1 3343 119 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 2 5562 33 ROLE OF HISTONE DEACETYLASES IN PANCREAS: IMPLICATIONS FOR PATHOGENESIS AND THERAPY. IN THE LAST YEARS, OUR KNOWLEDGE OF THE PATHOGENESIS IN ACUTE AND CHRONIC PANCREATITIS (AP/CP) AS WELL AS IN PANCREATIC CANCEROGENESIS HAS SIGNIFICANTLY DIVERSIFIED. NEVERTHELESS, THE MEDICINAL THERAPEUTIC OPTIONS ARE STILL LIMITED AND THERAPEUTIC SUCCESS AND PATIENT OUTCOME ARE POOR. EPIGENETIC DEREGULATION OF GENE EXPRESSION IS KNOWN TO CONTRIBUTE TO DEVELOPMENT AND PROGRESSION OF AP AND CP AS WELL AS OF PANCREATIC CANCER. THEREFORE, THE SELECTIVE INHIBITION OF ABERRANTLY ACTIVE EPIGENETIC REGULATORS CAN BE AN EFFECTIVE OPTION FOR FUTURE THERAPIES. HISTONE DEACETYLASES (HDACS) ARE ENZYMES THAT REMOVE AN ACETYL GROUP FROM HISTONE TAILS, THEREBY CAUSING CHROMATIN COMPACTION AND REPRESSION OF TRANSCRIPTION. IN THIS REVIEW WE PRESENT AN OVERVIEW OF THE CURRENTLY AVAILABLE LITERATURE ADDRESSING THE ROLE OF HDACS IN THE PANCREAS AND IN PANCREATIC DISEASES. IN PANCREATIC CANCEROGENESIS, HDACS PLAY A ROLE IN THE IMPORTANT PROCESS OF EPITHELIAL-MESENCHYMAL-TRANSITION, UBIQUITIN-PROTEASOME PATHWAY AND, HYPOXIA-INDUCIBLE-FACTOR-1-ANGIOGENESIS. FINALLY, WE FOCUS ON HDACS AS POTENTIAL THERAPEUTIC TARGETS BY SUMMARIZING CURRENTLY AVAILABLE HISTONE DEACETYLASE INHIBITORS. 2015 3 3197 35 HDAC INHIBITORS: TARGETS FOR TUMOR THERAPY, IMMUNE MODULATION AND LUNG DISEASES. HISTONE DEACETYLASES (HDACS) ARE ENZYMES THAT PLAY A KEY ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION BY REMODELING CHROMATIN. INHIBITION OF HDACS IS A PROSPECTIVE THERAPEUTIC APPROACH FOR REVERSING EPIGENETIC ALTERATION IN SEVERAL DISEASES. IN PRECLINICAL RESEARCH, NUMEROUS TYPES OF HDAC INHIBITORS WERE DISCOVERED TO EXHIBIT POWERFUL AND SELECTIVE ANTICANCER PROPERTIES. HOWEVER, SUCH RESEARCH HAS REVEALED THAT THE EFFECTS OF HDAC INHIBITORS MAY BE FAR BROADER AND MORE INTRICATE THAN PREVIOUSLY THOUGHT. THIS REVIEW WILL PROVIDE INSIGHT INTO THE HDAC INHIBITORS AND THEIR MECHANISM OF ACTION WITH SPECIAL EMPHASIS ON THE SIGNIFICANCE OF HDAC INHIBITORS IN THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER. NANOCARRIER-MEDIATED HDAC INHIBITOR DELIVERY AND NEW APPROACHES FOR TARGETING HDACS ARE ALSO DISCUSSED. 2022 4 5937 35 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 5 3335 31 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 6 834 28 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 7 3207 35 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 8 2550 28 EPIGENETICS IN OSTEOARTHRITIS: POTENTIAL OF HDAC INHIBITORS AS THERAPEUTICS. OSTEOARTHRITIS (OA) IS THE MOST COMMON JOINT DISEASE AND THE LEADING CAUSE OF CHRONIC DISABILITY IN MIDDLE-AGED AND OLDER POPULATIONS WORLDWIDE. THE DEVELOPMENT OF DISEASE MODIFYING THERAPY FOR OA IS IN ITS INFANCY LARGELY BECAUSE THE REGULATORY MECHANISMS FOR THE MOLECULAR EFFECTORS OF OA PATHOGENESIS ARE POORLY UNDERSTOOD. RECENT STUDIES IDENTIFIED EPIGENETIC EVENTS AS A CRITICAL REGULATOR OF MOLECULAR PLAYERS INVOLVED IN THE INDUCTION AND DEVELOPMENT OF OA. EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, NON-CODING RNA AND HISTONE MODIFICATIONS. THE AIM OF THIS REVIEW IS TO BRIEFLY HIGHLIGHT THE RECENT ADVANCES IN THE EPIGENETICS OF CARTILAGE AND POTENTIAL OF HDACS (HISTONE DEACETYLASES) INHIBITORS IN THE THERAPEUTIC MANAGEMENT OF OA. WE SUMMARIZE THE RECENT STUDIES UTILIZING HDAC INHIBITORS AS POTENTIAL THERAPEUTICS FOR INHIBITING DISEASE PROGRESSION AND PREVENTING THE CARTILAGE DESTRUCTION IN OA. HDACS CONTROL NORMAL CARTILAGE DEVELOPMENT AND HOMEOSTASIS AND UNDERSTANDING THE IMPACT OF HDACS INHIBITORS ON THE DISEASE PATHOGENESIS IS OF INTEREST BECAUSE OF ITS IMPORTANCE IN AFFECTING OVERALL CARTILAGE HEALTH AND HOMEOSTASIS. THESE FINDINGS ALSO SHED NEW LIGHT ON CARTILAGE DISEASE PATHOPHYSIOLOGY AND PROVIDE SUBSTANTIAL EVIDENCE THAT HDACS MAY BE POTENTIAL NOVEL THERAPEUTIC TARGETS IN OA. 2018 9 5561 36 ROLE OF HISTONE DEACETYLASES IN MONOCYTE FUNCTION IN HEALTH AND CHRONIC INFLAMMATORY DISEASES. HISTONE DEACETYLASES (HDACS) ARE A FAMILY OF 18 MEMBERS THAT PARTICIPATE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION. IN ADDITION TO HISTONES, SOME HDACS ALSO DEACETYLATE TRANSCRIPTION FACTORS AND SPECIFIC CYTOPLASMIC PROTEINS.MONOCYTES, AS PART OF THE INNATE IMMUNE SYSTEM, MAINTAIN TISSUE HOMEOSTASIS AND HELP FIGHT INFECTIONS AND CANCER. IN THESE CELLS, HDACS ARE INVOLVED IN MULTIPLE PROCESSES INCLUDING PROLIFERATION, MIGRATION, DIFFERENTIATION, INFLAMMATORY RESPONSE, INFECTIONS, AND TUMORIGENESIS. HERE, A SYSTEMATIC DESCRIPTION OF THE ROLE THAT MOST HDACS PLAY IN THESE FUNCTIONS IS REVIEWED. SPECIFICALLY, SOME HDACS INDUCE A PRO-INFLAMMATORY RESPONSE AND PLAY MAJOR ROLES IN HOST DEFENSE. CONVERSELY, OTHER HDACS REPROGRAM MONOCYTES AND MACROPHAGES TOWARDS AN IMMUNOSUPPRESSIVE PHENOTYPE. THE RIGHT BALANCE BETWEEN BOTH TYPES HELPS MONOCYTES TO RESPOND CORRECTLY TO THE DIFFERENT PHYSIOLOGICAL/PATHOLOGICAL STIMULI. HOWEVER, ABERRANT EXPRESSIONS OR ACTIVITIES OF SPECIFIC HDACS ARE ASSOCIATED WITH AUTOIMMUNE DISEASES ALONG WITH OTHER CHRONIC INFLAMMATORY DISEASES, INFECTIONS, OR CANCER.THIS PAPER CRITICALLY REVIEWS THE INTERESTING AND EXTENSIVE KNOWLEDGE REGARDING THE ROLE OF SOME HDACS IN THESE PATHOLOGIES. IT ALSO SHOWS THAT AS YET, VERY LITTLE PROGRESS HAS BEEN MADE TOWARD THE GOAL OF FINDING EFFECTIVE HDAC-TARGETED THERAPIES. HOWEVER, GIVEN THEIR OBVIOUS POTENTIAL, WE CONCLUDE THAT IT IS WORTH THE EFFORT TO DEVELOP MONOCYTE-SPECIFIC DRUGS THAT SELECTIVELY TARGET HDAC SUBTYPES WITH THE AIM OF FINDING EFFECTIVE TREATMENTS FOR DISEASES IN WHICH OUR INNATE IMMUNE SYSTEM IS INVOLVED. 2021 10 3333 33 HISTONE DEACETYLASE INHIBITORS AND DIABETIC KIDNEY DISEASE. DESPITE RECENT CLINICAL TRIAL ADVANCES AND IMPROVEMENTS IN CLINICAL CARE, KIDNEY DISEASE DUE TO DIABETES REMAINS THE MOST COMMON CAUSE OF CHRONIC KIDNEY FAILURE WORLDWIDE. IN THE SEARCH FOR NEW TREATMENTS, RECENT ATTENTIONS HAVE TURNED TO DRUG REPURPOSING OPPORTUNITIES, INCLUDING STUDY OF THE HISTONE DEACETYLASE (HDAC) INHIBITOR CLASS OF AGENTS. HDACS ARE A GROUP OF ENZYMES THAT REMOVE FUNCTIONAL ACETYL GROUPS FROM HISTONE AND NON-HISTONE PROTEINS AND THEY CAN AFFECT CELLULAR FUNCTION THROUGH BOTH EPIGENETIC AND NON-EPIGENETIC MEANS. OVER THE PAST DECADE, SEVERAL HDAC INHIBITORS HAVE BEEN ADOPTED INTO CLINICAL PRACTICE, PRIMARILY FOR THE TREATMENT OF HEMATOLOGICAL MALIGNANCY, WHEREAS OTHER EXISTING THERAPIES (FOR INSTANCE VALPROATE) HAVE BEEN FOUND TO HAVE HDAC INHIBITORY EFFECTS. HERE WE REVIEW THE CURRENT HDAC INHIBITORS IN THE CLINIC AND UNDER DEVELOPMENT; THE LITERATURE EVIDENCE SUPPORTING THE RENOPROTECTIVE EFFECTS OF HDAC INHIBITORS IN EXPERIMENTAL DIABETIC KIDNEY DISEASE; AND THE ADVERSE EFFECT PROFILES THAT MAY PREVENT EXISTING THERAPIES FROM ENTERING THE CLINIC FOR THIS INDICATION. WHEREAS RECENT RESEARCH EFFORTS HAVE SHED LIGHT ON THE FUNDAMENTAL ACTIONS OF HDACS IN THE DIABETIC KIDNEY, WHETHER THESE EFFORTS WILL TRANSLATE INTO NOVEL THERAPIES FOR PATIENTS WILL REQUIRE MORE SPECIFIC AND BETTER-TOLERATED THERAPIES. 2018 11 3855 26 IS THERE ANY THERAPEUTIC VALUE FOR THE USE OF HISTONE DEACETYLASE INHIBITORS FOR CHRONIC PAIN? CHRONIC PAIN IS A COMPLEX CLINICAL CONDITION THAT REDUCES THE QUALITY OF LIFE FOR BILLIONS OF PEOPLE. IN RECENT YEARS, THE ROLE OF EPIGENETIC MODULATION IN THE CONTROL OF LONG-TERM NEURONAL PLASTICITY HAS ATTRACTED THE ATTENTION OF PAIN RESEARCHERS. THE EPIGENETIC MECHANISMS INCLUDE COVALENT MODIFICATIONS OF DNA AND/OR HISTONE PROTEINS. MOUNTING EVIDENCE SUGGESTS THAT THE ACTIVITY OF HISTONE DEACETYLASES (HDACS) AND LEVELS OF HISTONE ACETYLATION ARE DYNAMIC AND THAT THESE ENZYMES MODULATE PAIN-RELATED SYNAPTIC PLASTICITY. THEREFORE, HDACS PLAY ESSENTIAL ROLES IN CHRONIC PAIN DEVELOPMENT AND MAINTENANCE. IN THIS MINI REVIEW, WE WILL DISCUSS THE ROLE OF HDACS IN THE PATHOGENESIS OF CHRONIC PAIN AND WILL CONSIDER THE THERAPEUTIC VALUE OF HDAC INHIBITORS IN TREATING CHRONIC PAIN. 2016 12 2254 32 EPIGENETIC MODULATION: RESEARCH PROGRESS ON HISTONE ACETYLATION LEVELS IN MAJOR DEPRESSIVE DISORDERS. DEPRESSION IS A SERIOUS MENTAL ILLNESS AND A PREVALENT CONDITION WITH MULTIPLE AETIOLOGIES. THE IMPACT OF THE CURRENT THERAPEUTIC STRATEGIES IS LIMITED AND THE PATHOGENESIS OF THE ILLNESS IS NOT WELL UNDERSTOOD. ACCORDING TO PREVIOUS STUDIES, DEPRESSION ONSET IS INFLUENCED BY A VARIETY OF ENVIRONMENTAL AND GENETIC FACTORS, INCLUDING CHRONIC STRESS, ABERRANT CHANGES IN GENE EXPRESSION, AND HEREDITARY PREDISPOSITION. TRANSCRIPTIONAL REGULATION IN EUKARYOTES IS CLOSELY RELATED TO CHROMOSOME PACKING AND IS CONTROLLED BY HISTONE POST-TRANSLATIONAL MODIFICATIONS. THE DEVELOPMENT OF NEW ANTIDEPRESSANTS MAY PROCEED ALONG A NEW PATH WITH MEDICATIONS THAT TARGET EPIGENETICS. HISTONE DEACETYLASE INHIBITORS (HDACIS) ARE A CLASS OF COMPOUNDS THAT INTERFERE WITH THE FUNCTION OF HISTONE DEACETYLASES (HDACS). THIS REVIEW EXPLORES THE RELATIONSHIP BETWEEN HDACS AND DEPRESSION AND FOCUSES ON THE CURRENT KNOWLEDGE ON THEIR REGULATORY MECHANISM IN DEPRESSION AND THE POTENTIAL THERAPEUTIC USE OF HDACIS WITH ANTIDEPRESSANT EFFICACY IN PRECLINICAL RESEARCH. FUTURE RESEARCH ON INHIBITORS IS ALSO PROPOSED AND DISCUSSED. 2023 13 6061 33 THE DEVELOPMENT PROSPECTION OF HDAC INHIBITORS AS A POTENTIAL THERAPEUTIC DIRECTION IN ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE, WHICH IS ASSOCIATED WITH LEARNING AND MEMORY IMPAIRMENT IN THE ELDERLY. RECENT STUDIES HAVE FOUND THAT TREATING AD IN THE WAY OF CHROMATIN REMODELING VIA HISTONE ACETYLATION IS A PROMISING THERAPEUTIC REGIMEN. IN A NUMBER OF RECENT STUDIES, INHIBITORS OF HISTONE DEACETYLASE (HDACS) HAVE BEEN FOUND TO BE A NOVEL PROMISING THERAPEUTIC AGENTS FOR NEUROLOGICAL DISORDERS, PARTICULARLY FOR AD AND OTHER NEURODEGENERATIVE DISEASES. ALTHOUGH HDAC INHIBITORS HAVE THE ABILITY TO AMELIORATE COGNITIVE IMPAIRMENT, SUCCESSFUL TREATMENTS IN THE CLASSIC AD ANIMAL MODEL ARE RARELY TRANSLATED INTO CLINICAL TRIALS. AS FOR THE REDUCTION OF UNWANTED SIDE EFFECTS, THE DEVELOPMENT OF HDAC INHIBITORS WITH INCREASED ISOFORM SELECTIVITY OR SEEKING OTHER DIRECTIONS IS A KEY ISSUE THAT NEEDS TO BE ADDRESSED. THE REVIEW FOCUSED ON LITERATURES ON EPIGENETIC MECHANISMS IN RECENT YEARS, ESPECIALLY ON HISTONE ACETYLATION IN TERMS OF THE ENHANCEMENT OF SPECIFICITY, EFFICACY AND AVOIDING SIDE EFFECTS FOR TREATING AD. 2017 14 2493 40 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 15 6896 28 [TARGETED EPIGENETIC THERAPY OF CANCER. ACHIEVEMENTS AND PERSPECTIVES]. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL EPIGENETIC CHANGES OF NORMAL CELLS AND CANCER CELLS, AND EMPHASIZE THE ACHIEVEMENTS AND THE PERSPECTIVES OF CANCER EPIGENETIC THERAPY. CANCER EPIGENETIC ALTERATIONS CORRESPOND FOREMOST TO HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES PROMOTORS, GLOBAL DNA HYPOMETHYLATION, AND OVEREXPRESSION AND ACTIVITY OF HISTONE DEACETYLASES. THE PURPOSE OF EPIGENETIC THERAPY IS TO REVERT THE EPIGENETIC ALTERATIONS IN CANCER CELLS AND OBTAIN THE "NORMAL EPIGENOME" RESTORATION. EPIGENETIC TARGETS IN CANCER THERAPY HAVE FOCUSED ON HDACS AND DNMTS INHIBITION. THE AZACITIDINE AND THE DECITABINE, THE VORINOSTAT AND THE ROMIDEPSIN WERE APPROVED BY US-FDA FOR TREATMENT OF MYELODYSPLASTIC SYNDROME, AND CUTANEOUS T-CELL LYMPHOMA, RESPECTIVELY. EPIGENETIC AND EPIGENOMIC CHANGES IN SINGLE OR MULTIPLE GENES HAVE SHOWED POTENTIAL IMPACT IN CANCER AS EARLY DETECTION, PROGNOSIS AND PREDICTIVE MARKS. THE EPIGENETIC REVOLUTION HAS ARRIVED FOR BIOLOGY. THE SIGNIFICANT PROGRESS IN EPIGENETIC STUDIES HAVE ALLOWED US, TO UNDERSTAND NEW LOOKS IN THE PHYSIOLOGY AND PATHOPHYSIOLOGY OF EMBRYONIC DEVELOPMENT, CANCER AND OTHER CHRONIC DISEASES. SPECIFIC MOLECULAR EPIGENETIC ALTERATIONS IN DIFFERENT CANCER TYPES, GIVE US NEW STRATEGIES TO DESIGN IMPROVED CANCER THERAPY. THE CHALLENGE FOR EPIGENETIC INVESTIGATORS IS DESIGN MORE SPECIFIC EPIDRUGS WITH LESSER SIDE EFFECTS. 2012 16 6103 34 THE EMERGING ROLE OF HDACS: PATHOLOGY AND THERAPEUTIC TARGETS IN DIABETES MELLITUS. DIABETES MELLITUS (DM) IS ONE OF THE PRINCIPAL MANIFESTATIONS OF METABOLIC SYNDROME AND ITS PREVALENCE WITH MODERN LIFESTYLE IS INCREASING INCESSANTLY. CHRONIC HYPERGLYCEMIA CAN INDUCE SEVERAL VASCULAR COMPLICATIONS THAT WERE REFERRED TO BE THE MAJOR CAUSE OF MORBIDITY AND MORTALITY IN DM. ALTHOUGH SEVERAL THERAPEUTIC TARGETS HAVE BEEN IDENTIFIED AND ACCESSED CLINICALLY, THE IMMINENT RISK OF DM AND ITS PREVALENCE ARE STILL ASCENDING. SUBSTANTIAL PIECES OF EVIDENCE REVEALED THAT HISTONE DEACETYLASE (HDAC) ISOFORMS CAN REGULATE VARIOUS MOLECULAR ACTIVITIES IN DM VIA EPIGENETIC AND POST-TRANSLATIONAL REGULATION OF SEVERAL TRANSCRIPTION FACTORS. TO DATE, 18 HDAC ISOFORMS HAVE BEEN IDENTIFIED IN MAMMALS THAT WERE CATEGORIZED INTO FOUR DIFFERENT CLASSES. CLASSES I, II, AND IV ARE REGARDED AS CLASSICAL HDACS, WHICH OPERATE THROUGH A ZN-BASED MECHANISM. IN CONTRAST, CLASS III HDACS OR SIRTUINS DEPEND ON NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)) FOR THEIR MOLECULAR ACTIVITY. FUNCTIONALLY, MOST OF THE HDAC ISOFORMS CAN REGULATE BETA CELL FATE, INSULIN RELEASE, INSULIN EXPRESSION AND SIGNALING, AND GLUCOSE METABOLISM. MOREOVER, THE ROLES OF HDAC MEMBERS HAVE BEEN IMPLICATED IN THE REGULATION OF OXIDATIVE STRESS, INFLAMMATION, APOPTOSIS, FIBROSIS, AND OTHER PATHOLOGICAL EVENTS, WHICH SUBSTANTIALLY CONTRIBUTE TO DIABETES-RELATED VASCULAR DYSFUNCTIONS. THEREFORE, HDACS COULD SERVE AS THE POTENTIAL THERAPEUTIC TARGET IN DM TOWARDS DEVELOPING NOVEL INTERVENTION STRATEGIES. THIS REVIEW SHEDS LIGHT ON THE EMERGING ROLE OF HDACS/ISOFORMS IN DIABETIC PATHOPHYSIOLOGY AND EMPHASIZED THE SCOPE OF THEIR TARGETING IN DM FOR CONSTITUTING NOVEL INTERVENTIONAL STRATEGIES FOR METABOLIC DISORDERS/COMPLICATIONS. 2021 17 3326 41 HISTONE DEACETYLASE 3 (HDAC3) AS AN IMPORTANT EPIGENETIC REGULATOR OF KIDNEY DISEASES. DEVELOPMENT AND PROGRESSION OF MANY KIDNEY DISEASES ARE SUBSTANTIALLY INFLUENCED BY ABERRANT PROTEIN ACETYLATION MODIFICATIONS OF GENE EXPRESSION CRUCIAL FOR KIDNEY FUNCTIONS. HISTONE DEACETYLASE (HDAC) EXPRESSION ALTERATIONS ARE DETECTED FROM RENAL SAMPLES OF PATIENTS AND ANIMAL MODELS OF VARIOUS KIDNEY DISEASES, AND THE ADMINISTRATIONS OF HDAC INHIBITORS DISPLAY IMPRESSIVE RENAL PROTECTIVE EFFECTS IN VITRO AND IN VIVO. HOWEVER, WHEN THE EXPRESSION ALTERATIONS OF MULTIPLE HDACS OCCUR, NOT ALL THE HDACS CAUSALLY AFFECT THE DISEASE ONSET OR PROGRESSION. IDENTIFICATION OF A SINGLE HDAC AS A DISEASE-CAUSING FACTOR WILL ALLOW SUBTYPE-TARGETED INTERVENTION WITH LESS SIDE EFFECT. HDAC3 IS A UNIQUE HDAC WITH DISTINCT STRUCTURAL AND SUBCELLULAR DISTRIBUTION FEATURES AND CO-REPRESSOR DEPENDENCY. HDAC3 IS REQUIRED FOR KIDNEY DEVELOPMENT AND ITS ABERRATIONS ACTIVELY PARTICIPATE IN MANY PATHOLOGICAL PROCESSES, SUCH AS CANCER, CARDIOVASCULAR DISEASES, DIABETES, AND NEURODEGENERATIVE DISORDERS, AND CONTRIBUTE SIGNIFICANTLY TO THE PATHOGENESIS OF KIDNEY DISEASES. THIS REVIEW WILL DISCUSS THE RECENT STUDIES THAT INVESTIGATE THE CRITICAL ROLES OF HDAC3 ABERRATIONS IN KIDNEY DEVELOPMENT, RENAL AGING, RENAL CELL CARCINOMA, RENAL FIBROSIS, CHRONIC KIDNEY DISEASE, POLYCYSTIC KIDNEY DISEASE, GLOMERULAR PODOCYTE INJURY, AND DIABETIC NEPHROPATHY. THESE STUDIES REVEAL THE DISTINCT CHARACTERS OF HDAC3 ABERRATIONS THAT ACT ON DIFFERENT MOLECULES/SIGNALING PATHWAYS UNDER VARIOUS RENAL PATHOLOGICAL CONDITIONS, WHICH MIGHT SHED LIGHTS INTO THE EPIGENETIC MECHANISMS OF RENAL DISEASES AND THE POTENTIALLY THERAPEUTIC STRATEGIES. 2022 18 3350 32 HISTONE DEACETYLATION MEETS MIRNA: EPIGENETICS AND POST-TRANSCRIPTIONAL REGULATION IN CANCER AND CHRONIC DISEASES. INTRODUCTION: EPIGENETIC REGULATION VIA DNA METHYLATION, HISTONE ACETYLATION, AS WELL AS BY MICRORNAS (MIRNAS) IS CURRENTLY IN THE SCIENTIFIC FOCUS DUE TO ITS ROLE IN CARCINOGENESIS AND ITS INVOLVEMENT IN INITIATION, PROGRESSION AND METASTASIS. WHILE MANY TARGET GENES OF DNA METHYLATION, HISTONE ACETYLATION AND MIRNAS ARE KNOWN, EVEN LESS INFORMATION EXISTS AS TO HOW THESE MECHANISMS COOPERATE AND HOW THEY MAY REGULATE EACH OTHER IN A SPECIFIC PATHOLOGICAL CONTEXT. FOR FURTHER DEVELOPMENT OF THERAPEUTIC APPROACHES, THIS REVIEW PRESENTS THE CURRENT STATUS OF THE CROSSTALK OF HISTONE ACETYLATION AND MIRNAS IN HUMAN CARCINOGENESIS AND CHRONIC DISEASES. AREAS COVERED: THIS ARTICLE REVIEWS INFORMATION FROM COMPREHENSIVE PUBMED SEARCHES TO EVALUATE RELEVANT LITERATURE WITH A FOCUS ON POSSIBLE ASSOCIATION BETWEEN HISTONE ACETYLATION, MIRNAS AND THEIR TARGETS. OUR ANALYSIS IDENTIFIED SPECIFIC MIRNAS WHICH COLLABORATE WITH HISTONE DEACETYLASES (HDACS) AND COOPERATIVELY REGULATE SEVERAL RELEVANT TARGET GENES. EXPERT OPINION: FOURTEEN MIRNAS COULD BE LINKED TO THE EXPRESSION OF EIGHT HDACS INFLUENCING THE ALPHA-(1,6)-FUCOSYLTRANSFERASE, POLYCYSTIN-2 AND THE FIBROBLAST-GROWTH-FACTOR 2 PATHWAYS. FOCUSING ON THE COMPLEX LINKAGE OF MIRNA AND HDAC EXPRESSION COULD GIVE DEEPER INSIGHTS IN NEW 'DRUGGABLE' TARGETS AND MIGHT PROVIDE POSSIBLE NOVEL THERAPEUTIC APPROACHES IN FUTURE. 2015 19 5288 28 PROSPECTS FOR EPIGENETIC COMPOUNDS IN THE TREATMENT OF AUTOIMMUNE DISEASE. THERE IS GROWING EVIDENCE FOR A ROLE FOR EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN MOST CASES OFAUTOIMMUNE DISEASE THE PRECISE EPIGENETIC MECHANISM INVOLVED REMAINS TO BE RESOLVED, HOWEVER DNA HYPOMETHYLATION ACCOMPANIED BY HYPOACETYLATION OFHISTONE H3/H4 IS COMMONLY OBSERVED. DUE TO THE REVERSIBLE NATURE OF EPIGENETIC MARKS THEIR MAINTENANCE ENZYMES SUCH AS DNA METHYLTRANSFERASES (DNMTS), HISTONE DEACETYLASES (HDACS) AND HISTONE LYSINE METHYLTRANSFERASES (HKMT) ARE ATTRACTIVE DRUG TARGETS. SMALL MOLECULE INHIBITORS OF HISTONE MODIFICATION AND DNA METHYLATION MAINTENANCE ARE INCREASINGLY BECOMING AVAILABLE AND WILL BE USEFUL CHEMICAL BIOLOGICAL TOOLS TO DISSECT EPIGENETIC MECHANISMS IN THESE DISEASES. HOWEVER, ALTHOUGH EPIGENETIC THERAPIES USED IN CANCER TREATMENT ARE A PROMISING STARTING POINT FOR THE EXPLORATION OF AUTOIMMUNE DISEASE TREATMENT, THERE IS A REQUIREMENT FOR MORE SPECIFIC AND LESS TOXIC AGENTS FOR THESE CHRONIC DISEASES OR FOR USE AS CHEMOPREVENTATIVE AGENTS. 2011 20 5550 31 ROLE OF EPIGENETICS IN INFLAMMATION-ASSOCIATED DISEASES. THERE IS CONSIDERABLE EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS MAY MEDIATE DEVELOPMENT OF CHRONIC INFLAMMATION BY MODULATING THE EXPRESSION OF PRO-INFLAMMATORY CYTOKINE TNF-ALPHA, INTERLEUKINS, TUMOR SUPPRESSOR GENES, ONCOGENES AND AUTOCRINE AND PARACRINE ACTIVATION OF THE TRANSCRIPTION FACTOR NF-KAPPAB. THESE MOLECULES ARE CONSTITUTIVELY PRODUCED BY A VARIETY OF CELLS UNDER CHRONIC INFLAMMATORY CONDITIONS, WHICH IN TURN LEADS TO THE DEVELOPMENT OF MAJOR DISEASES SUCH AS AUTOIMMUNE DISORDERS, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEURODEGENERATIVE DISEASES AND CANCER. DISTINCT OR GLOBAL CHANGES IN THE EPIGENETIC LANDSCAPE ARE HALLMARKS OF CHRONIC INFLAMMATION DRIVEN DISEASES. EPIGENETICS INCLUDE CHANGES TO DISTINCT MARKERS ON THE GENOME AND ASSOCIATED CELLULAR TRANSCRIPTIONAL MACHINERY THAT ARE COPIED DURING CELL DIVISION (MITOSIS AND MEIOSIS). THESE CHANGES APPEAR FOR A SHORT SPAN OF TIME AND THEY NECESSARILY DO NOT MAKE PERMANENT CHANGES TO THE PRIMARY DNA SEQUENCE ITSELF. HOWEVER, THE MOST FREQUENTLY OBSERVED EPIGENETIC CHANGES INCLUDE ABERRANT DNA METHYLATION, AND HISTONE ACETYLATION AND DEACETYLATION. IN THIS CHAPTER, WE FOCUS ON PRO-INFLAMMATORY MOLECULES THAT ARE REGULATED BY ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS ARGININE AND LYSINE METHYL TRANSFERASES, DNA METHYLTRANSFERASE, HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASES AND THEIR ROLE IN INFLAMMATION DRIVEN DISEASES. AGENTS THAT MODULATE OR INHIBIT THESE EPIGENETIC MODIFICATIONS, SUCH AS HAT OR HDAC INHIBITORS HAVE SHOWN GREAT POTENTIAL IN INHIBITING THE PROGRESSION OF THESE DISEASES. GIVEN THE PLASTICITY OF THESE EPIGENETIC CHANGES AND THEIR READINESS TO RESPOND TO INTERVENTION BY SMALL MOLECULE INHIBITORS, THERE IS A TREMENDOUS POTENTIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS THAT WILL SERVE AS DIRECT OR ADJUVANT THERAPEUTIC COMPOUNDS IN THE TREATMENT OF THESE DISEASES. 2013