1 6023 139 THE BET PROTAC INHIBITOR DBET6 PROTECTS AGAINST RETINAL DEGENERATION AND INHIBITS THE CGAS-STING IN RESPONSE TO LIGHT DAMAGE. BACKGROUND: CHRONIC INFLAMMATION SIGNIFICANTLY CONTRIBUTES TO PHOTORECEPTOR DEATH IN BLINDING RETINAL DISEASES SUCH AS AGE-RELATED MACULAR DEGENERATION (AMD) AND RETINITIS PIGMENTOSA (RP). BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT ACT AS KEY PROINFLAMMATORY FACTORS. WE RECENTLY FOUND THE FIRST-GENERATION BET INHIBITOR JQ1 ALLEVIATED SODIUM IODATE-INDUCED RETINAL DEGENERATION BY SUPPRESSING CGAS-STING INNATE IMMUNITY. HERE, WE INVESTIGATED THE EFFECTS AND MECHANISM OF DBET6, A PROTEOLYSIS?TARGETING CHIMERA (PROTAC) SMALL MOLECULE THAT SELECTIVELY DEGRADES BET BY THE UBIQUITIN?PROTEASOME SYSTEM, IN LIGHT-INDUCED RETINAL DEGENERATION. METHODS: MICE WERE EXPOSED TO BRIGHT LIGHT TO INDUCE RETINAL DEGENERATION, AND THE ACTIVATION OF CGAS-STING WAS DETERMINED BY RNA-SEQUENCING AND MOLECULAR BIOLOGY. RETINAL FUNCTION, MORPHOLOGY, PHOTORECEPTOR VIABILITY AND RETINAL INFLAMMATION WERE EXAMINED IN THE PRESENCE AND ABSENCE OF DBET6 TREATMENT. RESULTS: INTRAPERITONEAL INJECTION OF DBET6 LED TO THE RAPID DEGRADATION OF BET PROTEIN IN THE RETINA WITHOUT DETECTABLE TOXICITY. DBET6 IMPROVED RETINAL RESPONSIVENESS AND VISUAL ACUITY AFTER LIGHT DAMAGE (LD). DBET6 ALSO REPRESSED LD-INDUCED RETINAL MACROPHAGES/MICROGLIA ACTIVATION, MULLER CELL GLIOSIS, PHOTORECEPTOR DEATH AND RETINAL DEGENERATION. ANALYSIS OF SINGLE-CELL RNA-SEQUENCING RESULTS REVEALED CGAS-STING COMPONENTS WERE EXPRESSED IN RETINAL MICROGLIA. LD LED TO DRAMATIC ACTIVATION OF THE CGAS-STING PATHWAY, WHEREAS DBET6 SUPPRESSED LD-INDUCED STING EXPRESSION IN REACTIVE MACROPHAGES/MICROGLIA AND THE RELATED INFLAMMATORY RESPONSE. CONCLUSIONS: THIS STUDY INDICATES TARGETED DEGRADATION OF BET BY DBET6 EXERTS NEUROPROTECTIVE EFFECTS BY INHIBITING CGAS-STING IN REACTIVE RETINAL MACROPHAGES/MICROGLIA, AND IS EXPECTED TO BECOME A NEW STRATEGY FOR TREATMENT OF RETINAL DEGENERATION. 2023 2 2113 35 EPIGENETIC HALLMARKS OF AGE-RELATED MACULAR DEGENERATION ARE RECAPITULATED IN A PHOTOSENSITIVE MOUSE MODEL. AGE-RELATED MACULAR DEGENERATION (AMD) IS A CHRONIC, MULTIFACTORIAL DISORDER AND A LEADING CAUSE OF BLINDNESS IN THE ELDERLY. CHARACTERIZED BY PROGRESSIVE PHOTORECEPTOR DEGENERATION IN THE CENTRAL RETINA, DISEASE PROGRESSION INVOLVES EPIGENETIC CHANGES IN CHROMATIN ACCESSIBILITY RESULTING FROM ENVIRONMENTAL EXPOSURES AND CHRONIC STRESS. HERE, WE REPORT THAT A PHOTOSENSITIVE MOUSE MODEL OF ACUTE STRESS-INDUCED PHOTORECEPTOR DEGENERATION RECAPITULATES THE EPIGENETIC HALLMARKS OF HUMAN AMD. GLOBAL EPIGENOMIC PROFILING WAS ACCOMPLISHED BY EMPLOYING AN ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN USING SEQUENCING (ATAC-SEQ), WHICH REVEALED AN ASSOCIATION BETWEEN DECREASED CHROMATIN ACCESSIBILITY AND STRESS-INDUCED PHOTORECEPTOR CELL DEATH IN OUR MOUSE MODEL. THE EPIGENOMIC CHANGES INDUCED BY LIGHT DAMAGE INCLUDE REDUCED EUCHROMATIN AND INCREASED HETEROCHROMATIN ABUNDANCE, RESULTING IN TRANSCRIPTIONAL AND TRANSLATIONAL DYSREGULATION THAT ULTIMATELY DRIVES PHOTORECEPTOR APOPTOSIS AND AN INFLAMMATORY REACTIVE GLIOSIS IN THE RETINA. OF PARTICULAR INTEREST, PHARMACOLOGICAL INHIBITION OF HISTONE DEACETYLASE 11 (HDAC11) AND SUPPRESSOR OF VARIEGATION 3-9 HOMOLOG 2 (SUV39H2), KEY HISTONE-MODIFYING ENZYMES INVOLVED IN PROMOTING REDUCED CHROMATIN ACCESSIBILITY, AMELIORATED LIGHT DAMAGE IN OUR MOUSE MODEL, SUPPORTING A CAUSAL LINK BETWEEN DECREASED CHROMATIN ACCESSIBILITY AND PHOTORECEPTOR DEGENERATION, THEREBY ELUCIDATING A POTENTIAL NEW THERAPEUTIC STRATEGY TO COMBAT AMD. 2020 3 5006 35 PERIPHERAL NERVE INJURY IS ACCOMPANIED BY CHRONIC TRANSCRIPTOME-WIDE CHANGES IN THE MOUSE PREFRONTAL CORTEX. BACKGROUND: PERIPHERAL NERVE INJURY CAN HAVE LONG-TERM CONSEQUENCES INCLUDING PAIN-RELATED MANIFESTATIONS, SUCH AS HYPERSENSITIVITY TO CUTANEOUS STIMULI, AS WELL AS AFFECTIVE AND COGNITIVE DISTURBANCES, SUGGESTING THE INVOLVEMENT OF SUPRASPINAL MECHANISMS. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION ASSOCIATED WITH MANY CHRONIC PAIN CONDITIONS HAVE BEEN REPORTED IN THE PREFRONTAL CORTEX (PFC). THE PFC IS IMPLICATED IN PAIN-RELATED CO-MORBIDITIES SUCH AS DEPRESSION, ANXIETY AND IMPAIRED EMOTIONAL DECISION-MAKING ABILITY. WE RECENTLY REPORTED THAT THIS REGION IS SUBJECT TO SIGNIFICANT EPIGENETIC REPROGRAMMING FOLLOWING PERIPHERAL NERVE INJURY, AND NORMALIZATION OF PAIN-RELATED STRUCTURAL, FUNCTIONAL AND EPIGENETIC ABNORMALITIES IN THE PFC ARE ALL ASSOCIATED WITH EFFECTIVE PAIN REDUCTION. IN THIS STUDY, WE USED THE SPARED NERVE INJURY (SNI) MODEL OF NEUROPATHIC PAIN TO TEST THE HYPOTHESIS THAT PERIPHERAL NERVE INJURY TRIGGERS PERSISTENT LONG-LASTING CHANGES IN GENE EXPRESSION IN THE PFC, WHICH ALTER FUNCTIONAL GENE NETWORKS, THUS PROVIDING A POSSIBLE EXPLANATION FOR CHRONIC PAIN ASSOCIATED BEHAVIORS. RESULTS: SNI OR SHAM SURGERY WHERE PERFORMED IN MALE CD1 MICE AT THREE MONTHS OF AGE. SIX MONTHS AFTER INJURY, WE PERFORMED TRANSCRIPTOME-WIDE SEQUENCING (RNASEQ), WHICH REVEALED 1147 DIFFERENTIALLY REGULATED TRANSCRIPTS IN THE PFC IN NERVE-INJURED VS. CONTROL MICE. CHANGES IN GENE EXPRESSION OCCURRED ACROSS A NUMBER OF FUNCTIONAL GENE CLUSTERS ENCODING CARDINAL BIOLOGICAL PROCESSES AS REVEALED BY INGENUITY PATHWAY ANALYSIS. SIGNIFICANTLY ALTERED BIOLOGICAL PROCESSES INCLUDED NEUROLOGICAL DISEASE, SKELETAL MUSCULAR DISORDERS, BEHAVIOR, AND PSYCHOLOGICAL DISORDERS. SEVERAL OF THE CHANGES DETECTED BY RNASEQ WERE VALIDATED BY RT-QPCR AND INCLUDED TRANSCRIPTS WITH KNOWN ROLES IN CHRONIC PAIN AND/OR NEURONAL PLASTICITY INCLUDING THE NMDA RECEPTOR (GLUTAMATE RECEPTOR, IONOTROPIC, NMDA; GRIN1), NEURITE OUTGROWTH (ROUNDABOUT 3; ROBO3), GLIOSIS (GLIAL FIBRILLARY ACIDIC PROTEIN; GFAP), VESICULAR RELEASE (SYNAPTOTAGMIN 2; SYT2), AND NEURONAL EXCITABILITY (VOLTAGE-GATED SODIUM CHANNEL, TYPE I; SCN1A). CONCLUSIONS: THIS STUDY USED AN UNBIASED APPROACH TO DOCUMENT LONG-TERM ALTERATIONS IN GENE EXPRESSION IN THE BRAIN FOLLOWING PERIPHERAL NERVE INJURY. WE PROPOSE THAT THESE CHANGES ARE MAINTAINED AS A MEMORY OF AN INSULT THAT IS TEMPORALLY AND SPATIALLY DISTANT FROM THE INITIAL INJURY. 2013 4 6567 33 TRANSLATOMIC RESPONSE OF RETINAL MULLER GLIA TO ACUTE AND CHRONIC STRESS. ANALYSIS OF RETINA CELL TYPE-SPECIFIC EPIGENETIC AND TRANSCRIPTOMIC SIGNATURES IS CRUCIAL TO UNDERSTANDING THE PATHOPHYSIOLOGY OF RETINAL DEGENERATIONS SUCH AS AGE-RELATED MACULAR DEGENERATION (AMD) AND DELINEATING CELL AUTONOMOUS AND CELL-NON-AUTONOMOUS MECHANISMS. WE HAVE DISCOVERED THAT ALDH1L1 IS SPECIFICALLY EXPRESSED IN THE MAJOR MACROGLIA OF THE RETINA, MULLER GLIA, AND, UNLIKE THE BRAIN, IS NOT EXPRESSED IN RETINAL ASTROCYTES. THIS ALLOWS USE OF ALDH1L1 CRE DRIVERS AND NUCLEAR TAGGING AND TRANSLATING RIBOSOME AFFINITY PURIFICATION (NUTRAP) CONSTRUCTS FOR TEMPORALLY CONTROLLED LABELING AND PAIRED ANALYSIS OF MULLER GLIA EPIGENOMES AND TRANSLATOMES. AS VALIDATED THROUGH A VARIETY OF APPROACHES, THE ALDH1L1CRE/ERT2-NUTRAP MODEL PROVIDES MULLER GLIA SPECIFIC TRANSLATOMIC AND EPIGENOMIC PROFILES WITHOUT THE NEED TO ISOLATE WHOLE CELLS. APPLICATION OF THIS APPROACH TO MODELS OF ACUTE INJURY (OPTIC NERVE CRUSH) AND CHRONIC STRESS (AGING) UNCOVERED FEW COMMON MULLER GLIA-SPECIFIC TRANSCRIPTOME CHANGES IN INFLAMMATORY PATHWAYS, AND MOSTLY DIFFERENTIAL SIGNATURES FOR EACH STIMULUS. THE EXPRESSION OF MEMBERS OF THE IL-6 AND INTEGRIN-LINKED KINASE SIGNALING PATHWAYS WAS ENHANCED IN MULLER GLIA IN RESPONSE TO OPTIC NERVE CRUSH BUT NOT AGING. UNIQUE CHANGES IN NEUROINFLAMMATION AND FIBROSIS SIGNALING PATHWAYS WERE OBSERVED IN RESPONSE TO AGING BUT NOT WITH OPTIC NERVE CRUSH. THE ALDH1L1CRE/ERT2-NUTRAP MODEL ALLOWS FOCUSED MOLECULAR ANALYSES OF A SINGLE, MINORITY CELL TYPE WITHIN THE RETINA, PROVIDING MORE SUBSTANTIAL EFFECT SIZES THAN WHOLE TISSUE ANALYSES. THE NUTRAP MODEL, NUCLEIC ACID ISOLATION, AND VALIDATION APPROACHES PRESENTED HERE CAN BE APPLIED TO ANY RETINA CELL TYPE FOR WHICH A CELL TYPE-SPECIFIC CRE IS AVAILABLE. 2022 5 4582 37 N-TERMINAL BET BROMODOMAIN INHIBITORS DISRUPT A BRD4-P65 INTERACTION AND REDUCE INDUCIBLE NITRIC OXIDE SYNTHASE TRANSCRIPTION IN PANCREATIC BETA-CELLS. CHRONIC INFLAMMATION OF PANCREATIC ISLETS IS A KEY DRIVER OF BETA-CELL DAMAGE THAT CAN LEAD TO AUTOREACTIVITY AND THE EVENTUAL ONSET OF AUTOIMMUNE DIABETES (T1D). IN THE ISLET, ELEVATED LEVELS OF PROINFLAMMATORY CYTOKINES INDUCE THE TRANSCRIPTION OF THE INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) GENE, NOS2, ULTIMATELY RESULTING IN INCREASED NITRIC OXIDE (NO). EXCESSIVE OR PROLONGED EXPOSURE TO NO CAUSES BETA-CELL DYSFUNCTION AND FAILURE ASSOCIATED WITH DEFECTS IN MITOCHONDRIAL RESPIRATION. RECENT STUDIES SHOWED THAT INHIBITION OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) FAMILY OF PROTEINS, A DRUGGABLE CLASS OF EPIGENETIC READER PROTEINS, PREVENTS THE ONSET AND PROGRESSION OF T1D IN THE NON-OBESE DIABETIC MOUSE MODEL. WE HYPOTHESIZED THAT BET PROTEINS CO-ACTIVATE TRANSCRIPTION OF CYTOKINE-INDUCED INFLAMMATORY GENE TARGETS IN BETA-CELLS AND THAT SELECTIVE, CHEMOTHERAPEUTIC INHIBITION OF BET BROMODOMAINS COULD REDUCE SUCH TRANSCRIPTION. HERE, WE INVESTIGATED THE ABILITY OF BET BROMODOMAIN SMALL MOLECULE INHIBITORS TO REDUCE THE BETA-CELL RESPONSE TO THE PROINFLAMMATORY CYTOKINE INTERLEUKIN 1 BETA (IL-1BETA). BET BROMODOMAIN INHIBITION ATTENUATED IL-1BETA-INDUCED TRANSCRIPTION OF THE INFLAMMATORY MEDIATOR NOS2 AND CONSEQUENT INOS PROTEIN AND NO PRODUCTION. REDUCED NOS2 TRANSCRIPTION IS CONSISTENT WITH INHIBITION OF NF-KAPPAB FACILITATED BY DISRUPTING THE INTERACTION OF A SINGLE BET FAMILY MEMBER, BRD4, WITH THE NF-KAPPAB SUBUNIT, P65. USING RECENTLY REPORTED SELECTIVE INHIBITORS OF THE FIRST AND SECOND BET BROMODOMAINS, INHIBITION OF ONLY THE FIRST BROMODOMAIN WAS NECESSARY TO REDUCE THE INTERACTION OF BRD4 WITH P65 IN BETA-CELLS. MOREOVER, INHIBITION OF THE FIRST BROMODOMAIN WAS SUFFICIENT TO MITIGATE IL-1BETA-DRIVEN DECREASES IN MITOCHONDRIAL OXYGEN CONSUMPTION RATES AND BETA-CELL VIABILITY. BY IDENTIFYING A ROLE FOR THE INTERACTION BETWEEN BRD4 AND P65 IN CONTROLLING THE RESPONSE OF BETA-CELLS TO PROINFLAMMATORY CYTOKINES, WE PROVIDE MECHANISTIC INFORMATION ON HOW BET BROMODOMAIN INHIBITION CAN DECREASE INFLAMMATION. THESE STUDIES ALSO SUPPORT THE POTENTIAL THERAPEUTIC APPLICATION OF MORE SELECTIVE BET BROMODOMAIN INHIBITORS IN ATTENUATING BETA-CELL INFLAMMATION. 2022 6 593 47 BET PROTEIN INHIBITION REGULATES CYTOKINE PRODUCTION AND PROMOTES NEUROPROTECTION AFTER SPINAL CORD INJURY. BACKGROUND: SPINAL CORD INJURY (SCI) USUALLY CAUSES A DEVASTATING LIFELONG DISABILITY FOR PATIENTS. AFTER A TRAUMATIC LESION, DISRUPTION OF THE BLOOD-SPINAL CORD BARRIER INDUCES THE INFILTRATION OF MACROPHAGES INTO THE LESION SITE AND THE ACTIVATION OF RESIDENT GLIAL CELLS, WHICH RELEASE CYTOKINES AND CHEMOKINES. THESE EVENTS RESULT IN A PERSISTENT INFLAMMATION, WHICH HAS BOTH DETRIMENTAL AND BENEFICIAL EFFECTS, BUT EVENTUALLY LIMITS FUNCTIONAL RECOVERY AND CONTRIBUTES TO THE APPEARANCE OF NEUROPATHIC PAIN. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT REGULATE THE EXPRESSION OF INFLAMMATORY GENES BY INTERACTING WITH ACETYLATED LYSINE RESIDUES. WHILE BET INHIBITORS ARE A PROMISING THERAPEUTIC STRATEGY FOR CANCER, LITTLE IS KNOWN ABOUT THEIR IMPLICATION AFTER SCI. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE ANTI-INFLAMMATORY ROLE OF BET INHIBITORS IN THIS PATHOLOGIC CONDITION. METHODS: WE EVALUATED THE EFFECTIVENESS OF THE BET INHIBITOR JQ1 TO MODIFY MACROPHAGE REACTIVITY IN VITRO AND TO MODULATE INFLAMMATION IN A SCI MICE MODEL. WE ANALYZED THE EFFECTS OF BET INHIBITION IN PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINE PRODUCTION IN VITRO AND IN VIVO. WE DETERMINED THE EFFECTIVENESS OF BET INHIBITION IN TISSUE SPARING, INFLAMMATION, NEURONAL PROTECTION, AND BEHAVIORAL OUTCOME AFTER SCI. RESULTS: WE HAVE FOUND THAT THE BET INHIBITOR JQ1 REDUCED THE LEVELS OF PRO-INFLAMMATORY MEDIATORS AND INCREASED THE EXPRESSION OF ANTI-INFLAMMATORY CYTOKINES. A PROLONGED TREATMENT WITH JQ1 ALSO DECREASED REACTIVITY OF MICROGLIA/MACROPHAGES, ENHANCED NEUROPROTECTION AND FUNCTIONAL RECOVERY, AND ACUTELY REDUCED NEUROPATHIC PAIN AFTER SCI. CONCLUSIONS: BET PROTEIN INHIBITION IS AN EFFECTIVE TREATMENT TO REGULATE CYTOKINE PRODUCTION AND PROMOTE NEUROPROTECTION AFTER SCI. THESE NOVEL RESULTS DEMONSTRATE FOR THE FIRST TIME THAT TARGETING BET PROTEINS IS AN ENCOURAGING APPROACH FOR SCI REPAIR AND A POTENTIAL STRATEGY TO TREAT OTHER INFLAMMATORY PATHOLOGIES. 2019 7 2239 34 EPIGENETIC MODULATION BY APABETALONE COUNTERS CYTOKINE-DRIVEN ACUTE PHASE RESPONSE IN VITRO, IN MICE AND IN PATIENTS WITH CARDIOVASCULAR DISEASE. CHRONIC SYSTEMIC INFLAMMATION CONTRIBUTES TO CARDIOVASCULAR DISEASE (CVD) AND CORRELATES WITH THE ABUNDANCE OF ACUTE PHASE RESPONSE (APR) PROTEINS IN THE LIVER AND PLASMA. BROMODOMAIN AND EXTRATERMINAL (BET) PROTEINS ARE EPIGENETIC READERS THAT REGULATE INFLAMMATORY GENE TRANSCRIPTION. WE SHOW THAT BET INHIBITION BY THE SMALL MOLECULE APABETALONE REDUCES APR GENE AND PROTEIN EXPRESSION IN HUMAN HEPATOCYTES, MOUSE MODELS, AND PLASMA FROM CVD PATIENTS. STEADY-STATE EXPRESSION OF SERUM AMYLOID P, PLASMINOGEN ACTIVATOR INHIBITOR 1, AND CERULOPLASMIN, APR PROTEINS LINKED TO CVD RISK, IS REDUCED BY APABETALONE IN CULTURED HEPATOCYTES AND IN HUMANIZED MOUSE LIVER. IN CYTOKINE-STIMULATED HEPATOCYTES, APABETALONE REDUCES THE EXPRESSION OF C-REACTIVE PROTEIN (CRP), ALPHA-2-MACROGLOBULIN, AND SERUM AMYLOID P. THE LATTER TWO ARE ALSO REDUCED BY APABETALONE IN THE LIVER OF ENDOTOXEMIC MICE. BET KNOCKDOWN IN VITRO ALSO COUNTERS CYTOKINE-MEDIATED INDUCTION OF THE CRP GENE. MECHANISTICALLY, APABETALONE REDUCES THE CYTOKINE-DRIVEN INCREASE IN BRD4 BET OCCUPANCY AT THE CRP PROMOTER, CONFIRMING THAT TRANSCRIPTION OF CRP IS BET-DEPENDENT. IN PATIENTS WITH STABLE CORONARY DISEASE, PLASMA APR PROTEINS CRP, IL-1 RECEPTOR ANTAGONIST, AND FIBRINOGEN GAMMA DECREASE AFTER APABETALONE TREATMENT VERSUS PLACEBO, RESULTING IN A PREDICTED DOWNREGULATION OF THE APR PATHWAY AND CYTOKINE TARGETS. WE CONCLUDE THAT CRP AND COMPONENTS OF THE APR PATHWAY ARE REGULATED BY BET PROTEINS AND THAT APABETALONE COUNTERS CHRONIC CYTOKINE SIGNALING IN PATIENTS. 2020 8 6443 37 THERAPEUTIC APPROACHES TO HISTONE REPROGRAMMING IN RETINAL DEGENERATION. RECENT DATA HAVE REVEALED EPIGENETIC DERANGEMENTS AND SUBSEQUENT CHROMATIN REMODELING AS A POTENT BIOLOGIC SWITCH FOR CHRONIC INFLAMMATION AND CELL SURVIVAL WHICH ARE IMPORTANT THERAPEUTIC TARGETS IN THE PATHOGENESIS OF SEVERAL RETINAL DEGENERATIONS. HISTONE DEACETYLASES (HDACS) ARE A MAJOR COMPONENT OF THIS SYSTEM AND SERVE AS A UNIQUE CONTROL OF THE CHROMATIN REMODELING PROCESS. WITH A MULTITUDE OF TARGETED HDAC INHIBITORS NOW AVAILABLE, THEIR USE IN BOTH BASIC SCIENCE AND CLINICAL STUDIES HAS WIDENED SUBSTANTIALLY. IN THE FIELD OF OCULAR BIOLOGY, THERE ARE DATA TO SUGGEST THAT HDAC INHIBITION MAY SUPPRESS NEOVASCULARIZATION AND MAY BE A POSSIBLE TREATMENT FOR RETINITIS PIGMENTOSA AND DRY AGE-RELATED MACULAR DEGENERATION (AMD). HOWEVER, THE EFFECTS OF THESE INHIBITORS ON CELL SURVIVAL AND CHEMOKINE EXPRESSION IN THE CHORIORETINAL TISSUES REMAIN VERY UNCLEAR. HERE, WE REVIEW THE MULTIFACETED BIOLOGY OF HDAC ACTIVITY AND PHARMACOLOGIC INHIBITION WHILE OFFERING FURTHER INSIGHT INTO THE IMPORTANCE OF THIS EPIGENETIC PATHWAY IN RETINAL DEGENERATIONS. OUR LABORATORY INVESTIGATIONS AIM TO OPEN TRANSLATIONAL AVENUES TO ADVANCE DRY AMD THERAPEUTICS WHILE EXPLORING THE ROLE OF ACETYLATION ON INFLAMMATORY GENE EXPRESSION IN THE AGING AND DEGENERATING RETINA. 2016 9 4614 39 NERVE EXCITABILITY AND NEUROPATHIC PAIN IS REDUCED BY BET PROTEIN INHIBITION AFTER SPARED NERVE INJURY. NEUROPATHIC PAIN IS A COMMON DISABILITY PRODUCED BY ENHANCED NEURONAL EXCITABILITY AFTER NERVOUS SYSTEM INJURY. THE PATHOPHYSIOLOGICAL CHANGES THAT UNDERLIE THE GENERATION AND MAINTENANCE OF NEUROPATHIC PAIN REQUIRE MODIFICATIONS OF TRANSCRIPTIONAL PROGRAMS. IN PARTICULAR, THERE IS AN INDUCTION OF PRO-INFLAMMATORY NEUROMODULATORS LEVELS, AND CHANGES IN THE EXPRESSION OF ION CHANNELS AND OTHER FACTORS INTERVENING IN THE DETERMINATION OF THE MEMBRANE POTENTIAL IN NEURONAL CELLS. WE HAVE PREVIOUSLY FOUND THAT INHIBITION OF THE BET PROTEINS EPIGENETIC READERS REDUCED NEUROINFLAMMATION AFTER SPINAL CORD INJURY. WITHIN THE PRESENT STUDY WE AIMED TO DETERMINE IF BET PROTEIN INHIBITION MAY ALSO AFFECT NEUROINFLAMMATION AFTER A PERIPHERAL NERVE INJURY, AND IF THIS WOULD BENEFICIALLY ALTER NEURONAL EXCITABILITY AND NEUROPATHIC PAIN. FOR THIS PURPOSE, C57BL/6 FEMALE MICE UNDERWENT SPARED NERVE INJURY (SNI), AND WERE TREATED WITH THE BET INHIBITOR JQ1, OR VEHICLE. ELECTROPHYSIOLOGICAL AND ALGESIMETRY TESTS WERE PERFORMED ON THESE MICE. WE ALSO DETERMINED THE EFFECTS OF JQ1 TREATMENT AFTER INJURY ON NEUROINFLAMMATION, AND THE EXPRESSION OF NEURONAL COMPONENTS IMPORTANT FOR THE MAINTENANCE OF AXON MEMBRANE POTENTIAL. WE FOUND THAT TREATMENT WITH JQ1 AFFECTED NEURONAL EXCITABILITY AND MECHANICAL HYPERALGESIA AFTER SNI IN MICE. BET PROTEIN INHIBITION REGULATED CYTOKINE EXPRESSION AND REDUCED MICROGLIAL REACTIVITY AFTER INJURY. IN ADDITION, JQ1 TREATMENT ALTERED THE EXPRESSION OF SCN3A, SCN9A, KCNA1, KCNQ2, KCNQ3, HCN1 AND HCN2 ION CHANNELS, AS WELL AS THE EXPRESSION OF THE NA(+)/K(+) ATPASE PUMP SUBUNITS. IN CONCLUSION, BOTH, ALTERATION OF INFLAMMATION, AND NEURONAL TRANSCRIPTION, COULD BE THE RESPONSIBLE EPIGENETIC MECHANISMS FOR THE REDUCTION OF EXCITABILITY AND HYPERALGESIA OBSERVED AFTER BET INHIBITION. INHIBITION OF BET PROTEINS IS A PROMISING THERAPY FOR REDUCING NEUROPATHIC PAIN AFTER NEURAL INJURY. PERSPECTIVE: NEUROPATHIC PAIN IS A COMMON DISABILITY PRODUCED BY ENHANCED NEURONAL EXCITABILITY AFTER NERVOUS SYSTEM INJURY. THE UNDERLYING PATHOPHYSIOLOGICAL CHANGES REQUIRE MODIFICATIONS OF TRANSCRIPTIONAL PROGRAMS. THIS STUDY NOTES THAT INHIBITION OF BET PROTEINS IS A PROMISING THERAPY FOR REDUCING NEUROPATHIC PAIN AFTER NEURAL INJURY. 2021 10 4721 30 NONCODING RNAS IN MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS), A CHRONIC INFLAMMATORY DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS CHARACTERIZED BY AXONAL DEGENERATION AND GLIOSIS. ALTHOUGH THE CAUSES OF MS REMAIN UNKNOWN, GENE DYSREGULATION IN THE CENTRAL NERVOUS SYSTEM HAS BEEN ASSOCIATED WITH THE DISEASE PATHOGENESIS. AS SUCH, THE VARIOUS REGULATORS OF GENE EXPRESSION MAY BE CONTRIBUTING FACTORS. THE NONCODING (NC) RNAS HAVE PIQUED THE INTEREST OF MS RESEARCHERS DUE TO THEIR KNOWN FUNCTIONS IN HUMAN PHYSIOLOGY AND VARIOUS PATHOLOGICAL PROCESSES, DESPITE BEING GENERALLY CHARACTERIZED AS TRANSCRIPTS WITHOUT APPARENT PROTEIN-CODING CAPACITY. ACCUMULATING EVIDENCE HAS INDICATED THAT NCRNAS PARTICIPATE IN THE REGULATION OF MS BY ACTING AS EPIGENETIC FACTORS, ESPECIALLY THE LONG (L) NCRNAS AND THE MICRO (MI) RNAS, AND THEY ARE NOW RECOGNIZED AS KEY REGULATORY MOLECULES IN MS. IN THIS REVIEW, WE SUMMARIZE THE MOST CURRENT STUDIES ON THE CONTRIBUTION OF NCRNAS IN MS PATHOGENIC PROCESSES AND DISCUSS THEIR POTENTIAL APPLICATIONS IN THE DIAGNOSIS AND TREATMENT OF MS. 2018 11 1105 37 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 12 4106 31 MECHANISM OF INFLAMMATION IN AGE-RELATED MACULAR DEGENERATION. AGE-RELATED MACULAR DEGENERATION (AMD) IS A MULTIFACTORIAL DISEASE THAT REPRESENTS THE MOST COMMON CAUSE OF IRREVERSIBLE VISUAL IMPAIRMENT AMONG PEOPLE OVER THE AGE OF 50 IN EUROPE, THE UNITED STATES, AND AUSTRALIA, ACCOUNTING FOR UP TO 50% OF ALL CASES OF CENTRAL BLINDNESS. RISK FACTORS OF AMD ARE HETEROGENEOUS, MAINLY INCLUDING INCREASING AGE AND DIFFERENT GENETIC PREDISPOSITIONS, TOGETHER WITH SEVERAL ENVIRONMENTAL/EPIGENETIC FACTORS, THAT IS, CIGARETTE SMOKING, DIETARY HABITS, AND PHOTOTOXIC EXPOSURE. IN THE AGING RETINA, FREE RADICALS AND OXIDIZED LIPOPROTEINS ARE CONSIDERED TO BE MAJOR CAUSES OF TISSUE STRESS RESULTING IN LOCAL TRIGGERS FOR PARAINFLAMMATION, A CHRONIC STATUS WHICH CONTRIBUTES TO INITIATION AND/OR PROGRESSION OF MANY HUMAN NEURODEGENERATIVE DISEASES SUCH AS AMD. EXPERIMENTAL AND CLINICAL EVIDENCES STRONGLY INDICATE THE PATHOGENETIC ROLE OF IMMUNOLOGIC PROCESSES IN AMD OCCURRENCE, CONSISTING OF PRODUCTION OF INFLAMMATORY RELATED MOLECULES, RECRUITMENT OF MACROPHAGES, COMPLEMENT ACTIVATION, MICROGLIAL ACTIVATION AND ACCUMULATION WITHIN THOSE STRUCTURES THAT COMPOSE AN ESSENTIAL AREA OF THE RETINA KNOWN AS MACULA LUTEA. THIS PAPER REVIEWS SOME ATTRACTIVE ASPECTS OF THE LITERATURE ABOUT THE MECHANISMS OF INFLAMMATION IN AMD, ESPECIALLY FOCUSING ON THOSE FINDINGS OR ARGUMENTS MORE DIRECTLY TRANSLATABLE TO IMPROVE THE CLINICAL MANAGEMENT OF PATIENTS WITH AMD AND TO PREVENT THE SEVERE VISION LOSS CAUSED BY THIS DISEASE. 2012 13 592 35 BET BROMODOMAIN PROTEINS REGULATE TRANSCRIPTIONAL REPROGRAMMING IN GENETIC DILATED CARDIOMYOPATHY. THE BROMODOMAIN AND EXTRATERMINAL (BET) FAMILY COMPRISES EPIGENETIC READER PROTEINS THAT ARE IMPORTANT REGULATORS OF INFLAMMATORY AND HYPERTROPHIC GENE EXPRESSION IN THE HEART. WE PREVIOUSLY IDENTIFIED THE ACTIVATION OF PROINFLAMMATORY GENE NETWORKS AS A KEY EARLY DRIVER OF DILATED CARDIOMYOPATHY (DCM) IN TRANSGENIC MICE EXPRESSING A MUTANT FORM OF PHOSPHOLAMBAN (PLNR9C) - A GENETIC CAUSE OF DCM IN HUMANS. WE HYPOTHESIZED THAT BETS COACTIVATE THIS INFLAMMATORY PROCESS, REPRESENTING A CRITICAL NODE IN THE PROGRESSION OF DCM. TO TEST THIS HYPOTHESIS, WE TREATED PLNR9C OR AGE-MATCHED WT MICE LONGITUDINALLY WITH THE SMALL MOLECULE BET BROMODOMAIN INHIBITOR JQ1 OR VEHICLE. BET INHIBITION ABROGATED ADVERSE CARDIAC REMODELING, REDUCED CARDIAC FIBROSIS, AND PROLONGED SURVIVAL IN PLNR9C MICE BY INHIBITING EXPRESSION OF PROINFLAMMATORY GENE NETWORKS AT ALL STAGES OF DISEASE. SPECIFICALLY, JQ1 HAD PROFOUND EFFECTS ON PROINFLAMMATORY GENE NETWORK EXPRESSION IN CARDIAC FIBROBLASTS, WHILE HAVING LITTLE EFFECT ON GENE EXPRESSION IN CARDIOMYOCYTES. CARDIAC FIBROBLAST PROLIFERATION WAS ALSO SUBSTANTIALLY REDUCED BY JQ1. MECHANISTICALLY, WE DEMONSTRATED THAT BRD4 SERVES AS A DIRECT AND ESSENTIAL REGULATOR OF NF-KAPPAB-MEDIATED PROINFLAMMATORY GENE EXPRESSION IN CARDIAC FIBROBLASTS. SUPPRESSING PROINFLAMMATORY GENE EXPRESSION VIA BET BROMODOMAIN INHIBITION COULD BE A NOVEL THERAPEUTIC STRATEGY FOR CHRONIC DCM IN HUMANS. 2020 14 5426 34 REGULATION OF SIRTUIN EXPRESSION IN AUTOIMMUNE NEUROINFLAMMATION: INDUCTION OF SIRT1 IN OLIGODENDROCYTE PROGENITOR CELLS. IN MULTIPLE SCLEROSIS (MS) REGENERATION OF OLIGODENDROCYTES FOLLOWING INFLAMMATORY DEMYELINATION IS LIMITED BY THE COMPROMISED ABILITY OF PROGENITORS TO REPOPULATE LESIONED AREAS AND TRANSITION TO FUNCTIONALLY COMPETENT OLIGODENDROCYTES. REGARDING UNDERLYING MECHANISMS, THE INVOLVEMENT OF EPIGENETIC PROCESSES HAS BEEN SUGGESTED, E.G. THE CONTRIBUTION OF HISTONE DEACETYLASES (HDAC) KNOWN TO REGULATE OLIGODENDROCYTE PROGENITOR CELL (OPC) DIFFERENTIATION. HOWEVER, THEIR PRECISE EXPRESSION PATTERNS, PARTICULAR OF REDOX-SENSITIVE NAD(+) HDACS, REMAINS LARGELY UNKNOWN. IN THIS STUDY, WE DETERMINED THE EXPRESSION AND ACTIVITY OF SIRTUINS, MEMBERS OF THE HDAC CLASS III FAMILY WITH A SPECIFIC FOCUS ON SIRT1, PREVIOUSLY ASSOCIATED WITH NEURODEGENERATIVE, INFLAMMATORY AND DEMYELINATING DISORDERS OF THE CENTRAL NERVOUS SYSTEM (CNS). BY INVESTIGATING MOUSE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), A MODEL FOR MS, WE FOUND THAT TRANSCRIPTION OF SIRT1, SIRT2 AND SIRT6 WAS SIGNIFICANTLY INCREASED IN THE CNS DURING CHRONIC DISEASE STAGES. WE CONFIRMED THIS FINDING FOR SIRT1 PROTEIN EXPRESSION AND WERE ABLE TO LOCALIZE UPREGULATED SIRT1 IN NUCLEI OF NG2(+) OR PDGFRALPHA(+) OPCS IN DEMYELINATED BRAIN LESIONS. IN CULTURED MOUSE A2B5(+) OPCS BLOCKADE OF SIRT1 ACTIVITY BY THE SMALL MOLECULE COMPOUND EX527 ENHANCED MITOTIC ACTIVITY BUT DID NOT AFFECT THE CAPACITY TO DIFFERENTIATE. A SIMILAR PATTERN WAS DETECTABLE IN OPCS DERIVED FROM SIRT1-DEFICIENT ANIMALS. TAKEN TOGETHER, OUR DATA SUGGEST THAT SIRT1 INHIBITION MAY HELP TO EXPAND THE ENDOGENOUS POOL OF OPCS WITHOUT AFFECTING THEIR DIFFERENTIATION. 2019 15 697 36 BROMODOMAIN AND EXTRATERMINAL PROTEINS AS NOVEL EPIGENETIC TARGETS FOR RENAL DISEASES. EPIGENETIC MECHANISMS, ESPECIALLY DNA METHYLATION AND HISTONE MODIFICATIONS, ARE DYNAMIC PROCESSES THAT REGULATE THE GENE EXPRESSION TRANSCRIPTIONAL PROGRAM IN NORMAL AND DISEASED STATES. THE BROMODOMAIN AND EXTRATERMINAL (BET) PROTEIN FAMILY (BRD2, BRD3, BRD4, AND BRDT) ARE EPIGENETIC READERS THAT, VIA BROMODOMAINS, REGULATE GENE TRANSCRIPTION BY BINDING TO ACETYLATED LYSINE RESIDUES ON HISTONES AND MASTER TRANSCRIPTIONAL FACTORS. EXPERIMENTAL DATA HAVE DEMONSTRATED THE INVOLVEMENT OF SOME BET PROTEINS IN MANY PATHOLOGICAL CONDITIONS, INCLUDING TUMOR DEVELOPMENT, INFECTIONS, AUTOIMMUNITY, AND INFLAMMATION. SELECTIVE BROMODOMAIN INHIBITORS ARE EPIGENETIC DRUGS THAT BLOCK THE INTERACTION BETWEEN BET PROTEINS AND ACETYLATED PROTEINS, THUS EXERTING BENEFICIAL EFFECTS. RECENT DATA HAVE DESCRIBED THE BENEFICIAL EFFECT OF BET INHIBITION ON EXPERIMENTAL RENAL DISEASES. EMERGING EVIDENCE UNDERSCORES THE IMPORTANCE OF ENVIRONMENTAL MODIFICATIONS IN THE ORIGIN OF PATHOLOGICAL FEATURES IN CHRONIC KIDNEY DISEASES (CKD). SEVERAL CELLULAR PROCESSES SUCH AS OXIDATION, METABOLIC DISORDERS, CYTOKINES, INFLAMMATION, OR ACCUMULATED UREMIC TOXINS MAY INDUCE EPIGENETIC MODIFICATIONS THAT REGULATE KEY PROCESSES INVOLVED IN RENAL DAMAGE AND IN OTHER PATHOLOGICAL CONDITIONS OBSERVED IN CKD PATIENTS. HERE, WE REVIEW HOW TARGETING BROMODOMAINS IN BET PROTEINS MAY REGULATE ESSENTIAL PROCESSES INVOLVED IN RENAL DISEASES AND IN ASSOCIATED COMPLICATIONS FOUND IN CKD PATIENTS, SUCH AS CARDIOVASCULAR DAMAGE, HIGHLIGHTING THE POTENTIAL OF EPIGENETIC THERAPEUTIC STRATEGIES AGAINST BET PROTEINS FOR CKD TREATMENT AND ASSOCIATED RISKS. 2019 16 3196 23 HDAC INHIBITORS RESTORE C-FIBRE SENSITIVITY IN EXPERIMENTAL NEUROPATHIC PAIN MODEL. BACKGROUND AND PURPOSE: HYPOESTHESIA IS A CLINICAL FEATURE OF NEUROPATHIC PAIN. THE FEATURE IS PARTLY EXPLAINED BY THE EVIDENCE OF EPIGENETIC REPRESSION OF NAV 1.8 SODIUM CHANNEL IN THE DORSAL ROOT GANGLION (DRG). EXPERIMENTAL APPROACH: WE INVESTIGATED THE POSSIBILITY OF TRICHOSTATIN A (TSA), VALPROIC ACID (VPA) AND SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) TO REVERSE THE UNIQUE C-FIBRE SENSITIVITY OBSERVED FOLLOWING PARTIAL LIGATION OF SCIATIC NERVE IN MICE. KEY RESULTS: NERVE INJURY-INDUCED DOWN-REGULATION OF DRG NAV 1.8 SODIUM CHANNEL AND C-FIBRE-RELATED HYPOESTHESIA WERE REVERSED BY TSA, VPA AND SAHA TREATMENTS, WHICH INHIBIT HISTONE DEACETYLASE (HDAC), AND INCREASE HISTONE ACETYLATION AT THE REGULATORY SEQUENCE OF NAV 1.8. CONCLUSIONS AND IMPLICATIONS: TAKEN TOGETHER, THESE STUDIES PROVIDE THE EVIDENCE THAT HYPOESTHESIA AND UNDERLYING DOWN-REGULATION OF NAV 1.8, NEGATIVE SYMPTOMS OBSERVED IN NERVE INJURY-INDUCED NEUROPATHIC PAIN MODELS ARE REGULATED BY AN EPIGENETIC CHROMATIN REMODELLING THROUGH HDAC-RELATED MACHINERIES. 2013 17 689 37 BRD4 AS A THERAPEUTIC TARGET IN PULMONARY DISEASES. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC MODULATORS THAT REGULATE GENE TRANSCRIPTION THROUGH INTERACTING WITH ACETYLATED LYSINE RESIDUES OF HISTONE PROTEINS. BET PROTEINS HAVE MULTIPLE ROLES IN REGULATING KEY CELLULAR FUNCTIONS SUCH AS CELL PROLIFERATION, DIFFERENTIATION, INFLAMMATION, OXIDATIVE AND REDOX BALANCE, AND IMMUNE RESPONSES. AS A RESULT, BET PROTEINS HAVE BEEN FOUND TO BE ACTIVELY INVOLVED IN A BROAD RANGE OF HUMAN LUNG DISEASES INCLUDING ACUTE LUNG INFLAMMATION, ASTHMA, PULMONARY ARTERIAL HYPERTENSION, PULMONARY FIBROSIS, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). DUE TO THE IDENTIFICATION OF SPECIFIC SMALL MOLECULAR INHIBITORS OF BET PROTEINS, TARGETING BET IN THESE LUNG DISEASES HAS BECOME AN AREA OF INCREASING INTEREST. EMERGING EVIDENCE HAS DEMONSTRATED THE BENEFICIAL EFFECTS OF BET INHIBITORS IN PRECLINICAL MODELS OF VARIOUS HUMAN LUNG DISEASES. THIS IS, IN GENERAL, LARGELY RELATED TO THE ABILITY OF BET PROTEINS TO BIND TO PROMOTERS OF GENES THAT ARE CRITICAL FOR INFLAMMATION, DIFFERENTIATION, AND BEYOND. BY MODULATING THESE CRITICAL GENES, BET PROTEINS ARE INTEGRATED INTO THE PATHOGENESIS OF DISEASE PROGRESSION. THE INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY OF BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) IS OF PARTICULAR INTEREST, SEEMS TO ACT INDEPENDENTLY OF ITS BROMODOMAIN BINDING ACTIVITY, AND HAS IMPLICATION IN SOME CONTEXTS. IN THIS REVIEW, WE PROVIDE A BRIEF OVERVIEW OF THE RESEARCH ON BET PROTEINS WITH A FOCUS ON BRD4 IN SEVERAL MAJOR HUMAN LUNG DISEASES, THE UNDERLYING MOLECULAR MECHANISMS, AS WELL AS FINDINGS OF TARGETING BET PROTEINS USING PHARMACEUTICAL INHIBITORS IN DIFFERENT LUNG DISEASES PRECLINICALLY. 2023 18 2882 27 G-PROTEIN-COUPLED RECEPTOR GPR17 REGULATES OLIGODENDROCYTE DIFFERENTIATION IN RESPONSE TO LYSOLECITHIN-INDUCED DEMYELINATION. OLIGODENDROCYTES ARE THE MYELIN-PRODUCING CELLS OF THE CENTRAL NERVOUS SYSTEM (CNS). A VARIETY OF BRAIN DISORDERS FROM "CLASSICAL" DEMYELINATING DISEASES, SUCH AS MULTIPLE SCLEROSIS, STROKE, SCHIZOPHRENIA, DEPRESSION, DOWN SYNDROME AND AUTISM, ARE SHOWN MYELINATION DEFECTS. OLIGODENDROCYTE MYELINATION IS REGULATED BY A COMPLEX INTERPLAY OF INTRINSIC, EPIGENETIC AND EXTRINSIC FACTORS. GPR17 (G PROTEIN-COUPLED RECEPTOR 17) IS A G PROTEIN-COUPLED RECEPTOR, AND HAS BEEN IDENTIFIED TO BE A REGULATOR FOR OLIGODENDROCYTE DEVELOPMENT. HERE, WE DEMONSTRATE THAT THE ABSENCE OF GPR17 ENHANCES REMYELINATION IN VIVO WITH A TOXIN-INDUCED MODEL WHEREBY FOCAL DEMYELINATED LESIONS ARE GENERATED IN SPINAL CORD WHITE MATTER OF ADULT MICE BY LOCALIZED INJECTION OF LPC(L-A-LYSOPHOSPHATIDYLCHOLINE). THE INCREASED EXPRESSION OF THE ACTIVATED FORM OF ERK1/2 (PHOSPHO-ERK1/2) IN LESION AREAS SUGGESTED THE POTENTIAL ROLE OF ERK1/2 ACTIVITY ON THE GPR17-DEPENDENT MODULATION OF MYELINATION. THE ABSENCE OF GPR17 ENHANCES REMYELINATION IS CORRELATE WITH THE ACTIVATED ERK1/2 (PHOSPHO-ERK1/2).BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL DRUGGABLE TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC CNS DISEASES. 2018 19 445 41 APABETALONE (RVX-208) REDUCES VASCULAR INFLAMMATION IN VITRO AND IN CVD PATIENTS BY A BET-DEPENDENT EPIGENETIC MECHANISM. BACKGROUND: APABETALONE (RVX-208) IS A BROMODOMAIN AND EXTRATERMINAL PROTEIN INHIBITOR (BETI) THAT IN PHASE II TRIALS REDUCED THE RELATIVE RISK (RR) OF MAJOR ADVERSE CARDIAC EVENTS (MACE) IN PATIENTS WITH CARDIOVASCULAR DISEASE (CVD) BY 44% AND IN DIABETIC CVD PATIENTS BY 57% ON TOP OF STATINS. A PHASE III TRIAL, BETONMACE, IS CURRENTLY ASSESSING APABETALONE'S ABILITY TO REDUCE MACE IN STATIN-TREATED POST-ACUTE CORONARY SYNDROME TYPE 2 DIABETIC CVD PATIENTS WITH LOW HIGH-DENSITY LIPOPROTEIN C. THE LEADING CAUSE OF MACE IS ATHEROSCLEROSIS, DRIVEN BY DYSFUNCTIONAL LIPID METABOLISM AND CHRONIC VASCULAR INFLAMMATION (VI). IN VITRO STUDIES HAVE IMPLICATED THE BET PROTEIN BRD4 AS AN EPIGENETIC DRIVER OF INFLAMMATION AND ATHEROGENESIS, SUGGESTING THAT BETI MAY BE CLINICALLY EFFECTIVE IN COMBATING VI. HERE, WE ASSESSED APABETALONE'S ABILITY TO REGULATE INFLAMMATION-DRIVEN GENE EXPRESSION AND CELL ADHESION IN VITRO AND INVESTIGATED THE MECHANISM BY WHICH APABETALONE SUPPRESSES EXPRESSION. THE CLINICAL IMPACT OF APABETALONE ON MEDIATORS OF VI WAS ASSESSED WITH PROTEOMIC ANALYSIS OF PHASE II CVD PATIENT PLASMA. RESULTS: IN VITRO, APABETALONE PREVENTED INFLAMMATORY (TNFALPHA, LPS, OR IL-1BETA) INDUCTION OF KEY FACTORS THAT DRIVE ENDOTHELIAL ACTIVATION, MONOCYTE RECRUITMENT, ADHESION, AND PLAQUE DESTABILIZATION. BRD4 ABUNDANCE ON INFLAMMATORY AND ADHESION GENE PROMOTERS AND ENHANCERS WAS REDUCED BY APABETALONE. BRD2-4 DEGRADATION BY MZ-1 ALSO PREVENTED TNFALPHA-INDUCED TRANSCRIPTION OF MONOCYTE AND ENDOTHELIAL CELL ADHESION MOLECULES AND INFLAMMATORY MEDIATORS, CONFIRMING BET-DEPENDENT REGULATION. TRANSCRIPTIONAL REGULATION BY APABETALONE TRANSLATED INTO A REDUCTION IN MONOCYTE ADHESION TO AN ENDOTHELIAL MONOLAYER. IN A PHASE II TRIAL, APABETALONE TREATMENT REDUCED THE ABUNDANCE OF MULTIPLE VI MEDIATORS IN THE PLASMA OF CVD PATIENTS (SOMASCAN(R) 1.3 K). THESE PROTEINS CORRELATE WITH CVD RISK AND INCLUDE ADHESION MOLECULES, CYTOKINES, AND METALLOPROTEINASES. INGENUITY(R) PATHWAY ANALYSIS (IPA(R)) PREDICTED THAT APABETALONE INHIBITS PRO-ATHEROGENIC REGULATORS AND PATHWAYS AND PREVENTS DISEASE STATES ARISING FROM LEUKOCYTE RECRUITMENT. CONCLUSIONS: APABETALONE SUPPRESSED GENE EXPRESSION OF VI MEDIATORS IN MONOCYTES AND ENDOTHELIAL CELLS BY INHIBITING BET-DEPENDENT TRANSCRIPTION INDUCED BY MULTIPLE INFLAMMATORY STIMULI. IN CVD PATIENTS, APABETALONE TREATMENT REDUCED CIRCULATING LEVELS OF VI MEDIATORS, AN OUTCOME CONDUCIVE WITH ATHEROSCLEROTIC PLAQUE STABILIZATION AND MACE REDUCTION. INHIBITION OF INFLAMMATORY AND ADHESION MOLECULE GENE EXPRESSION BY APABETALONE IS PREDICTED TO CONTRIBUTE TO MACE REDUCTION IN THE PHASE III BETONMACE TRIAL. 2019 20 589 37 BET BROMODOMAIN INHIBITORS SUPPRESS INFLAMMATORY ACTIVATION OF GINGIVAL FIBROBLASTS AND EPITHELIAL CELLS FROM PERIODONTITIS PATIENTS. BET BROMODOMAIN PROTEINS ARE IMPORTANT EPIGENETIC REGULATORS OF GENE EXPRESSION THAT BIND ACETYLATED HISTONE TAILS AND REGULATE THE FORMATION OF ACETYLATION-DEPENDENT CHROMATIN COMPLEXES. BET INHIBITORS SUPPRESS INFLAMMATORY RESPONSES IN MULTIPLE CELL TYPES AND ANIMAL MODELS, AND PROTECT AGAINST BONE LOSS IN EXPERIMENTAL PERIODONTITIS IN MICE. HERE, WE ANALYZED THE ROLE OF BET PROTEINS IN INFLAMMATORY ACTIVATION OF GINGIVAL FIBROBLASTS (GFS) AND GINGIVAL EPITHELIAL CELLS (GECS). WE SHOW THAT THE BET INHIBITORS I-BET151 AND JQ1 SIGNIFICANTLY REDUCED EXPRESSION AND/OR PRODUCTION OF DISTINCT, BUT OVERLAPPING, PROFILES OF CYTOKINE-INDUCIBLE MEDIATORS OF INFLAMMATION AND BONE RESORPTION IN GFS FROM HEALTHY DONORS (IL6, IL8, IL1B, CCL2, CCL5, COX2, AND MMP3) AND THE GEC LINE TIGK (IL6, IL8, IL1B, CXCL10, MMP9) WITHOUT AFFECTING CELL VIABILITY. ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASE AND NUCLEAR FACTOR-KAPPAB PATHWAYS WAS UNAFFECTED BY I-BET151, AS WAS THE HISTONE ACETYLATION STATUS, AND NEW PROTEIN SYNTHESIS WAS NOT REQUIRED FOR THE ANTI-INFLAMMATORY EFFECTS OF BET INHIBITION. I-BET151 AND JQ1 ALSO SUPPRESSED EXPRESSION OF INFLAMMATORY CYTOKINES, CHEMOKINES, AND OSTEOCLASTOGENIC MEDIATORS IN GFS AND TIGKS INFECTED WITH THE KEY PERIODONTAL PATHOGEN PORPHYROMONAS GINGIVALIS. NOTABLY, P. GINGIVALIS INTERNALIZATION AND INTRACELLULAR SURVIVAL IN GFS AND TIGKS REMAINED UNAFFECTED BY BET INHIBITORS. FINALLY, INHIBITION OF BET PROTEINS SIGNIFICANTLY REDUCED P. GINGIVALIS-INDUCED INFLAMMATORY MEDIATOR EXPRESSION IN GECS AND GFS FROM PATIENTS WITH PERIODONTITIS. OUR RESULTS DEMONSTRATE THAT BET INHIBITORS MAY BLOCK THE EXCESSIVE INFLAMMATORY MEDIATOR PRODUCTION BY RESIDENT CELLS OF THE GINGIVAL TISSUE AND IDENTIFY THE BET FAMILY OF EPIGENETIC READER PROTEINS AS A POTENTIAL THERAPEUTIC TARGET IN THE TREATMENT OF PERIODONTAL DISEASE. 2019