABLE TO DEXAMETHASONE (~90% INHIBITION OF CLINICAL SCORES). TUBASTATIN SHOWED SIGNIFICANT INHIBITION OF IL-6 IN PAW TISSUES OF ARTHRITIC MICE. THE PRESENT WORK HAS DEMONSTRATED ANTI-INFLAMMATORY AND ANTIRHEUMATIC EFFECTS OF A SELECTIVE HDAC6 INHIBITOR TUBASTATIN.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17   26  38 A 6-ALKYLSALICYLATE HISTONE ACETYLTRANSFERASE INHIBITOR INHIBITS HISTONE ACETYLATION AND PRO-INFLAMMATORY GENE EXPRESSION IN MURINE PRECISION-CUT LUNG SLICES. LYSINE ACETYLATIONS ARE POST-TRANSLATIONAL MODIFICATIONS OF CELLULAR PROTEINS, THAT ARE CRUCIAL IN THE REGULATION OF MANY CELLULAR PROCESSES. LYSINE ACETYLATIONS ON HISTONE PROTEINS ARE PART OF THE EPIGENETIC CODE REGULATING GENE EXPRESSION AND ARE INSTALLED BY HISTONE ACETYLTRANSFERASES. OBSERVATIONS THAT INFLAMMATORY LUNG DISEASES, SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ARE CHARACTERIZED BY INCREASED HISTONE ACETYLTRANSFERASE ACTIVITY INDICATE THAT DEVELOPMENT OF SMALL MOLECULE INHIBITORS FOR THESE ENZYMES MIGHT BE A VALUABLE APPROACH TOWARDS NEW THERAPIES FOR THESE DISEASES. THE 6-ALKYLSALICYLATE MG149 IS A CANDIDATE TO EXPLORE THIS HYPOTHESIS BECAUSE IT HAS BEEN DEMONSTRATED TO INHIBIT THE MYST TYPE HISTONE ACETYLTRANSFERASES. IN THIS STUDY, WE DETERMINED THE K(I) VALUE FOR INHIBITION OF THE MYST TYPE HISTONE ACETYLTRANSFERASE KAT8 BY MG149 TO BE 39 +/- 7.7 MUM. UPON INVESTIGATING WHETHER THE INHIBITION OF HISTONE ACETYLTRANSFERASES BY MG149 CORRELATES WITH INHIBITION OF HISTONE ACETYLATION IN MURINE PRECISION-CUT LUNG SLICES, INHIBITION OF ACETYLATION WAS OBSERVED USING AN LC-MS/MS BASED ASSAY ON HISTONE H4 RES 4-17, WHICH CONTAINS THE TARGET LYSINE OF KAT8. FOLLOWING UP ON THIS, UPON TREATMENT WITH MG149, REDUCED PRO-INFLAMMATORY GENE EXPRESSION WAS OBSERVED IN LIPOPOLYSACCHARIDE AND INTERFERON GAMMA STIMULATED MURINE PRECISION-CUT LUNG SLICES. BASED ON THIS, WE PROPOSE THAT 6-ALKYLSALICYLATES SUCH AS MG149 HAVE POTENTIAL FOR DEVELOPMENT TOWARDS APPLICATIONS IN THE TREATMENT OF INFLAMMATORY LUNG DISEASES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
18 4742  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19   78  28 A NEW MECHANISTIC APPROACH FOR THE TREATMENT OF CHRONIC NEUROPATHIC PAIN WITH NITROUS OXIDE INTEGRATED FROM A SYSTEMS BIOLOGY NARRATIVE REVIEW. THE LIMITATIONS OF THE CURRENTLY AVAILABLE TREATMENTS FOR CHRONIC NEUROPATHIC PAIN HIGHLIGHT THE NEED FOR SAFER AND MORE EFFECTIVE ALTERNATIVES. THE AUTHORS CARRIED OUT A FOCUSED REVIEW USING A SYSTEMS BIOLOGY APPROACH TO INTEGRATE THE COMPLEX MECHANISMS OF NOCICEPTION AND NEUROPATHIC PAIN, AND TO DECIPHER THE EFFECTS OF NITROUS OXIDE (N(2)O) ON THOSE PATHWAYS, BEYOND THE KNOWN EFFECT OF N(2)O ON N-METHYL-D-ASPARTATE RECEPTORS. THIS REVIEW IDENTIFIED A NUMBER OF POTENTIAL MECHANISMS BY WHICH N(2)O COULD IMPACT THE PROCESSES INVOLVED IN PERIPHERAL AND CENTRAL SENSITIZATION. IN THE ASCENDING PATHWAY, THE EFFECTS OF N(2)O INCLUDE ACTIVATING TWIK-RELATED K(+) CHANNEL 1 POTASSIUM CHANNELS ON FIRST-ORDER NEURONS, BLOCKING VOLTAGE-DEPENDENT CALCIUM CHANNELS TO ATTENUATE NEURONAL EXCITABILITY, ATTENUATING POSTSYNAPTIC GLUTAMATERGIC RECEPTOR ACTIVATION, AND POSSIBLY BLOCKING VOLTAGE-DEPENDENT SODIUM CHANNELS. IN THE DESCENDING PATHWAY, N(2)O INDUCES THE RELEASE OF ENDOGENOUS OPIOID LIGANDS AND STIMULATES NOREPINEPHRINE RELEASE. IN ADDITION, N(2)O MAY MEDIATE EPIGENETIC CHANGES BY INHIBITING METHIONINE SYNTHASE, A KEY ENZYME INVOLVED IN DNA AND RNA METHYLATION. THIS COULD EXPLAIN WHY THIS SHORT-ACTING ANALGESIC HAS SHOWN LONG-LASTING ANTI-PAIN SENSITIZATION EFFECTS IN ANIMAL MODELS OF CHRONIC PAIN. THESE NEW HYPOTHESES SUPPORT THE RATIONALE FOR INVESTIGATING N(2)O, EITHER ALONE OR IN COMBINATION WITH OTHER ANALGESICS, FOR THE MANAGEMENT OF CHRONIC NEUROPATHIC PAIN.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
20 4297  34 MICRORNA-1224 SPLICING CIRCULARRNA-FILIP1L IN AN AGO2-DEPENDENT MANNER REGULATES CHRONIC INFLAMMATORY PAIN VIA TARGETING UBR5. DYSFUNCTIONS OF GENE TRANSCRIPTION AND TRANSLATION IN THE NOCICEPTIVE PATHWAYS PLAY THE CRITICAL ROLE IN DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN. CIRCULAR RNAS (CIRCRNAS) ARE EMERGING AS NEW PLAYERS IN REGULATION OF GENE EXPRESSION, BUT WHETHER AND HOW CIRCRNAS ARE INVOLVED IN CHRONIC PAIN REMAIN ELUSIVE. WE SHOWED HERE THAT COMPLETE FREUND'S ADJUVANT-INDUCED CHRONIC INFLAMMATION PAIN SIGNIFICANTLY INCREASED CIRCRNA-FILIP1L (FILAMIN A INTERACTING PROTEIN 1-LIKE) EXPRESSION IN SPINAL NEURONS OF MICE. BLOCKAGE OF THIS INCREASE ATTENUATED COMPLETE FREUND'S ADJUVANT-INDUCED NOCICEPTIVE BEHAVIORS, AND OVEREXPRESSION OF SPINAL CIRCRNA-FILIP1L IN NAIVE MICE MIMICKED THE NOCICEPTIVE BEHAVIORS AS EVIDENCED BY DECREASED THERMAL AND MECHANICAL NOCICEPTIVE THRESHOLD. FURTHERMORE, WE FOUND THAT MATURE CIRCRNA-FILIP1L EXPRESSION WAS NEGATIVELY REGULATED BY MIRNA-1224 VIA BINDING AND SPLICING OF PRECURSOR OF CIRCRNA-FILIP1L (PRE-CIRCRNA-FILIP1L) IN THE ARGONAUTE-2 (AGO2)-DEPENDENT MANNER. INCREASE OF SPINAL CIRCRNA-FILIP1L EXPRESSION RESULTED FROM THE DECREASE OF MIRNA-1224 EXPRESSION UNDER CHRONIC INFLAMMATION PAIN STATE. MIRNA-1224 KNOCKDOWN OR AGO2 OVEREXPRESSION INDUCED NOCICEPTIVE BEHAVIORS IN NAIVE MICE, WHICH WAS PREVENTED BY THE KNOCKDOWN OF SPINAL CIRCRNA-FILIP1L. FINALLY, WE DEMONSTRATED THAT A UBIQUITIN PROTEIN LIGASE E3 COMPONENT N-RECOGNIN 5 (UBR5), VALIDATED AS A TARGET OF CIRCRNA-FILIP1L, PLAYS A PIVOTAL ROLE IN REGULATION OF NOCICEPTION BY SPINAL CIRCRNA-FILIP1L. THESE DATA SUGGEST THAT MIRNA-1224-MEDIATED AND AGO2-DEPENDENT MODULATION OF SPINAL CIRCRNA-FILIP1L EXPRESSION REGULATES NOCICEPTION VIA TARGETING UBR5, REVEALING A NOVEL EPIGENETIC MECHANISM OF INTERACTION BETWEEN MIRNA AND CIRCRNA IN CHRONIC INFLAMMATION PAIN.SIGNIFICANCE STATEMENT CIRCRNAS ARE EMERGING AS NEW PLAYERS IN REGULATION OF GENE EXPRESSION. HERE, WE FOUND THAT THE INCREASE OF CIRCRNA-FILIP1L MEDIATED BY MIRNA-1224 IN AN AGO2-DEPENDENT WAY IN THE SPINAL CORD IS INVOLVED IN REGULATION OF NOCICEPTION VIA TARGETING UBR5 OUR STUDY REVEALS A NOVEL EPIGENETIC MECHANISM OF INTERACTION BETWEEN MIRNA AND CIRCRNA IN CHRONIC INFLAMMATION PAIN.	2019