1 6224 175 THE LEUCINE CATABOLITE AND DIETARY SUPPLEMENT BETA-HYDROXY-BETA-METHYL BUTYRATE (HMB) AS AN EPIGENETIC REGULATOR IN MUSCLE PROGENITOR CELLS. BETA-HYDROXY-BETA-METHYL BUTYRATE (HMB) IS A NATURAL CATABOLITE OF LEUCINE DEEMED TO PLAY A ROLE IN AMINO ACID SIGNALING AND THE MAINTENANCE OF LEAN MUSCLE MASS. ACCORDINGLY, HMB IS USED AS A DIETARY SUPPLEMENT BY SPORTSMEN AND HAS SHOWN SOME CLINICAL EFFECTIVENESS IN PREVENTING MUSCLE WASTING IN CANCER AND CHRONIC LUNG DISEASE, AS WELL AS IN AGE-DEPENDENT SARCOPENIA. HOWEVER, THE MOLECULAR CASCADES UNDERLYING THESE BENEFICIAL EFFECTS ARE LARGELY UNKNOWN. HMB BEARS A SIGNIFICANT STRUCTURAL SIMILARITY WITH BUTYRATE AND BETA-HYDROXYBUTYRATE (BETAHB), TWO COMPOUNDS RECOGNIZED FOR IMPORTANT EPIGENETIC AND HISTONE-MARKING ACTIVITIES IN MULTIPLE CELL TYPES INCLUDING MUSCLE CELLS. WE ASKED WHETHER SIMILAR CHROMATIN-MODIFYING ACTIONS COULD BE ASSIGNED TO HMB AS WELL. EXPOSURE OF MURINE C2C12 MYOBLASTS TO MILLIMOLAR CONCENTRATIONS OF HMB LED TO AN INCREASE IN GLOBAL HISTONE ACETYLATION, AS MONITORED BY ANTI-ACETYLATED LYSINE IMMUNOBLOTTING, WHILE PREVENTING MYOTUBE DIFFERENTIATION. IN THESE EFFECTS, HMB RESEMBLED, ALTHOUGH WITH LESS POTENCY, THE HISTONE DEACETYLASE (HDAC) INHIBITOR SODIUM BUTYRATE. HOWEVER, INITIAL STUDIES DID NOT CONFIRM A DIRECT INHIBITORY EFFECT OF HMB ON HDACS IN VITRO. BETA-HYDROXYBUTYRATE, A KETONE BODY PRODUCED BY THE LIVER DURING STARVATION OR INTENSE EXERCISE, HAS A MODEST EFFECT ON HISTONE ACETYLATION OF C2C12 CELLS OR IN VITRO HDAC INHIBITOR ACTIVITIES, AND, UNLIKE BUTYRATE AND HMB, DID NOT INTERFERE WITH MYOTUBE FORMATION IN A MYOBLAST DIFFERENTIATION ASSAY. INSTEAD, BETAHB DRAMATICALLY INCREASED LYSINE BETA-HYDROXYBUTYRYLATION (KBHB) OF HISTONE TAILS, AN EPIGENETIC MARK ASSOCIATED WITH FASTING RESPONSES AND MUSCLE CATABOLIC STATES. HOWEVER, WHEN C2C12 CELLS WERE EXPOSED TO BETAHB IN THE PRESENCE OF EQUIMOLAR HMB THIS CHROMATIN MODIFICATION WAS DRASTICALLY REDUCED, POINTING TO A ROLE FOR HMB IN ATTENUATING KETOSIS-ASSOCIATED MUSCLE WASTING. IN CONCLUSION, WHILE THEIR MECHANISTIC UNDERPINNINGS REMAIN TO BE CLARIFIED, THESE PRELIMINARY OBSERVATIONS HIGHLIGHT NOVEL AND POTENTIALLY IMPORTANT ACTIVITIES OF HMB AS AN EPIGENETIC REGULATOR AND BETAHB ANTAGONIST IN MUSCLE PRECURSOR CELLS, TO BE FURTHER EXPLORED IN THEIR BIOMEDICAL IMPLICATIONS. 2021 2 3633 44 INCREASE IN HDAC9 SUPPRESSES MYOBLAST DIFFERENTIATION VIA EPIGENETIC REGULATION OF AUTOPHAGY IN HYPOXIA. EXTREMELY REDUCED OXYGEN (O(2)) LEVELS ARE DETRIMENTAL TO MYOGENIC DIFFERENTIATION AND MULTINUCLEATED MYOTUBE FORMATION, AND CHRONIC EXPOSURE TO HIGH-ALTITUDE HYPOXIA HAS BEEN REPORTED TO BE AN IMPORTANT FACTOR IN SKELETAL MUSCLE ATROPHY. HOWEVER, HOW CHRONIC HYPOXIA CAUSES MUSCLE DYSFUNCTION REMAINS UNKNOWN. IN THE PRESENT STUDY, WE FOUND THAT SEVERE HYPOXIA (1% O(2)) SIGNIFICANTLY INHIBITED THE FUNCTION OF C2C12 CELLS (FROM A MYOBLAST CELL LINE). IMPORTANTLY, THE IMPAIRMENT WAS CONTINUOUSLY MANIFESTED EVEN DURING CULTURE UNDER NORMOXIC CONDITIONS FOR SEVERAL PASSAGES. MECHANISTICALLY, WE REVEALED THAT HISTONE DEACETYLASES 9 (HDAC9), A MEMBER OF THE HISTONE DEACETYLASE FAMILY, WAS SIGNIFICANTLY INCREASED IN C2C12 CELLS UNDER HYPOXIC CONDITIONS, THEREBY INHIBITING INTRACELLULAR AUTOPHAGY LEVELS BY DIRECTLY BINDING TO THE PROMOTER REGIONS OF ATG7, BECLIN1, AND LC3. THIS PHENOMENON RESULTED IN THE SEQUENTIAL DEPHOSPHORYLATION OF GSK3BETA AND INACTIVATION OF THE CANONICAL WNT PATHWAY, IMPAIRING THE FUNCTION OF THE C2C12 CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT HYPOXIA-INDUCED MYOBLAST DYSFUNCTION IS DUE TO ABERRANT EPIGENETIC REGULATION OF AUTOPHAGY, AND OUR EXPERIMENTAL EVIDENCE REVEALS THE POSSIBLE MOLECULAR PATHOGENESIS RESPONSIBLE FOR SOME MUSCLE DISEASES CAUSED BY CHRONIC HYPOXIA AND SUGGESTS A POTENTIAL THERAPEUTIC OPTION. 2019 3 706 45 BUTYRATE AND DIETARY SOLUBLE FIBER IMPROVE NEUROINFLAMMATION ASSOCIATED WITH AGING IN MICE. AGING RESULTS IN CHRONIC SYSTEMIC INFLAMMATION THAT CAN ALTER NEUROINFLAMMATION OF THE BRAIN. SPECIFICALLY, MICROGLIA SHIFT TO A PRO-INFLAMMATORY PHENOTYPE PREDISPOSING THEM TO HYPERACTIVATION UPON STIMULATION BY PERIPHERAL IMMUNE SIGNALS. IT IS PROPOSED THAT CERTAIN NUTRIENTS CAN DELAY BRAIN AGING BY PREVENTING OR REVERSING MICROGLIAL HYPERACTIVATION. BUTYRATE, A SHORT-CHAIN FATTY ACID (SCFA) PRODUCED PRIMARILY BY BACTERIAL FERMENTATION OF FIBER IN THE COLON, HAS BEEN EXTENSIVELY STUDIED PHARMACOLOGICALLY AS A HISTONE DEACETYLASE INHIBITOR AND SERVES AS AN ATTRACTIVE THERAPEUTIC CANDIDATE, AS BUTYRATE HAS ALSO BEEN SHOWN TO BE ANTI-INFLAMMATORY AND IMPROVE MEMORY IN ANIMAL MODELS. IN THIS STUDY, WE DEMONSTRATE THAT BUTYRATE CAN ATTENUATE PRO-INFLAMMATORY CYTOKINE EXPRESSION IN MICROGLIA IN AGED MICE. IT IS STILL NOT FULLY UNDERSTOOD, HOWEVER, IF AN INCREASE IN BUTYRATE-PRODUCING BACTERIA IN THE GUT AS A CONSEQUENCE OF A DIET HIGH IN SOLUBLE FIBER COULD AFFECT MICROGLIAL ACTIVATION DURING AGING. ADULT AND AGED MICE WERE FED EITHER A 1% CELLULOSE (LOW FIBER) OR 5% INULIN (HIGH FIBER) DIET FOR 4 WEEKS. FINDINGS INDICATE THAT MICE FED INULIN HAD AN ALTERED GUT MICROBIOME AND INCREASED BUTYRATE, ACETATE, AND TOTAL SCFA PRODUCTION. IN ADDITION, HISTOLOGICAL SCORING OF THE DISTAL COLON DEMONSTRATED THAT AGED ANIMALS ON THE LOW FIBER DIET HAD INCREASED INFLAMMATORY INFILTRATE THAT WAS SIGNIFICANTLY REDUCED IN ANIMALS CONSUMING THE HIGH FIBER DIET. FURTHERMORE, GENE EXPRESSION OF INFLAMMATORY MARKERS, EPIGENETIC REGULATORS, AND THE MICROGLIAL SENSORY APPARATUS (I.E., THE SENSOME) WERE ALTERED BY BOTH DIET AND AGE, WITH AGED ANIMALS EXHIBITING A MORE ANTI-INFLAMMATORY MICROGLIAL PROFILE ON THE HIGH FIBER DIET. TAKEN TOGETHER, HIGH FIBER SUPPLEMENTATION IN AGING IS A NON-INVASIVE STRATEGY TO INCREASE BUTYRATE LEVELS, AND THESE DATA SUGGEST THAT AN INCREASE IN BUTYRATE THROUGH ADDED SOLUBLE FIBER SUCH AS INULIN COULD COUNTERBALANCE THE AGE-RELATED MICROBIOTA DYSBIOSIS, POTENTIALLY LEADING TO NEUROLOGICAL BENEFITS. 2018 4 3882 30 KETONE BODIES AS METABOLITES AND SIGNALLING MOLECULES AT THE CROSSROAD BETWEEN INFLAMMATION AND EPIGENETIC CONTROL OF CARDIOMETABOLIC DISORDERS. FOR MANY YEARS, IT HAS BEEN CLEAR THAT A WESTERN DIET RICH IN SATURATED FATS AND SUGARS PROMOTES AN INFLAMMATORY ENVIRONMENT PREDISPOSING A PERSON TO CHRONIC CARDIOMETABOLIC DISEASES. IN PARALLEL, THE EMERGENCE OF KETOGENIC DIETS, DEPRIVED OF CARBOHYDRATES AND PROMOTING THE SYNTHESIS OF KETONE BODIES IMITATING THE METABOLIC EFFECTS OF FASTING, HAS BEEN SHOWN TO PROVIDE A POSSIBLE NUTRITIONAL SOLUTION TO ALLEVIATING DISEASES TRIGGERED BY AN INFLAMMATORY ENVIRONMENT. THE MAIN KETONE BODY, BETA-HYDROXYBUTYRATE (BHB), ACTS AS AN ALTERNATIVE FUEL, AND ALSO AS A SUBSTRATE FOR A NOVEL HISTONE POST-TRANSLATIONAL MODIFICATION, BETA-HYDROXYBUTYRYLATION. BETA-HYDROXYBUTYRYLATION INFLUENCES THE STATE OF CHROMATIN ARCHITECTURE AND PROMOTES THE TRANSCRIPTION OF MULTIPLE GENES. BHB HAS ALSO BEEN SHOWN TO MODULATE INFLAMMATION IN CHRONIC DISEASES. IN THIS REVIEW, WE DISCUSS, IN THE PATHOLOGICAL CONTEXT OF CARDIOVASCULAR RISKS, THE CURRENT UNDERSTANDING OF HOW KETONE BODIES, OR A KETOGENIC DIET, ARE ABLE TO MODULATE, TRIGGER, OR INHIBIT INFLAMMATION AND HOW THE EPIGENOME AND CHROMATIN REMODELING MAY BE A KEY CONTRIBUTOR. 2022 5 5947 39 TARGETING THE EPIGENOME: SCREENING BIOACTIVE COMPOUNDS THAT REGULATE HISTONE DEACETYLASE ACTIVITY. SCOPE: NUTRIGENOMICS IS A RAPIDLY EXPANDING FIELD THAT ELUCIDATES THE LINK BETWEEN DIET-GENOME INTERACTIONS. RECENT EVIDENCE DEMONSTRATES THAT REGULATION OF THE EPIGENOME, AND IN PARTICULAR INHIBITION OF HISTONE DEACETYLASES (HDACS), IMPACT PATHOGENETIC MECHANISMS INVOLVED IN CHRONIC DISEASE. FEW STUDIES, TO DATE, HAVE SCREENED LIBRARIES OF BIOACTIVE COMPOUNDS THAT ACT AS EPIGENETIC MODIFIERS. THIS STUDY SCREENED A LIBRARY OF 131 NATURAL COMPOUNDS TO DETERMINE BIOACTIVE COMPOUNDS THAT INHIBIT ZN-DEPENDENT HDAC ACTIVITY. METHODS AND RESULTS: USING CLASS-SPECIFIC HDAC SUBSTRATES, WE SCREENED 131 NATURAL COMPOUNDS FOR HDAC ACTIVITY IN BOVINE CARDIAC TISSUE. FROM THIS SCREEN, WE IDENTIFIED 18 BIOACTIVE COMPOUND HDAC INHIBITORS. USING OUR CLASS-SPECIFIC HDAC SUBSTRATES, WE NEXT SCREENED THESE 18 BIOACTIVE COMPOUNDS AGAINST RECOMBINANT HDAC PROTEINS. CONSISTENT WITH INHIBITION OF HDAC ACTIVITY, THESE COMPOUNDS WERE CAPABLE OF INHIBITING ACTIVITY OF INDIVIDUAL HDAC ISOFORMS. LASTLY, WE REPORT THAT TREATMENT OF H9C2 CARDIAC MYOBLASTS WITH BIOACTIVE HDAC INHIBITORS WAS SUFFICIENT TO INCREASE LYSINE ACETYLATION AS ASSESSED VIA IMMUNOBLOT. CONCLUSION: THIS STUDY PROVIDED THE FIRST STEP IN IDENTIFYING MULTIPLE BIOACTIVE COMPOUND HDAC INHIBITORS. TAKEN TOGETHER, THIS REPORT SETS THE STAGE FOR FUTURE EXPLORATION OF THESE BIOACTIVE COMPOUNDS AS EPIGENETIC REGULATORS TO POTENTIALLY AMELIORATE CHRONIC DISEASE. 2017 6 1339 41 DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION, AND STRUCTURAL CHARACTERIZATION OF POTENT HISTONE DEACETYLASE INHIBITORS BASED ON CYCLIC ALPHA/BETA-TETRAPEPTIDE ARCHITECTURES. HISTONE DEACETYLASES (HDACS) ARE A FAMILY OF ENZYMES FOUND IN BACTERIA, FUNGI, PLANTS, AND ANIMALS THAT PROFOUNDLY AFFECT CELLULAR FUNCTION BY CATALYZING THE REMOVAL OF ACETYL GROUPS FROM -N-ACETYLATED LYSINE RESIDUES OF VARIOUS PROTEIN SUBSTRATES INCLUDING HISTONES, TRANSCRIPTION FACTORS, ALPHA-TUBULIN, AND NUCLEAR IMPORTERS. ALTHOUGH THE PRECISE ROLES OF HDAC ISOFORMS IN CELLULAR FUNCTION ARE NOT YET COMPLETELY UNDERSTOOD, INHIBITION OF HDAC ACTIVITY HAS EMERGED AS A PROMISING APPROACH FOR REVERSING THE ABERRANT EPIGENETIC STATES ASSOCIATED WITH CANCER AND OTHER CHRONIC DISEASES. POTENT NEW ISOFORM-SELECTIVE HDAC INHIBITORS WOULD THEREFORE HELP EXPAND OUR UNDERSTANDING OF THE HDAC ENZYMES AND REPRESENT ATTRACTIVE LEAD COMPOUNDS FOR DRUG DESIGN, ESPECIALLY IF COMBINED WITH HIGH-RESOLUTION STRUCTURAL ANALYSES OF SUCH INHIBITORS TO SHED LIGHT ON THE THREE-DIMENSIONAL PHARMACOPHORIC FEATURES NECESSARY FOR THE FUTURE DESIGN OF MORE POTENT AND SELECTIVE COMPOUNDS. HERE WE PRESENT STRUCTURAL AND FUNCTIONAL ANALYSES OF A SERIES OF BETA-AMINO-ACID-CONTAINING HDAC INHIBITORS INSPIRED BY CYCLIC TETRAPEPTIDE NATURAL PRODUCTS. TO SURVEY A DIVERSE ENSEMBLE OF PHARMACOPHORIC CONFIGURATIONS, WE SYSTEMATICALLY VARIED THE POSITION OF THE BETA-AMINO ACID, AMINO ACID CHIRALITY, FUNCTIONALIZATION OF THE ZN(2+)-COORDINATING AMINO ACID SIDE CHAIN, AND ALKYLATION OF THE BACKBONE AMIDE NITROGEN ATOMS AROUND THE MACROCYCLE. IN MANY CASES, THE COMPOUNDS WERE A SINGLE CONFORMATION IN SOLUTION AND EXHIBITED POTENT ACTIVITIES AGAINST A NUMBER OF HDAC ISOFORMS AS WELL AS EFFECTIVE ANTIPROLIFERATIVE AND CYTOTOXIC ACTIVITIES AGAINST HUMAN TUMOR CELLS. HIGH-RESOLUTION NMR SOLUTION STRUCTURES WERE DETERMINED FOR A SELECTION OF THE INHIBITORS, PROVIDING A USEFUL MEANS OF CORRELATING DETAILED STRUCTURAL INFORMATION WITH POTENCY. THE STRUCTURE-BASED APPROACH DESCRIBED HERE IS EXPECTED TO FURNISH VALUABLE INSIGHTS TOWARD THE FUTURE DESIGN OF MORE SELECTIVE HDAC INHIBITORS. 2009 7 3335 32 HISTONE DEACETYLASE INHIBITORS FOR CARDIOVASCULAR CONDITIONS AND HEALTHY LONGEVITY. HISTONE DEACETYLASE INHIBITORS (HDACI) REGULATE GENE EXPRESSION VIA EPIGENETIC MECHANISMS. ACCUMULATING EVIDENCE SUGGESTS THAT HDACI EXERT ANTIPROLIFERATIVE, ANTIOXIDANT, ANTINEOPLASTIC, AND PROAPOPTOTIC EFFECTS THROUGH EPIGENETIC MECHANISMS. FURTHERMORE, HDACI ALSO EXERT ANTITHROMBOTIC AND ANTIFIBROTIC EFFECTS THROUGH REGULATION OF THROMBOTIC AND FIBROTIC TRANSDUCTION MECHANISMS. ONE OF THE OLDEST HDACI IS VALPROIC ACID, WHICH WAS FIRST SYNTHESISED IN 1882. AFTER THE DISCOVERY OF ITS ANTICONVULSANT PROPERTIES FOR THE TREATMENT OF EPILEPSY, THE USE OF VALPROIC ACID WAS EXTENDED TO OTHER CONDITIONS, SUCH AS BIPOLAR DISORDER AND MIGRAINE. GIVEN THE ACCUMULATING EVIDENCE SUPPORTING THE ROLE OF HDACI IN THE TREATMENT OF MULTIPLE MEDICAL CONDITIONS BEYOND EPILEPSY, THE INTEREST IN NOVEL POTENTIAL INDICATIONS FOR HDACI HAS BEEN RENEWED. CONSIDERING THE PLEOTROPIC EPIGENETIC EFFECTS OF HDACI, FUTURE STUDIES COULD ASSESS THEIR EFFICACY AND SAFETY FOR CARDIOVASCULAR DISEASE PREVENTION AND TREATMENT; TREATMENT OF VENOUS THROMBOSIS, ALZHEIMER'S DISEASE, AUTOIMMUNE AND PROINFLAMMATORY CONDITIONS, CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION, AND PULMONARY ARTERIAL HYPERTENSION; AND AS A COADJUVANT THERAPY FOR CANCER. ADEQUATELY DESIGNED AND POWERED CLINICAL TRIALS ARE REQUIRED TO ASSESS THE EFFICACY AND SAFETY OF HDACI BEFORE THEIR CLINICAL REPURPOSING. 2021 8 2119 36 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 9 3348 42 HISTONE DEACETYLASES MEET MICRORNA-ASSOCIATED MMP-9 EXPRESSION REGULATION IN GLUCOCORTICOID-SENSITIVE AND -RESISTANT CELL LINES. GLUCOCORTICOIDS ARE LARGELY USED IN THE TREATMENT OF INFLAMMATORY PATHOLOGIES AND/OR HEMATOLOGICAL MALIGNANCIES AND REGULATE THE EXPRESSION OF A VARIETY OF GENES INVOLVED IN INFLAMMATION OR METASTASIS SUCH AS MATRIX METALLOPROTEINASES (MMP). LONG-TERM EXPOSURE TO GLUCOCORTICOIDS CAN RESULT IN FAILURE OF RESPONSIVENESS, WHICH IS OFTEN ASSOCIATED WITH AN UNWANTED GENE EXPRESSION. EPIGENETIC MECHANISMS ARE INVOLVED IN GENE EXPRESSION MODULATED AFTER DEVELOPMENT OF GLUCOCORTICOID RESISTANCE BUT HOW THESE MECHANISMS TAKE PLACE MUST BE FURTHER STUDIED. THE EFFECTS OF HDAC INHIBITORS (HDACI) IN A CONTEXT OF GLUCOCORTICOID RESISTANCE ARE STILL NOT WELL UNDERSTOOD AND NEED TO BE FURTHER INVESTIGATED. WE HYPOTHESIZED THAT ACQUIRED GLUCOCORTICOID RESISTANCE ASSOCIATED TO HDACI COULD DISTURBS EPIGENETIC LANDSCAPE, ESPECIALLY MIR EXPRESSION, LEADING TO A MODULATION OF MMP-9 GENE EXPRESSION AND/OR PROTEIN SECRETION, DESCRIBED AS LARGELY INVOLVED IN BONE REMODELING AND TUMOR INVASION IN MULTIPLE MYELOMA. TO THIS AIM, WE USED SENSITIVE RPMI-8226 CELL LINE AND ITS DEXAMETHASONE- AND METHYLPREDNISOLONE-RESISTANT DERIVATIVES. THE RESISTANT CELL LINES DISPLAYED AN 'OPEN CHROMATIN' AND AN MMP-9 OVEREXPRESSION COMPARATIVELY TO THE SENSITIVE CELL LINE. HDACI TREATMENT WITH MS-275 INCREASED EVEN MORE MMP-9 OVEREXPRESSION NOT ONLY AT AN MRNA LEVEL BUT ALSO AT THE PROTEIN LEVEL. WE SHOWED THAT MMP-9 EXPRESSION REGULATION WAS NOT DIRECTLY LINKED WITH HAT/HDAC BALANCE ALTERATIONS BUT RATHER WITH THE DEREGULATION OF MMP-9-TARGETING MIRS. THEN, WE FIRST DEMONSTRATED THAT MIR?149 DOWNREGULATION WAS DIRECTLY INVOLVED IN THE MMP-9 OVEREXPRESSION FOLLOWING A CHRONIC GLUCOCORTICOID EXPOSURE AND THAT MS-275 COULD AMPLIFY THIS OVEREXPRESSION BY INHIBITION OF MIR?149 EXPRESSION AND MIR?520C OVEREXPRESSION. TAKEN TOGETHER, THESE RESULTS INDICATE THAT THE USE OF HDACI IN A CONTEXT OF ACQUIRED GLUCOCORTICOID RESISTANCE COULD MODIFY THE EPIGENETIC LANDSCAPE, HIGHLIGHTING THE IMPORTANCE OF TAKING THE GLUCOCORTICOID RESPONSE STATUS INTO CONSIDERATION IN TREATMENT WITH HDACI. 2017 10 3207 42 HDACI: CELLULAR EFFECTS, OPPORTUNITIES FOR RESTORATIVE DENTISTRY. ACETYLATION OF HISTONE AND NON-HISTONE PROTEINS ALTERS GENE EXPRESSION AND INDUCES A HOST OF CELLULAR EFFECTS. THE ACETYLATION PROCESS IS HOMEOSTATICALLY BALANCED BY TWO GROUPS OF CELLULAR ENZYMES, HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS). HAT ACTIVITY RELAXES THE STRUCTURE OF THE HUMAN CHROMATIN, RENDERING IT TRANSCRIPTIONALLY ACTIVE, THEREBY INCREASING GENE EXPRESSION. IN CONTRAST, HDAC ACTIVITY LEADS TO GENE SILENCING. THE ENZYMATIC BALANCE CAN BE 'TIPPED' BY HISTONE DEACETYLASE INHIBITORS (HDACI), LEADING TO AN ACCUMULATION OF ACETYLATED PROTEINS, WHICH SUBSEQUENTLY MODIFY CELLULAR PROCESSES INCLUDING STEM CELL DIFFERENTIATION, CELL CYCLE, APOPTOSIS, GENE EXPRESSION, AND ANGIOGENESIS. THERE IS A VARIETY OF NATURAL AND SYNTHETIC HDACI AVAILABLE, AND THEIR PLEIOTROPIC EFFECTS HAVE CONTRIBUTED TO DIVERSE CLINICAL APPLICATIONS, NOT ONLY IN CANCER BUT ALSO IN NON-CANCER AREAS, SUCH AS CHRONIC INFLAMMATORY DISEASE, BONE ENGINEERING, AND NEURODEGENERATIVE DISEASE. INDEED, IT APPEARS THAT HDACI-MODULATED EFFECTS MAY DIFFER BETWEEN 'NORMAL' AND TRANSFORMED CELLS, PARTICULARLY WITH REGARD TO REACTIVE OXYGEN SPECIES ACCUMULATION, APOPTOSIS, PROLIFERATION, AND CELL CYCLE ARREST. THE POTENTIAL BENEFICIAL EFFECTS OF HDACI FOR HEALTH, RESULTING FROM THEIR ABILITY TO REGULATE GLOBAL GENE EXPRESSION BY EPIGENETIC MODIFICATION OF DNA-ASSOCIATED PROTEINS, ALSO OFFER POTENTIAL FOR APPLICATION WITHIN RESTORATIVE DENTISTRY, WHERE THEY MAY PROMOTE DENTAL TISSUE REGENERATION FOLLOWING PULPAL DAMAGE. 2011 11 6232 34 THE LONG NONCODING RNA MEG3 REGULATES MYOBLAST PLASTICITY AND MUSCLE REGENERATION THROUGH EPITHELIAL-MESENCHYMAL TRANSITION. FORMATION OF SKELETAL MUSCLE IS AMONG THE MOST STRIKING EXAMPLES OF CELLULAR PLASTICITY IN ANIMAL TISSUE DEVELOPMENT, AND WHILE MUSCLE PROGENITOR CELLS ARE REPROGRAMMED BY EPITHELIAL-MESENCHYMAL TRANSITION (EMT) TO MIGRATE DURING EMBRYONIC DEVELOPMENT, THE REGULATION OF EMT IN POST-NATAL MYOGENESIS REMAINS POORLY UNDERSTOOD. HERE, WE DEMONSTRATE THAT THE LONG NONCODING RNA (LNCRNA) MEG3 REGULATES EMT IN MYOBLAST DIFFERENTIATION AND SKELETAL MUSCLE REGENERATION. CHRONIC INHIBITION OF MEG3 IN C2C12 MYOBLASTS INDUCED EMT, AND SUPPRESSED CELL STATE TRANSITIONS REQUIRED FOR DIFFERENTIATION. FURTHERMORE, ADENOVIRAL MEG3 KNOCKDOWN COMPROMISED MUSCLE REGENERATION, WHICH WAS ACCOMPANIED BY ABNORMAL MESENCHYMAL GENE EXPRESSION AND INTERSTITIAL CELL PROLIFERATION. TRANSCRIPTOMIC AND PATHWAY ANALYSES OF MEG3-DEPLETED C2C12 MYOBLASTS AND INJURED SKELETAL MUSCLE REVEALED A SIGNIFICANT DYSREGULATION OF EMT-RELATED GENES, AND IDENTIFIED TGFBETA AS A KEY UPSTREAM REGULATOR. IMPORTANTLY, INHIBITION OF TGFBETAR1 AND ITS DOWNSTREAM EFFECTORS, AND THE EMT TRANSCRIPTION FACTOR SNAI2, RESTORED MANY ASPECTS OF MYOGENIC DIFFERENTIATION IN MEG3-DEPLETED MYOBLASTS IN VITRO WE FURTHER DEMONSTRATE THAT REDUCTION OF MEG3-DEPENDENT EZH2 ACTIVITY RESULTS IN EPIGENETIC ALTERATIONS ASSOCIATED WITH TGFBETA ACTIVATION. THUS, MEG3 REGULATES MYOBLAST IDENTITY TO FACILITATE PROGRESSION INTO DIFFERENTIATION. 2021 12 4391 38 MODERATE EXERCISE INDUCES TRAINED IMMUNITY IN MACROPHAGES. DESPITE ITS IMPORTANCE IN PROTECTING THE HOST FROM INFECTIONS AND INJURY, EXCESSIVE INFLAMMATION MAY LEAD TO SERIOUS HUMAN DISEASES INCLUDING AUTOIMMUNE DISORDERS, CARDIOVASCULAR DISEASES, DIABETES, AND CANCER. EXERCISE IS A KNOWN IMMUNOMODULATOR; HOWEVER, WHETHER EXERCISE CAUSES LONG-TERM CHANGES IN INFLAMMATORY RESPONSES AND HOW THESE CHANGES OCCUR ARE LACKING. HERE, WE SHOW THAT CHRONIC MODERATE-INTENSITY TRAINING OF MICE LEADS TO PERSISTENT METABOLIC REWIRING AND CHANGES TO CHROMATIN ACCESSIBILITY IN BONE MARROW-DERIVED MACROPHAGES (BMDMS), WHICH, IN TURN, TEMPERS THEIR INFLAMMATORY RESPONSES. WE SHOW THAT BMDMS FROM EXERCISED MICE EXHIBITED A DECREASE IN LIPOPOLYSACCHARIDE (LPS)-INDUCED NF-KAPPAB ACTIVATION AND PROINFLAMMATORY GENE EXPRESSION ALONG WITH AN INCREASE IN M2-LIKE-ASSOCIATED GENES WHEN COMPARED WITH BMDMS FROM SEDENTARY MICE. THIS WAS ASSOCIATED WITH IMPROVED MITOCHONDRIAL QUALITY AND INCREASED RELIANCE ON OXIDATIVE PHOSPHORYLATION ACCOMPANIED WITH REDUCED MITOCHONDRIAL REACTIVE OXYGEN SPECIES (ROS) PRODUCTION. MECHANISTICALLY, ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN (ATAC)-SEQ ANALYSIS SHOWED CHANGES IN CHROMATIN ACCESSIBILITY OF GENES ASSOCIATED WITH INFLAMMATORY AND METABOLIC PATHWAYS. OVERALL, OUR DATA SUGGEST THAT CHRONIC MODERATE EXERCISE CAN INFLUENCE THE INFLAMMATORY RESPONSES OF MACROPHAGES BY REPROGRAMMING THEIR METABOLIC AND EPIGENETIC LANDSCAPE.NEW & NOTEWORTHY IN THIS STUDY, WE EXPLAIN HOW LONG-TERM MODERATE EXERCISE TRAINING CAN REDUCE INFLAMMATION IN MOUSE MACROPHAGES BY REPROGRAMMING THE WAY THEY SENSE AND RESPOND TO THE PRESENCE OF PATHOGENS. WE COMPLETED A THOROUGH ANALYSIS AND SHOWED THAT THESE CHANGES PERSIST IN MACROPHAGES BECAUSE EXERCISE IMPROVES THE ABILITY OF CELLS TO UTILIZE OXYGEN WITHOUT PRODUCING DAMAGING COMPOUNDS, AND CHANGES THE WAY THEY ACCESS THEIR DNA. 2023 13 5937 38 TARGETING HISTONE DEACETYLASE ACTIVITY IN RHEUMATOID ARTHRITIS AND ASTHMA AS PROTOTYPES OF INFLAMMATORY DISEASE: SHOULD WE KEEP OUR HATS ON? CELLULAR ACTIVATION, PROLIFERATION AND SURVIVAL IN CHRONIC INFLAMMATORY DISEASES IS REGULATED NOT ONLY BY ENGAGEMENT OF SIGNAL TRANS-DUCTION PATHWAYS THAT MODULATE TRANSCRIPTION FACTORS REQUIRED FOR THESE PROCESSES, BUT ALSO BY EPIGENETIC REGULATION OF TRANSCRIPTION FACTOR ACCESS TO GENE PROMOTER REGIONS. HISTONE ACETYL TRANSFERASES COORDINATE THE RECRUITMENT AND ACTIVATION OF TRANSCRIPTION FACTORS WITH CONFORMATIONAL CHANGES IN HISTONES THAT ALLOW GENE PROMOTER EXPOSURE. HISTONE DEACETYLASES (HDACS) COUNTERACT HISTONE ACETYL TRANSFERASE ACTIVITY THROUGH THE TARGETING OF BOTH HISTONES AS WELL AS NONHISTONE SIGNAL TRANSDUCTION PROTEINS IMPORTANT IN INFLAMMATION. NUMEROUS STUDIES HAVE INDICATED THAT DEPRESSED HDAC ACTIVITY IN PATIENTS WITH INFLAMMATORY AIRWAY DISEASES MAY CONTRIBUTE TO LOCAL PROINFLAMMATORY CYTOKINE PRODUCTION AND DIMINISH PATIENT RESPONSES TO CORTICOSTEROID TREATMENT. RECENT OBSERVATIONS THAT HDAC ACTIVITY IS DEPRESSED IN RHEUMATOID ARTHRITIS PATIENT SYNOVIAL TISSUE HAVE PREDICTED THAT STRATEGIES RESTORING HDAC FUNCTION MAY BE THERAPEUTIC IN THIS DISEASE AS WELL. PHARMACOLOGICAL INHIBITORS OF HDAC ACTIVITY, HOWEVER, HAVE DEMONSTRATED POTENT THERAPEUTIC EFFECTS IN ANIMAL MODELS OF ARTHRITIS AND OTHER CHRONIC INFLAMMATORY DISEASES. IN THE PRESENT REVIEW WE ASSESS AND RECONCILE THESE OUTWARDLY PARADOXICAL STUDY RESULTS TO PROVIDE A WORKING MODEL FOR HOW ALTERATIONS IN HDAC ACTIVITY MAY CONTRIBUTE TO PATHOLOGY IN RHEUMATOID ARTHRITIS, AND HIGHLIGHT KEY QUESTIONS TO BE ANSWERED IN THE PRECLINICAL EVALUATION OF COMPOUNDS MODULATING THESE ENZYMES. 2008 14 1035 44 CLASS I HISTONE DEACETYLASE INHIBITION IMPROVES PANCREATITIS OUTCOME BY LIMITING LEUKOCYTE RECRUITMENT AND ACINAR-TO-DUCTAL METAPLASIA. BACKGROUND AND PURPOSE: PANCREATITIS IS A COMMON INFLAMMATION OF THE PANCREAS WITH RISING INCIDENCE IN MANY COUNTRIES. DESPITE IMPROVEMENTS IN DIAGNOSTIC TECHNIQUES, THE DISEASE IS ASSOCIATED WITH HIGH RISK OF SEVERE MORBIDITY AND MORTALITY AND THERE IS AN URGENT NEED FOR NEW THERAPEUTIC INTERVENTIONS. IN THIS STUDY, WE EVALUATED WHETHER HISTONE DEACETYLASES (HDACS), KEY EPIGENETIC REGULATORS OF GENE TRANSCRIPTION, ARE INVOLVED IN THE DEVELOPMENT OF THE DISEASE. EXPERIMENTAL APPROACH: WE ANALYSED HDAC REGULATION DURING CERULEIN-INDUCED ACUTE, CHRONIC AND AUTOIMMUNE PANCREATITIS USING DIFFERENT TRANSGENIC MOUSE MODELS. THE FUNCTIONAL RELEVANCE OF CLASS I HDACS WAS TESTED WITH THE SELECTIVE INHIBITOR MS-275 IN VIVO UPON PANCREATITIS INDUCTION AND IN VITRO IN ACTIVATED MACROPHAGES AND PRIMARY ACINAR CELL EXPLANTS. KEY RESULTS: HDAC EXPRESSION AND ACTIVITY WERE UP-REGULATED IN A TIME-DEPENDENT MANNER FOLLOWING INDUCTION OF PANCREATITIS, WITH THE HIGHEST ABUNDANCE OBSERVED FOR CLASS I HDACS. CLASS I HDAC INHIBITION DID NOT PREVENT THE INITIAL ACINAR CELL DAMAGE. HOWEVER, IT EFFECTIVELY REDUCED THE INFILTRATION OF INFLAMMATORY CELLS, INCLUDING MACROPHAGES AND T CELLS, IN BOTH ACUTE AND CHRONIC PHASES OF THE DISEASE, AND DIRECTLY DISRUPTED MACROPHAGE ACTIVATION. IN ADDITION, MS-275 TREATMENT REDUCED DNA DAMAGE IN ACINAR CELLS AND LIMITED ACINAR DE-DIFFERENTIATION INTO ACINAR-TO-DUCTAL METAPLASIA IN A CELL-AUTONOMOUS MANNER BY IMPEDING THE EGF RECEPTOR SIGNALLING AXIS. CONCLUSIONS AND IMPLICATIONS: THESE RESULTS DEMONSTRATE THAT CLASS I HDACS ARE CRITICALLY INVOLVED IN THE DEVELOPMENT OF ACUTE AND CHRONIC FORMS OF PANCREATITIS AND SUGGEST THAT BLOCKADE OF CLASS I HDAC ISOFORMS IS A PROMISING TARGET TO IMPROVE THE OUTCOME OF THE DISEASE. 2017 15 2499 33 EPIGENETICS AND EXERCISE. EPIGENETICS CAN BE DEFINED AS 'THE STRUCTURAL ADAPTATION OF CHROMOSOMAL REGIONS SO AS TO REGISTER, SIGNAL, OR PERPETUATE ALTERED ACTIVITY STATES.' INCREASED TRANSCRIPTION OF KEY REGULATORY, METABOLIC, AND MYOGENIC GENES IS AN EARLY RESPONSE TO EXERCISE AND IS IMPORTANT IN MEDIATING SUBSEQUENT ADAPTATIONS IN SKELETAL MUSCLE. DNA HYPOMETHYLATION AND HISTONE HYPERACETYLATION ARE EMERGING AS IMPORTANT CRUCIAL EVENTS FOR INCREASED TRANSCRIPTION. THE COMPLEX INTERACTIONS BETWEEN MULTIPLE EPIGENETIC MODIFICATIONS AND THEIR REGULATION BY METABOLIC CHANGES AND SIGNALING EVENTS DURING EXERCISE, WITH IMPLICATIONS FOR ENHANCED UNDERSTANDING OF THE ACUTE AND CHRONIC ADAPTATIONS TO EXERCISE, ARE QUESTIONS FOR FURTHER INVESTIGATION. 2019 16 834 32 CHEMICAL BIOLOGY OF LYSINE DEMETHYLASES. ABNORMAL LEVELS OF DNA METHYLATION AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. METHYLATION OF LYSINES WITHIN HISTONE TAILS IS A KEY MODIFICATION THAT CONTRIBUTES TO INCREASED GENE EXPRESSION OR REPRESSION DEPENDING ON THE SPECIFIC RESIDUE AND DEGREE OF METHYLATION, WHICH IS IN TURN CONTROLLED BY THE INTERPLAY OF LYSINE METHYL TRANSFERASES AND DEMETHYLASES. DRUGS THAT TARGET THESE AND OTHER ENZYMES CONTROLLING CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS ACTING ON DOWNSTREAM BIOCHEMICAL PATHWAYS THAT ARE SUSCEPTIBLE TO DEGENERACY. LYSINE DEMETHYLASES, FIRST DISCOVERED IN 2004, ARE THE SUBJECT OF INCREASING INTEREST AS THERAPEUTIC TARGETS. THIS REVIEW PROVIDES AN OVERVIEW OF RECENT FINDINGS IMPLICATING LYSINE DEMETHYLASES IN A RANGE OF THERAPEUTIC AREAS INCLUDING ONCOLOGY, IMMUNOINFLAMMATION, METABOLIC DISORDERS, NEUROSCIENCE, VIROLOGY AND REGENERATIVE MEDICINE, TOGETHER WITH A SUMMARY OF RECENT ADVANCES IN STRUCTURAL BIOLOGY AND SMALL MOLECULE INHIBITOR DISCOVERY, SUPPORTING THE TRACTABILITY OF THE PROTEIN FAMILY FOR THE DEVELOPMENT OF SELECTIVE DRUGLIKE INHIBITORS. 2011 17 1442 38 DIFFERENTIAL RESPONSE OF HUMAN HEPATOCYTE CHROMATIN TO HDAC INHIBITORS AS A FUNCTION OF MICROENVIRONMENTAL GLUCOSE LEVEL. DIABETES IS A COMPLEX MULTIFACTORIAL DISORDER CHARACTERIZED BY CHRONIC HYPERGLYCEMIA DUE TO IMPAIRED INSULIN SECRETION. RECENT OBSERVATIONS SUGGEST THAT THE COMPLEXITY OF THE DISEASE CANNOT BE ENTIRELY ACCOUNTED FOR GENETIC PREDISPOSITION AND A COMPELLING ARGUMENT FOR AN EPIGENETIC COMPONENT IS RAPIDLY EMERGING. THE USE OF HISTONE DEACETYLASE INHIBITOR (HDACI) IN CLINICAL SETTING IS AN EMERGING AREA OF INVESTIGATION. IN THIS STUDY, WE HAVE AIMED TO UNDERSTAND AND COMPARE THE RESPONSE OF HEPATOCYTE CHROMATIN TO VALPROIC ACID (VPA) AND TRICHOSTATIN A (TSA) TREATMENTS UNDER NORMOGLYCEMIC OR HYPERGLYCEMIC CONDITIONS TO EXPAND OUR KNOWLEDGE ABOUT THE CONSEQUENCES OF HDACI TREATMENT IN A DIABETES CELL MODEL. UNDER NORMOGLYCEMIC CONDITIONS, THESE TREATMENTS PROMOTED CHROMATIN REMODELING, AS ASSESSED BY IMAGE ANALYSIS AND H3K9AC AND H3K9ME2 ABUNDANCE. SIMULTANEOUSLY, H3K9AC MARKS SHIFTED TO THE NUCLEAR PERIPHERY ACCOMPANIED BY HP1 DISSOCIATION FROM THE HETEROCHROMATIN AND A G1 CELL CYCLE ARREST. MORE STRIKING CHANGES IN THE CELL CYCLE PROGRESSION AND MITOTIC RATIOS REQUIRED DRASTIC TREATMENT. UNDER HYPERGLYCEMIC CONDITIONS, HIGH GLUCOSE PER SE PROMOTED CHROMATIN CHANGES SIMILAR TO THOSE PROMOTED BY VPA AND TSA. NONETHELESS, THESE RESULTS WERE NOT INTENSIFIED IN CELLS TREATED WITH HDACIS UNDER HYPERGLYCEMIC CONDITIONS. DESPITE THE ABSENCE OF MORPHOLOGICAL CHANGES BEING PROMOTED, HDACI TREATMENT SEEMS TO CONFER A PHYSIOLOGICAL MEANING, AMELIORATING THE CELLULAR HYPERGLYCEMIC STATE THROUGH REDUCTION OF GLUCOSE PRODUCTION. THESE OBSERVATIONS ALLOW US TO CONCLUDE THAT THE GLUCOSE LEVEL TO WHICH THE HEPATOCYTES ARE SUBJECTED AFFECTS HOW CHROMATIN RESPONDS TO HDACI AND THEIR ACTION UNDER HIGH-GLUCOSE ENVIRONMENT MIGHT NOT REFLECT ON CHROMATIN REMODELING. J. CELL. PHYSIOL. 231: 2257-2265, 2016. (C) 2016 WILEY PERIODICALS, INC. 2016 18 5318 39 PSYCHONEUROENDOCRINE INTERVENTIONS AIMED AT ATTENUATING IMMUNOSENESCENCE: A REVIEW. THERE IS EVIDENCE SUGGESTING THAT IMMUNOSENESCENCE CAN BE ACCELERATED BY EXTERNAL FACTORS SUCH AS CHRONIC STRESS. HERE WE REVIEW POTENTIAL PSYCHONEUROENDOCRINE DETERMINANTS OF PREMATURE AGING OF THE IMMUNE SYSTEM AND DISCUSS AVAILABLE INTERVENTIONS AIMED AT ATTENUATING IMMUNOSENESCENCE. CHRONIC STRESS MAY ACCELERATE VARIOUS FEATURES OF IMMUNOSENESCENCE BY ACTIVATING KEY ALLOSTATIC SYSTEMS, NOTABLY THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. THE IMMUNOLOGICAL IMPACT OF SUCH NEUROENDOCRINE DYSREGULATION MAY BE FURTHER AMPLIFIED BY A DRAMATIC DECLINE IN DEHYDROEPIANDROSTERONE (DHEA) LEVELS, ACTING IN PART AS AN ENDOGENOUS GLUCOCORTICOID ANTAGONIST. STRESS-BUFFERING STRATEGIES SHOW BENEFICIAL EFFECTS ON VARIOUS BIOMARKERS IN ELDERLY POPULATIONS. LIKEWISE, SUPPLEMENTATION OF DHEA, MELATONIN OR GROWTH HORMONE HAS YIELDED SIGNIFICANT BENEFICIAL EFFECTS IN A NUMBER OF STUDIES, INCLUDING: INCREASED WELL-BEING, MEMORY PERFORMANCE, BONE MINERAL DENSITY AND IMPROVED IMMUNOCOMPETENCE AS EVIDENCED BY RESULTS OF IN VITRO (T CELL PROLIFERATION, CYTOTOXICITY, CYTOKINE PRODUCTION), AND IN VIVO IMMUNE CHALLENGES. HOWEVER, THE SIDE-EFFECTS OF HORMONAL SUPPLEMENTATION ARE ALSO DISCUSSED. FINALLY, MODERATE EXERCISE VIA THE PROMOTION OF CORTISOL/DHEA BALANCE OR EPIGENETIC MODIFICATIONS, IS ASSOCIATED WITH LOWER SERUM PRO-INFLAMMATORY CYTOKINES, GREATER LYMPHOPROLIFERATIVE RESPONSES AND LOWER COUNTS OF SENESCENT T CELLS. TAKEN TOGETHER, THESE DATA SUGGEST THAT IMMUNE SYSTEM IS PLASTIC AND IMMUNOSENESCENCE CAN BE ATTENUATED PSYCHONEUROENDOCRINE INTERVENTIONS. 2013 19 3343 34 HISTONE DEACETYLASES (HDAC) IN PHYSIOLOGICAL AND PATHOLOGICAL BONE REMODELLING. HISTONE DEACETYLASES (HDACS)(2) PLAY IMPORTANT ROLES IN THE EPIGENETIC REGULATION OF GENE EXPRESSION IN CELLS AND ARE EMERGING THERAPEUTIC TARGETS FOR TREATING A WIDE RANGE OF DISEASES. HDAC INHIBITORS (HDACI)(3) THAT ACT ON MULTIPLE HDAC ENZYMES HAVE BEEN USED CLINICALLY TO TREAT A NUMBER OF SOLID AND HEMATOLOGICAL MALIGNANCIES. HDACI ARE ALSO CURRENTLY BEING STUDIED FOR THEIR EFFICACY IN NON-MALIGNANT DISEASES, INCLUDING PATHOLOGIC BONE LOSS, BUT THIS HAS NECESSITATED A BETTER UNDERSTANDING OF THE ROLES OF INDIVIDUAL HDAC ENZYMES, PARTICULARLY THE ELEVEN ZINC-CONTAINING ISOZYMES. SELECTIVE ISOZYME-SPECIFIC INHIBITORS CURRENTLY BEING DEVELOPED AGAINST CLASS I HDACS (1, 2, 3 AND 8) AND CLASS II HDACS (4, 5, 6, 7, 9 AND 10) WILL BE VALUABLE TOOLS FOR ELUCIDATING THE ROLES PLAYED BY INDIVIDUAL HDACS IN DIFFERENT PHYSIOLOGICAL AND PATHOLOGICAL SETTINGS. ISOZYME-SPECIFIC HDACI PROMISE TO HAVE GREATER EFFICACY AND REDUCED SIDE EFFECTS, AS REQUIRED FOR TREATING CHRONIC DISEASE OVER EXTENDED PERIODS OF TIME. THIS ARTICLE REVIEWS THE CURRENT UNDERSTANDING OF ROLES FOR INDIVIDUAL HDAC ISOZYMES AND EFFECTS OF HDACI ON BONE CELLS, (OSTEOBLASTS, OSTEOCLASTS AND OSTEOCYTES), IN RELATION TO BONE REMODELLING IN CONDITIONS CHARACTERISED BY PATHOLOGICAL BONE LOSS, INCLUDING PERIODONTITIS, RHEUMATOID ARTHRITIS AND MYELOMA BONE DISEASE. 2017 20 2493 41 EPIGENETICS AND CHROMATIN REMODELING PLAY A ROLE IN LUNG DISEASE. EPIGENETICS IS DEFINED AS HERITABLE CHANGES THAT AFFECT GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. EPIGENETIC REGULATION OF GENE EXPRESSION IS FACILITATED THROUGH DIFFERENT MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-ASSOCIATED SILENCING BY SMALL NON-CODING RNAS. ALL THESE MECHANISMS ARE CRUCIAL FOR NORMAL DEVELOPMENT, DIFFERENTIATION AND TISSUE-SPECIFIC GENE EXPRESSION. THESE THREE SYSTEMS INTERACT AND STABILIZE ONE ANOTHER AND CAN INITIATE AND SUSTAIN EPIGENETIC SILENCING, THUS DETERMINING HERITABLE CHANGES IN GENE EXPRESSION. HISTONE ACETYLATION REGULATES DIVERSE CELLULAR FUNCTIONS INCLUDING INFLAMMATORY GENE EXPRESSION, DNA REPAIR AND CELL PROLIFERATION. TRANSCRIPTIONAL COACTIVATORS POSSESS INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY AND THIS ACTIVITY DRIVES INFLAMMATORY GENE EXPRESSION. ELEVEN CLASSICAL HISTONE DEACETYLASES (HDACS) ACT TO REGULATE THE EXPRESSION OF DISTINCT SUBSETS OF INFLAMMATORY/IMMUNE GENES. THUS, LOSS OF HDAC ACTIVITY OR THE PRESENCE OF HDAC INHIBITORS CAN FURTHER ENHANCE INFLAMMATORY GENE EXPRESSION BY PRODUCING A GENE-SPECIFIC CHANGE IN HAT ACTIVITY. FOR EXAMPLE, HDAC2 EXPRESSION AND ACTIVITY ARE REDUCED IN LUNG MACROPHAGES, BIOPSY SPECIMENS, AND BLOOD CELLS FROM PATIENTS WITH SEVERE ASTHMA AND SMOKING ASTHMATICS, AS WELL AS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS MAY ACCOUNT, AT LEAST IN PART, FOR THE ENHANCED INFLAMMATION AND REDUCED STEROID RESPONSIVENESS SEEN IN THESE PATIENTS. OTHER PROTEINS, PARTICULARLY TRANSCRIPTION FACTORS, ARE ALSO ACETYLATED AND ARE TARGETS FOR DEACETYLATION BY HDACS AND SIRTUINS, A RELATED FAMILY OF 7 PREDOMINANTLY PROTEIN DEACETYLASES. THUS THE ACETYLATION/DEACETYLATION STATUS OF NF-KAPPAB AND THE GLUCOCORTICOID RECEPTOR CAN ALSO AFFECT THE OVERALL EXPRESSION PATTERN OF INFLAMMATORY GENES AND REGULATE THE INFLAMMATORY RESPONSE. UNDERSTANDING AND TARGETING SPECIFIC ENZYMES INVOLVED IN THIS PROCESS MIGHT LEAD TO NEW THERAPEUTIC AGENTS, PARTICULARLY IN SITUATIONS IN WHICH CURRENT ANTI-INFLAMMATORY THERAPIES ARE SUBOPTIMAL. 2011