1 854 130 CHONDROPROTECTIVE EFFECTS OF A HISTONE DEACETYLASE INHIBITOR, PANOBINOSTAT, ON PAIN BEHAVIOR AND CARTILAGE DEGRADATION IN ANTERIOR CRUCIATE LIGAMENT TRANSECTION-INDUCED EXPERIMENTAL OSTEOARTHRITIC RATS. OSTEOARTHRITIS (OA) IS THE MOST COMMON ARTICULAR DEGENERATIVE DISEASE CHARACTERIZED BY CHRONIC PAIN, JOINT INFLAMMATION, AND MOVEMENT LIMITATIONS, WHICH ARE SIGNIFICANTLY INFLUENCED BY ABERRANT EPIGENETIC MODIFICATIONS OF NUMEROUS OA-SUSCEPTIBLE GENES. RECENT STUDIES REVEALED THAT BOTH THE ABNORMAL ACTIVATION AND DIFFERENTIAL EXPRESSION OF HISTONE DEACETYLASES (HDACS) MIGHT CONTRIBUTE TO OA PATHOGENESIS. IN THIS STUDY, WE INVESTIGATED THE CHONDROPROTECTIVE EFFECTS OF A MARINE-DERIVED HDAC INHIBITOR, PANOBINOSTAT, ON ANTERIOR CRUCIATE LIGAMENT TRANSECTION (ACLT)-INDUCED EXPERIMENTAL OA RATS. THE INTRA-ARTICULAR ADMINISTRATION OF 2 OR 10 MICROG OF PANOBINOSTAT (EACH GROUP, N = 7) PER WEEK FROM THE 6TH TO 17TH WEEK ATTENUATES ACLT-INDUCED NOCICEPTIVE BEHAVIORS, INCLUDING SECONDARY MECHANICAL ALLODYNIA AND WEIGHT-BEARING DISTRIBUTION. HISTOPATHOLOGICAL AND MICROCOMPUTED TOMOGRAPHY ANALYSIS SHOWED THAT PANOBINOSTAT SIGNIFICANTLY PREVENTS CARTILAGE DEGENERATION AFTER ACLT. MOREOVER, INTRA-ARTICULAR PANOBINOSTAT EXERTS HYPERTROPHIC EFFECTS IN THE CHONDROCYTES OF ARTICULAR CARTILAGE BY REGULATING THE PROTEIN EXPRESSIONS OF HDAC4, HDAC6, HDAC7, RUNT-DOMAIN TRANSCRIPTION FACTOR-2, AND MATRIX METALLOPROTEINASE-13. THE STUDY INDICATED THAT HDACS MIGHT HAVE DIFFERENT MODULATIONS ON THE CHONDROCYTE PHENOTYPE IN THE EARLY STAGES OF OA DEVELOPMENT. THESE RESULTS PROVIDE NEW EVIDENCE THAT PANOBINOSTAT MAY BE A POTENTIAL THERAPEUTIC DRUG FOR OA. 2021 2 148 52 ABERRANT FLUID SHEAR STRESS CONTRIBUTES TO ARTICULAR CARTILAGE PATHOGENESIS VIA EPIGENETIC REGULATION OF ZBTB20 BY H3K4ME3. PURPOSE: OSTEOARTHRITIS (OA) IS A COMMON DISEASE FOR HUMAN BEINGS, CHARACTERIZED BY SEVERE INFLAMMATION, CARTILAGE DEGRADATION, AND SUBCHONDRAL BONE DESTRUCTION. HOWEVER, CURRENT THERAPIES ARE LIMITED TO RELIEVING PAIN OR JOINT REPLACEMENT AND NO EFFECTIVE TREATMENT METHODS HAVE BEEN DISCOVERED TO IMPROVE DEGENERATIVE CHANGES. CURRENTLY, A VARIETY OF EVIDENCES HAVE INDICATED THAT ABERRANT MECHANICAL STIMULI IS CLOSELY ASSOCIATED WITH ARTICULAR JOINT PATHOGENESIS, WHILE THE DETAILED UNDERLYING MECHANISM REMAINS UNELUCIDATED. IN THE PRESENT STUDY, WE DETERMINED TO INVESTIGATE THE IMPACT OF EXCESSIVE HIGH FLUID SHEAR STRESS (FSS) ON PRIMARY CHONDROCYTES AND THE UNDERLYING EPIGENETIC MECHANISMS. MATERIALS AND METHODS: PHALLOIDIN STAINING AND EDU STAINING WERE USED TO EVALUATE CELL MORPHOLOGY AND VIABILITY. THE MRNA LEVEL AND PROTEIN LEVEL OF GENES WERE DETERMINED BY QPCR, WESTERN BLOT ASSAY, AND IMMUNOFLUORESCENCE STAINING. MECHANISTIC INVESTIGATION WAS PERFORMED THROUGH RNA-SEQUENCING AND CUT&TAG SEQUENCING. IN VIVO, WE ADOPTED UNILATERAL ANTERIOR CROSSBITES (UAC) MICE MODEL TO INVESTIGATE THE EXPRESSION OF H3K4ME3 AND ZBTB20 IN ABERRANT FORCE-RELATED CARTILAGE PATHOGENESIS. RESULTS: THE RESULTS DEMONSTRATED THAT FSS GREATLY DISRUPTS CELL MORPHOLOGY AND SIGNIFICANTLY DECREASED CHONDROCYTE VIABILITY. ABERRANT FSS INDUCES REMARKABLE INFLAMMATORY MEDIATORS PRODUCTION, LEADING TO CARTILAGE DEGENERATION AND DEGRADATION. IN DEPTH MECHANISTIC STUDY SHOWED THAT FSS RESULTS IN MORE THAN 10-FOLD UPREGULATION OF H3K4ME3, AND THE MODULATORY EFFECT OF H3K4ME3 ON CARTILAGE WAS OBTAINED BY DIRECTLY TARGETING ZBTB20. FURTHERMORE, WNT SIGNALING WAS STRONGLY ACTIVATED IN HIGH FSS-INDUCED OA PATHOGENESIS, AND THE NEGATIVE IMPACT OF ZBTB20 ON CHONDROCYTES WAS ALSO ACHIEVED THROUGH ACTIVATING WNT SIGNALING PATHWAY. MOREOVER, PHARMACOLOGICAL INHIBITION OF H3K4ME3 ACTIVATION BY MM-102 OR TREATMENT WITH WNT PATHWAY INHIBITOR LF3 COULD EFFECTIVELY ALLEVIATE THE DESTRUCTIVE EFFECT OF FSS ON CHONDROCYTES. IN VIVO UAC MICE MODEL VALIDATED THE DYSREGULATION OF H3K4ME3 AND ZBTB20 IN ABERRANT FORCE-INDUCED CARTILAGE PATHOGENESIS. CONCLUSION: THROUGH THE COMBINATION OF IN VITRO FSS MODEL AND IN VIVO UAC MODEL, KMT2B-H3K4ME3-ZBTB20 AXIS WAS FIRST IDENTIFIED IN ABERRANT FSS-INDUCED CARTILAGE PATHOGENESIS, WHICH MAY PROVIDE EVIDENCES FOR EPIGENETIC-BASED THERAPY IN THE FUTURE. 2021 3 6000 37 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 4 5474 31 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 5 4861 32 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 6 6586 29 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 7 984 34 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 8 26 35 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 9 1689 45 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 10 3330 38 HISTONE DEACETYLASE INHIBITOR GIVINOSTAT ALLEVIATES LIVER FIBROSIS BY REGULATING HEPATIC STELLATE CELL ACTIVATION. HEPATIC FIBROSIS, A COMMON PATHOLOGICAL MANIFESTATION OF CHRONIC LIVER INJURY, IS GENERALLY CONSIDERED TO BE THE END RESULT OF AN INCREASE IN EXTRACELLULAR MATRIX PRODUCED BY ACTIVATED HEPATIC STELLATE CELLS (HSCS). THE AIM OF THE PRESENT STUDY WAS TO TARGET THE MECHANISMS UNDERLYING HSC ACTIVATION IN ORDER TO PROVIDE A POWERFUL THERAPEUTIC STRATEGY FOR THE PREVENTION AND TREATMENT OF LIVER FIBROSIS. IN THE PRESENT STUDY, A HIGH?THROUGHPUT SCREENING ASSAY WAS ESTABLISHED, AND THE HISTONE DEACETYLASE INHIBITOR GIVINOSTAT WAS IDENTIFIED AS A POTENT INHIBITOR OF HSC ACTIVATION IN VITRO. GIVINOSTAT SIGNIFICANTLY INHIBITED HSC ACTIVATION IN VIVO, AMELIORATED CARBON TETRACHLORIDE?INDUCED MOUSE LIVER FIBROSIS AND LOWERED PLASMA AMINOTRANSFERASES. TRANSCRIPTOMIC ANALYSIS REVEALED THE MOST SIGNIFICANTLY REGULATED GENES IN THE GIVINOSTAT TREATMENT GROUP IN COMPARISON WITH THOSE IN THE SOLVENT GROUP, AMONG WHICH, DERMOKINE (DMKN), MESOTHELIN (MSLN) AND UROPLAKIN?3B (UPK3B) WERE IDENTIFIED AS POTENTIAL REGULATORS OF HSC ACTIVATION. GIVINOSTAT SIGNIFICANTLY REDUCED THE MRNA EXPRESSION OF DMKN, MSLN AND UPK3B IN BOTH A MOUSE LIVER FIBROSIS MODEL AND IN HSC?LX2 CELLS. KNOCKDOWN OF ANY OF THE AFOREMENTIONED GENES INHIBITED THE TGF?BETA1?INDUCED EXPRESSION OF ALPHA?SMOOTH MUSCLE ACTIN AND COLLAGEN TYPE I, INDICATING THAT THEY ARE CRUCIAL FOR HSC ACTIVATION. IN SUMMARY, USING A NOVEL STRATEGY TARGETING HSC ACTIVATION, THE PRESENT STUDY IDENTIFIED A POTENTIAL EPIGENETIC DRUG FOR THE TREATMENT OF HEPATIC FIBROSIS AND REVEALED NOVEL REGULATORS OF HSC ACTIVATION. 2021 11 3390 33 HOPX PLAYS A CRITICAL ROLE IN ANTIRETROVIRAL DRUGS INDUCED EPIGENETIC MODIFICATION AND CARDIAC HYPERTROPHY. PEOPLE LIVING WITH HIV (PLWH) HAVE TO TAKE AN ANTIRETROVIRAL THERAPY (ART) FOR LIFE AND SHOW NONCOMMUNICABLE ILLNESSES SUCH AS CHRONIC INFLAMMATION, IMMUNE ACTIVATION, AND MULTIORGAN DYSREGULATION. RECENT STUDIES SUGGEST THAT LONG-TERM USE OF ART INDUCES COMORBID CONDITIONS AND IS ONE OF THE LEADING CAUSES OF HEART FAILURE IN PLWH. HOWEVER, THE MOLECULAR MECHANISM OF ANTIRETROVIRAL DRUGS (ARVS) INDUCED HEART FAILURE IS UNCLEAR. TO DETERMINE THE MECHANISM OF ARVS INDUCED CARDIAC DYSFUNCTION, WE PERFORMED GLOBAL TRANSCRIPTOMIC PROFILING OF ARVS TREATED NEONATAL RAT VENTRICULAR CARDIOMYOCYTES IN CULTURE. DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED BY RNA-SEQUENCING. OUR DATA SHOW THAT ARVS TREATMENT CAUSES UPREGULATION OF SEVERAL BIOLOGICAL FUNCTIONS ASSOCIATED WITH CARDIOTOXICITY, HYPERTROPHY, AND HEART FAILURE. GLOBAL GENE EXPRESSION DATA WERE VALIDATED IN CARDIAC TISSUE ISOLATED FROM HIV PATIENTS HAVING A HISTORY OF ART. INTERESTINGLY, WE FOUND THAT HOMEODOMAIN-ONLY PROTEIN HOMEOBOX (HOPX) EXPRESSION WAS SIGNIFICANTLY INCREASED IN CARDIOMYOCYTES TREATED WITH ARVS AND IN THE HEART TISSUE OF HIV PATIENTS. FURTHERMORE, WE FOUND THAT HOPX PLAYS A CRUCIAL ROLE IN ARVS MEDIATED CELLULAR HYPERTROPHY. MECHANISTICALLY, WE FOUND THAT HOPX PLAYS A CRITICAL ROLE IN EPIGENETIC REGULATION, THROUGH DEACETYLATION OF HISTONE, WHILE THE HDAC INHIBITOR, TRICHOSTATIN A, CAN RESTORE THE ACETYLATION LEVEL OF HISTONE 3 IN THE PRESENCE OF ARVS. 2021 12 3327 35 HISTONE DEACETYLASE 4 PROMOTES CHOLESTATIC LIVER INJURY IN THE ABSENCE OF PROHIBITIN-1. PROHIBITIN-1 (PHB1) IS AN EVOLUTIONARILY CONSERVED PLEIOTROPIC PROTEIN THAT PARTICIPATES IN DIVERSE PROCESSES DEPENDING ON ITS SUBCELLULAR LOCALIZATION AND INTERACTOME. RECENT DATA HAVE INDICATED A DIVERSE ROLE FOR PHB1 IN THE PATHOGENESIS OF OBESITY, CANCER, AND INFLAMMATORY BOWEL DISEASE, AMONG OTHERS. DATA PRESENTED HERE SUGGEST THAT PHB1 IS ALSO LINKED TO CHOLESTATIC LIVER DISEASE. EXPRESSION OF PHB1 IS MARKEDLY REDUCED IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS AND BILIARY ATRESIA OR WITH ALAGILLE SYNDROME, TWO MAJOR PEDIATRIC CHOLESTATIC CONDITIONS. IN THE EXPERIMENTAL MODEL OF BILE DUCT LIGATION, SILENCING OF PHB1 INDUCED LIVER FIBROSIS, REDUCED ANIMAL SURVIVAL, AND INDUCED BILE DUCT PROLIFERATION. IMPORTANTLY, THE MODULATORY EFFECT OF PHB1 IS NOT DEPENDENT ON ITS KNOWN MITOCHONDRIAL FUNCTION. ALSO, PHB1 INTERACTS WITH HISTONE DEACETYLASE 4 (HDAC4) IN THE PRESENCE OF BILE ACIDS. HENCE, PHB1 DEPLETION LEADS TO INCREASED NUCLEAR HDAC4 CONTENT AND ITS ASSOCIATED EPIGENETIC CHANGES. REMARKABLY, HDAC4 SILENCING AND THE ADMINISTRATION OF THE HDAC INHIBITOR PARTHENOLIDE DURING OBSTRUCTIVE CHOLESTASIS IN VIVO PROMOTE GENOMIC REPROGRAMMING, LEADING TO REGRESSION OF THE FIBROTIC PHENOTYPE IN LIVER-SPECIFIC PHB1 KNOCKOUT MICE. CONCLUSION: PHB1 IS AN IMPORTANT MEDIATOR OF CHOLESTATIC LIVER INJURY THAT REGULATES THE ACTIVITY OF HDAC4, WHICH CONTROLS SPECIFIC EPIGENETIC MARKERS; THESE RESULTS IDENTIFY POTENTIAL NOVEL STRATEGIES TO TREAT LIVER INJURY AND FIBROSIS, PARTICULARLY AS A CONSEQUENCE OF CHRONIC CHOLESTASIS. 2015 13 889 33 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 14 2246 25 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 15 3468 32 HYPOXIA-INDUCED DNA HYPERMETHYLATION IN HUMAN PULMONARY FIBROBLASTS IS ASSOCIATED WITH THY-1 PROMOTER METHYLATION AND THE DEVELOPMENT OF A PRO-FIBROTIC PHENOTYPE. BACKGROUND: PULMONARY FIBROSIS IS A DEBILITATING AND LETHAL DISEASE WITH NO EFFECTIVE TREATMENT OPTIONS. UNDERSTANDING THE PATHOLOGICAL PROCESSES AT PLAY WILL DIRECT THE APPLICATION OF NOVEL THERAPEUTIC AVENUES. HYPOXIA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF PULMONARY FIBROSIS YET THE PRECISE MECHANISM BY WHICH IT CONTRIBUTES TO DISEASE PROGRESSION REMAINS TO BE FULLY ELUCIDATED. IT HAS BEEN SHOWN THAT CHRONIC HYPOXIA CAN ALTER DNA METHYLATION PATTERNS IN TUMOUR-DERIVED CELL LINES. THIS EPIGENETIC ALTERATION CAN INDUCE CHANGES IN CELLULAR PHENOTYPE WITH PROMOTER METHYLATION BEING ASSOCIATED WITH GENE SILENCING. OF PARTICULAR RELEVANCE TO IDIOPATHIC PULMONARY FIBROSIS (IPF) IS THE OBSERVATION THAT THY-1 PROMOTER METHYLATION IS ASSOCIATED WITH A MYOFIBROBLAST PHENOTYPE WHERE LOSS OF THY-1 OCCURS ALONGSIDE INCREASED ALPHA SMOOTH MUSCLE ACTIN (ALPHA-SMA) EXPRESSION. THE INITIAL AIM OF THIS STUDY WAS TO DETERMINE WHETHER HYPOXIA REGULATES DNA METHYLATION IN NORMAL HUMAN LUNG FIBROBLASTS (CCD19LU). AS IT HAS BEEN REPORTED THAT HYPOXIA SUPPRESSES THY-1 EXPRESSION DURING LUNG DEVELOPMENT WE ALSO STUDIED THE EFFECT OF HYPOXIA ON THY-1 PROMOTER METHYLATION AND GENE EXPRESSION. METHODS: CCD19LU WERE GROWN FOR UP TO 8 DAYS IN HYPOXIA AND ASSESSED FOR GLOBAL CHANGES IN DNA METHYLATION USING FLOW CYTOMETRY. REAL-TIME PCR WAS USED TO QUANTIFY EXPRESSION OF THY-1, ALPHA-SMA, COLLAGEN I AND III. GENOMIC DNA WAS BISULPHITE TREATED AND METHYLATION SPECIFIC PCR (MSPCR) WAS USED TO EXAMINE THE METHYLATION STATUS OF THE THY-1 PROMOTER. RESULTS: SIGNIFICANT GLOBAL HYPERMETHYLATION WAS DETECTED IN HYPOXIC FIBROBLASTS RELATIVE TO NORMOXIC CONTROLS AND WAS ACCOMPANIED BY INCREASED EXPRESSION OF MYOFIBROBLAST MARKERS. THY-1 MRNA EXPRESSION WAS SUPPRESSED IN HYPOXIC CELLS, WHICH WAS RESTORED WITH THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE. MSPCR REVEALED THAT THY-1 BECAME METHYLATED FOLLOWING FIBROBLAST EXPOSURE TO 1% O2. CONCLUSION: THESE DATA SUGGEST THAT GLOBAL AND GENE-SPECIFIC CHANGES IN DNA METHYLATION MAY PLAY AN IMPORTANT ROLE IN FIBROBLAST FUNCTION IN HYPOXIA. 2012 16 3198 32 HDAC-LINKED "PROLIFERATIVE" MIRNA EXPRESSION PATTERN IN PANCREATIC NEUROENDOCRINE TUMORS. EPIGENETIC FACTORS ARE ESSENTIALLY INVOLVED IN CARCINOGENESIS, TUMOR PROMOTION, AND CHEMORESISTANCE. TWO EPIGENETIC KEY PLAYERS ARE MIRNAS AND HISTONE DEACETYLASES (HDACS). AS PREVIOUSLY SHOWN BY OWN THEORETICAL DATABANK ANALYSIS, THE CROSSTALK BETWEEN MIRNAS AND HDACS IS RELEVANT IN DIFFERENT HUMAN CHRONIC DISEASES AND CANCEROGENIC PATHWAYS. WE AIMED TO INVESTIGATE A POTENTIAL CONNECTION BETWEEN THE EXPRESSION OF A WELL-DEFINED SUBSET OF "PROLIFERATION-ASSOCIATED" MIRNAS AND THE EXPRESSION OF HDACS AS WELL AS CLINICAL PARAMETERS IN PANCREATIC NEUROENDOCRINE TUMORS (PNETS). MATERIALS AND METHODS: EXPRESSION LEVELS OF MIRNA132-3P, MIRNA145-5P, MIRNA183-5P, MIRNA34A-5P, AND MIRNA449A IN 57 PNETS RESECTED BETWEEN 1997 AND 2015 WERE MEASURED AND LINKED TO THE IMMUNOHISTOCHEMICAL EXPRESSION PATTERN OF MEMBERS OF THE FOUR HDAC CLASSES ON HUMAN TISSUE MICROARRAYS. ALL PNET CASES WERE CLINICALLY AND PATHOLOGICALLY CHARACTERIZED ACCORDING TO PUBLISHED GUIDELINES. CORRELATION ANALYSIS REVEALED A SIGNIFICANT ASSOCIATION BETWEEN EXPRESSION OF SPECIFIC MIRNAS AND TWO MEMBERS OF THE HDAC FAMILY (HDAC3 AND HDAC4). ADDITIONALLY, A LINKAGE BETWEEN MIRNA EXPRESSION AND CLINICO-PATHOLOGICAL PARAMETERS LIKE GRADING, TNM-STAGING, AND HORMONE ACTIVITY WAS FOUND. MOREOVER, OVERALL AND DISEASE-FREE SURVIVAL IS STATISTICALLY CORRELATED WITH THE EXPRESSION OF THE INVESTIGATED MIRNAS. OVERALL, WE DEMONSTRATED THAT SPECIFIC MIRNAS COULD BE LINKED TO HDAC EXPRESSION IN PNETS. ESPECIALLY MIRNA449A (ASSOCIATED WITH HDAC3/4) SEEMS TO PLAY AN IMPORTANT ROLE IN PNET PROLIFERATION AND COULD BE A POTENTIAL PROGNOSTIC FACTOR FOR POOR SURVIVAL. THESE FIRST DATA COULD HELP, TO IMPROVE OUR KNOWLEDGE OF THE COMPLEX INTERACTIONS OF THE EPIGENETIC DRIVERS IN PNETS FOR FURTHER THERAPEUTIC APPROACHES. 2018 17 2340 37 EPIGENETIC REGULATION OF LEUKOCYTE INFLAMMATORY MEDIATOR PRODUCTION DICTATES STAPHYLOCOCCUS AUREUS CRANIOTOMY INFECTION OUTCOME. STAPHYLOCOCCUS AUREUS IS A COMMON CAUSE OF SURGICAL-SITE INFECTIONS, INCLUDING THOSE ARISING AFTER CRANIOTOMY, WHICH IS PERFORMED TO ACCESS THE BRAIN FOR THE TREATMENT OF TUMORS, EPILEPSY, OR HEMORRHAGE. CRANIOTOMY INFECTION IS CHARACTERIZED BY COMPLEX SPATIAL AND TEMPORAL DYNAMICS OF LEUKOCYTE RECRUITMENT AND MICROGLIAL ACTIVATION. WE RECENTLY IDENTIFIED UNIQUE TRANSCRIPTIONAL PROFILES OF THESE IMMUNE POPULATIONS DURING S. AUREUS CRANIOTOMY INFECTION. EPIGENETIC PROCESSES ALLOW RAPID AND REVERSIBLE CONTROL OVER GENE TRANSCRIPTION; HOWEVER, LITTLE IS KNOWN ABOUT HOW EPIGENETIC PATHWAYS INFLUENCE IMMUNITY TO LIVE S. AUREUS. AN EPIGENETIC COMPOUND LIBRARY SCREEN IDENTIFIED BROMODOMAIN AND EXTRATERMINAL DOMAIN-CONTAINING (BET) PROTEINS AND HISTONE DEACETYLASES (HDACS) AS CRITICAL FOR REGULATING TNF, IL-6, IL-10, AND CCL2 PRODUCTION BY PRIMARY MOUSE MICROGLIA, MACROPHAGES, NEUTROPHILS, AND GRANULOCYTIC MYELOID-DERIVED SUPPRESSOR CELLS IN RESPONSE TO LIVE S. AUREUS. CLASS I HDACS (C1HDACS) WERE INCREASED IN THESE CELL TYPES IN VITRO AND IN VIVO DURING ACUTE DISEASE IN A MOUSE MODEL OF S. AUREUS CRANIOTOMY INFECTION. HOWEVER, SUBSTANTIAL REDUCTIONS IN C1HDACS WERE OBSERVED DURING CHRONIC INFECTION, HIGHLIGHTING TEMPORAL REGULATION AND THE IMPORTANCE OF THE TISSUE MICROENVIRONMENT FOR DICTATING C1HDAC EXPRESSION. MICROPARTICLE DELIVERY OF HDAC AND BET INHIBITORS IN VIVO CAUSED WIDESPREAD DECREASES IN INFLAMMATORY MEDIATOR PRODUCTION, WHICH SIGNIFICANTLY INCREASED BACTERIAL BURDEN IN THE BRAIN, GALEA, AND BONE FLAP. THESE FINDINGS IDENTIFY HISTONE ACETYLATION AS AN IMPORTANT MECHANISM FOR REGULATING CYTOKINE AND CHEMOKINE PRODUCTION ACROSS DIVERSE IMMUNE CELL LINEAGES THAT IS CRITICAL FOR BACTERIAL CONTAINMENT. ACCORDINGLY, ABERRANT EPIGENETIC REGULATION MAY BE IMPORTANT FOR PROMOTING S. AUREUS PERSISTENCE DURING CRANIOTOMY INFECTION. 2023 18 5859 35 SULFORAPHANE PREVENTS AND REVERSES ALLERGIC AIRWAYS DISEASE IN MICE VIA ANTI-INFLAMMATORY, ANTIOXIDANT, AND EPIGENETIC MECHANISMS. SULFORAPHANE HAS BEEN INVESTIGATED IN HUMAN PATHOLOGIES AND PRECLINICAL MODELS OF AIRWAY DISEASES. TO PROVIDE FURTHER MECHANISTIC INSIGHTS, WE EXPLORED L-SULFORAPHANE (LSF) IN THE OVALBUMIN (OVA)-INDUCED CHRONIC ALLERGIC AIRWAYS MURINE MODEL, WITH KEY HALLMARKS OF ASTHMA. HISTOLOGICAL ANALYSIS INDICATED THAT LSF PREVENTED OR REVERSED OVA-INDUCED EPITHELIAL THICKENING, COLLAGEN DEPOSITION, GOBLET CELL METAPLASIA, AND INFLAMMATION. WELL-KNOWN ANTIOXIDANT AND ANTI-INFLAMMATORY MECHANISMS CONTRIBUTE TO THE BENEFICIAL EFFECTS OF LSF. FOURIER TRANSFORM INFRARED MICROSPECTROSCOPY REVEALED ALTERED COMPOSITION OF MACROMOLECULES, FOLLOWING OVA SENSITIZATION, WHICH WERE RESTORED BY LSF. RNA SEQUENCING IN HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS HIGHLIGHTED THE ANTI-INFLAMMATORY SIGNATURE OF LSF. FINDINGS INDICATED THAT LSF MAY ALTER GENE EXPRESSION VIA AN EPIGENETIC MECHANISM WHICH INVOLVES REGULATION OF PROTEIN ACETYLATION STATUS. LSF RESULTED IN HISTONE AND ALPHA-TUBULIN HYPERACETYLATION IN VIVO, AND CELLULAR AND ENZYMATIC ASSAYS INDICATED DECREASED EXPRESSION AND MODEST HISTONE DEACETYLASE (HDAC) INHIBITION ACTIVITY, IN COMPARISON WITH THE WELL-KNOWN PAN-HDAC INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA). MOLECULAR MODELING CONFIRMED INTERACTION OF LSF AND LSF METABOLITES WITH THE CATALYTIC DOMAIN OF METAL-DEPENDENT HDAC ENZYMES. MORE GENERALLY, THIS STUDY CONFIRMED KNOWN MECHANISMS AND IDENTIFIED POTENTIAL EPIGENETIC PATHWAYS ACCOUNTING FOR THE PROTECTIVE EFFECTS AND PROVIDE SUPPORT FOR THE POTENTIAL CLINICAL UTILITY OF LSF IN ALLERGIC AIRWAYS DISEASE. 2022 19 3049 29 GENOME-WIDE ANALYSIS REVEALS ZINC TRANSPORTER ZIP9 REGULATED BY DNA METHYLATION PROMOTES RADIATION-INDUCED SKIN FIBROSIS VIA THE TGF-BETA SIGNALING PATHWAY. RADIATION-INDUCED SKIN FIBROSIS IS A DETRIMENTAL AND CHRONIC DISORDER THAT OCCURS AFTER RADIATION EXPOSURE. DNA METHYLATION HAS BEEN CHARACTERIZED AS AN IMPORTANT REGULATORY MECHANISM OF MULTIPLE PATHOLOGICAL PROCESSES. IN THIS STUDY, WE COMPARED THE GENOME-WIDE DNA METHYLATION STATUS IN RADIATION-INDUCED FIBROTIC SKIN AND ADJACENT NORMAL TISSUES OF RATS BY METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING. RADIATION-INDUCED FIBROTIC SKIN SHOWED DIFFERENTIALLY METHYLATED REGIONS ASSOCIATED WITH 3,650 PROTEIN-CODING GENES, 72 MICRORNAS, 5,836 LONG NONCODING RNAS AND 3 PIWI-INTERACTING RNAS. BY INTEGRATING THE MRNA AND METHYLATION PROFILES, THE ZINC TRANSPORTER SLC39A9/ZIP9 WAS INVESTIGATED IN GREATER DETAIL. THE PROTEIN LEVEL OF ZIP9 WAS INCREASED IN IRRADIATED SKIN TISSUES OF HUMANS, MONKEYS, AND RATS, ESPECIALLY IN RADIOGENIC FIBROTIC SKIN TISSUES. RADIATION INDUCED THE DEMETHYLATION OF A CPG DINUCLEOTIDE IN EXON 1 OF ZIP9 THAT RESULTED IN RECRUITMENT OF THE TRANSCRIPTIONAL FACTOR SP1 AND INCREASED ZIP9 EXPRESSION. OVEREXPRESSION OF ZIP9 RESULTED IN ACTIVATION OF THE PROFIBROTIC TRANSFORMING GROWTH FACTOR-BETA SIGNALING PATHWAY THROUGH PROTEIN KINASE B IN HUMAN FIBROBLASTS. IN ADDITION, RADIATION-INDUCED SKIN FIBROSIS WAS ASSOCIATED WITH INCREASED ZINC ACCUMULATION. THE ZINC CHELATOR N,N,N',N'-TETRAKIS(2-PYRIDYLMETHYL)-1,2-ETHYLENEDIAMINE ABROGATED ZIP9-INDUCED ACTIVATION OF THE TRANSFORMING GROWTH FACTOR-BETA SIGNALING PATHWAY AND ATTENUATED RADIATION-INDUCED SKIN FIBROSIS IN A RAT MODEL. IN SUMMARY, OUR FINDINGS ILLUSTRATE EPIGENETIC REGULATION OF ZIP9 AND ITS CRITICAL ROLE IN PROMOTING RADIATION-INDUCED SKIN FIBROSIS. 2020 20 5153 26 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION. 2019