1 6569 152 TRANSPLANTATION OF EPIGENETICALLY MODIFIED ADULT CARDIAC C-KIT+ CELLS RETARDS REMODELING AND IMPROVES CARDIAC FUNCTION IN ISCHEMIC HEART FAILURE MODEL. CARDIAC C-KIT+ CELLS HAVE A MODEST CARDIOGENIC POTENTIAL THAT COULD LIMIT THEIR EFFICACY IN HEART DISEASE TREATMENT. THE PRESENT STUDY WAS DESIGNED TO AUGMENT THE CARDIOGENIC POTENTIAL OF CARDIAC C-KIT+ CELLS THROUGH CLASS I HISTONE DEACETYLASE (HDAC) INHIBITION AND EVALUATE THEIR THERAPEUTIC POTENCY IN THE CHRONIC HEART FAILURE (CHF) ANIMAL MODEL. MYOCARDIAL INFARCTION (MI) WAS CREATED BY CORONARY ARTERY OCCLUSION IN RATS. C-KIT+ CELLS WERE TREATED WITH MOCETINOSTAT (MOCE), A SPECIFIC CLASS I HDAC INHIBITOR. AT 3 WEEKS AFTER MI, CHF ANIMALS WERE RETROGRADELY INFUSED WITH UNTREATED (CONTROL) OR MOCE-TREATED C-KIT+ CELLS (MOCE/C-KIT+ CELLS) AND EVALUATED AT 3 WEEKS AFTER CELL INFUSION. WE FOUND THAT CLASS I HDAC INHIBITION IN C-KIT+ CELLS ELEVATED THE LEVEL OF ACETYLATED HISTONE H3 (ACH3) AND INCREASED ACH3 LEVELS IN THE PROMOTER REGIONS OF PLURIPOTENT AND CARDIAC-SPECIFIC GENES. EPIGENETIC CHANGES WERE ACCOMPANIED BY INCREASED EXPRESSION OF CARDIAC-SPECIFIC MARKERS. TRANSPLANTATION OF CHF RATS WITH EITHER CONTROL OR MOCE/C-KIT+ CELLS RESULTED IN AN IMPROVEMENT IN CARDIAC FUNCTION, RETARDATION OF CHF REMODELING MADE EVIDENT BY INCREASED VASCULARIZATION AND SCAR SIZE, AND CARDIOMYOCYTE HYPERTROPHY REDUCTION. COMPARED WITH CHF INFUSED WITH CONTROL CELLS, INFUSION OF MOCE/C-KIT+ CELLS RESULTED IN A FURTHER REDUCTION IN LEFT VENTRICLE END-DIASTOLIC PRESSURE AND TOTAL COLLAGEN AND AN INCREASE IN INTERLEUKIN-6 EXPRESSION. THE LOW ENGRAFTMENT OF INFUSED CELLS SUGGESTS THAT PARACRINE EFFECTS MIGHT ACCOUNT FOR THE BENEFICIAL EFFECTS OF C-KIT+ CELLS IN CHF. IN CONCLUSION, SELECTIVE INHIBITION OF CLASS I HDACS INDUCED EXPRESSION OF CARDIAC MARKERS IN C-KIT+ CELLS AND PARTIALLY AUGMENTED THE EFFICACY OF THESE CELLS FOR CHF REPAIR. SIGNIFICANCE: THE STUDY HAS SHOWN THAT SELECTIVE CLASS 1 HISTONE DEACETYLASE INHIBITION IS SUFFICIENT TO REDIRECT C-KIT+ CELLS TOWARD A CARDIAC FATE. EPIGENETICALLY MODIFIED C-KIT+ CELLS IMPROVED CONTRACTILE FUNCTION AND RETARDED REMODELING OF THE CONGESTIVE HEART FAILURE HEART. THIS STUDY PROVIDES NEW INSIGHTS INTO THE EFFICACY OF CARDIAC C-KIT+ CELLS IN THE ISCHEMIC HEART FAILURE MODEL.	2015	

2 3360  34 HISTONE H4K20 TRIMETHYLATION IS DECREASED IN MURINE MODELS OF HEART DISEASE. HEART DISEASE IS THE LEADING CAUSE OF DEATH IN THE DEVELOPED WORLD, AND ITS COMORBIDITIES SUCH AS HYPERTENSION, DIABETES, AND HEART FAILURE ARE ACCOMPANIED BY MAJOR TRANSCRIPTOMIC CHANGES IN THE HEART. DURING CARDIAC DYSFUNCTION, WHICH LEADS TO HEART FAILURE, THERE ARE GLOBAL EPIGENETIC ALTERATIONS TO CHROMATIN THAT OCCUR CONCOMITANTLY WITH MORPHOLOGICAL CHANGES IN THE HEART IN RESPONSE TO ACUTE AND CHRONIC STRESS. THESE EPIGENETIC ALTERATIONS INCLUDE THE REVERSIBLE METHYLATION OF LYSINE RESIDUES ON HISTONE PROTEINS. LYSINE METHYLATIONS ON HISTONES H3K4 AND H3K9 WERE AMONG THE FIRST METHYLATED LYSINE RESIDUES IDENTIFIED AND HAVE BEEN LINKED TO GENE ACTIVATION AND SILENCING, RESPECTIVELY. HOWEVER, MUCH LESS IS KNOWN REGARDING OTHER METHYLATED HISTONE RESIDUES, INCLUDING HISTONE H4K20. TRIMETHYLATION OF HISTONE H4K20 HAS BEEN SHOWN TO REPRESS GENE EXPRESSION; HOWEVER, THIS MODIFICATION HAS NEVER BEEN EXAMINED IN THE HEART. HERE, WE UTILIZED IMMUNOBLOTTING AND MASS SPECTROMETRY TO QUANTIFY HISTONE H4K20 TRIMETHYLATION IN THREE MODELS OF CARDIAC DYSFUNCTION. OUR RESULTS SHOW THAT LYSINE METHYLATION AT THIS SITE IS DIFFERENTIALLY REGULATED IN THE CARDIOMYOCYTE, LEADING TO INCREASED H4K20 TRIMETHYLATION DURING ACUTE HYPERTROPHIC STRESS IN CELL MODELS AND DECREASED H4K20 TRIMETHYLATION DURING SUSTAINED ISCHEMIC INJURY AND CARDIAC DYSFUNCTION IN ANIMAL MODELS. IN ADDITION, WE EXAMINED PUBLICLY AVAILABLE DATA SETS TO ANALYZE ENZYMES THAT REGULATE H4K20 METHYLATION AND IDENTIFIED TWO DEMETHYLASES (KDM7B AND KDM7C) AND TWO METHYLTRANSFERASES (KMT5A AND SMYD5) THAT WERE ALL DIFFERENTIALLY EXPRESSED IN HEART FAILURE PATIENTS. THIS IS THE FIRST STUDY TO EXAMINE HISTONE H4K20 TRIMETHYLATION IN THE HEART AND TO DETERMINE HOW THIS POST-TRANSLATIONAL MODIFICATION IS DIFFERENTIALLY REGULATED IN MULTIPLE MODELS OF CARDIAC DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                    
3 4544  36 MUSCLE HYPERTROPHY IN HYPOXIA WITH INFLAMMATION IS CONTROLLED BY BROMODOMAIN AND EXTRA-TERMINAL DOMAIN PROTEINS. SOME OF THE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS ENGAGED IN EXERCISE-BASED MUSCLE REHABILITATION PROGRAMS ARE UNRESPONSIVE. TO UNRAVEL THE RESPECTIVE ROLE OF CHRONIC HYPOXIA AND PULMONARY INFLAMMATION ON SOLEUS MUSCLE HYPERTROPHIC CAPACITIES, WE CHALLENGED MALE WISTAR RATS TO REPEATED LIPOPOLYSACCHARIDE INSTILLATIONS, ASSOCIATED OR NOT WITH A CHRONIC HYPOXIA EXPOSURE. MUSCLE HYPERTROPHY WAS INITIATED BY BILATERAL ABLATION OF SOLEUS AGONISTS 1 WEEK BEFORE SACRIFICE. TO UNDERSTAND THE ROLE PLAYED BY THE HISTONE ACETYLATION, WE ALSO TREATED OUR ANIMALS WITH AN INHIBITOR OF BROMODOMAINS AND EXTRA TERMINAL PROTEINS (I-BET) DURING THE WEEK AFTER SURGERY. PULMONARY INFLAMMATION TOTALLY INHIBITED THIS HYPERTROPHY RESPONSE UNDER BOTH NORMOXIC AND HYPOXIC CONDITIONS (26% LOWER THAN CONTROL SURGERY, P < 0.05), CONSISTENT WITH THE S6K1 AND MYOGENIN MEASUREMENTS. CHANGES IN HISTONE ACETYLATION AND CLASS IIA HISTONE DEACETYLASES EXPRESSION, FOLLOWING PULMONARY INFLAMMATION, SUGGESTED A PUTATIVE ROLE FOR HISTONE ACETYLATION SIGNALING IN THE ALTERED HYPERTROPHY RESPONSE. THE I-BET DRUG RESTORED THE HYPERTROPHY RESPONSE SUGGESTING THAT THE NON-RESPONSE OF MUSCLE TO A HYPERTROPHIC STIMULUS COULD BE MODULATED BY EPIGENETIC MECHANISMS, INCLUDING HISTONE-ACETYLATION DEPENDANT PATHWAYS. DRUGS TARGETING SUCH EPIGENETIC MECHANISMS MAY OPEN THERAPEUTIC PERSPECTIVES FOR COPD PATIENTS WITH SYSTEMIC INFLAMMATION WHO ARE UNRESPONSIVE TO REHABILITATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4 3719  38 INHIBITION OF BET PROTEINS REDUCES RIGHT VENTRICLE HYPERTROPHY AND PULMONARY HYPERTENSION RESULTING FROM COMBINED HYPOXIA AND PULMONARY INFLAMMATION. PULMONARY HYPERTENSION IS A CO-MORBIDITY, WHICH STRONGLY PARTICIPATES IN MORBI-MORTALITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). RECENT FINDINGS SHOWED THAT BROMODOMAIN-CONTAINING PROTEINS, IN CHARGE OF READING HISTONE ACETYLATION, COULD BE INVOLVED IN PULMONARY ARTERIAL HYPERTENSION. OUR AIM WAS TO STUDY THE EFFECT OF I-BET151, AN INHIBITOR OF BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET), ON THE RIGHT VENTRICLE HYPERTROPHY AND PULMONARY HYPERTENSION, INDUCED BY A COMBINATION OF CHRONIC HYPOXIA AND PULMONARY INFLAMMATION, AS THE TWO MAIN STIMULI ENCOUNTERED IN COPD. ADULT WISTAR MALE RATS, EXPOSED TO CHRONIC HYPOXIA PLUS PULMONARY INFLAMMATION (CHPI), SHOWED A SIGNIFICANT RIGHT VENTRICLE HYPERTROPHY (+57%, P < 0.001), AN INCREASE IN SYSTOLIC PRESSURE (+46%, P < 0.001) AND IN CONTRACTION SPEED (+36%, P < 0.001), WHEN COMPARED TO CONTROL ANIMALS. I-BET151 TREATED ANIMALS (CHPI-IB) SHOWED RESTORED HEMODYNAMIC PARAMETERS TO LEVELS SIMILAR TO CONTROL ANIMALS, DESPITE CHRONIC HYPOXIA PLUS EXPOSURE TO PULMONARY INFLAMMATION. THEY DISPLAYED LOWER RIGHT VENTRICLE HYPERTROPHY AND HEMATOCRIT COMPARED TO THE CHPI GROUP (RESPECTIVELY -16%, P < 0.001; AND -9%, P < 0.05). OUR DESCRIPTIVE STUDY SHOWS A VALUABLE EFFECT OF THE INHIBITION OF BROMODOMAIN AND EXTRA-TERMINAL DOMAIN PROTEINS ON HEMODYNAMIC PARAMETERS, DESPITE THE PRESENCE OF CHRONIC HYPOXIA AND PULMONARY INFLAMMATION. THIS SUGGESTS THAT SUCH INHIBITION COULD BE OF POTENTIAL INTEREST FOR COPD PATIENTS WITH PULMONARY HYPERTENSION. FURTHER STUDIES ARE NEEDED TO UNRAVEL THE UNDERLYING MECHANISMS INVOLVED AND THE NET BENEFITS OF INHIBITING ADAPTATIONS TO CHRONIC HYPOXIA.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5 4742  42 NOVEL HISTONE MODIFICATIONS IN MICROGLIA DERIVED FROM A MOUSE MODEL OF CHRONIC PAIN. AS THE RESIDENT IMMUNE CELLS IN THE CENTRAL NERVOUS SYSTEM, MICROGLIA PLAY AN IMPORTANT ROLE IN THE MAINTENANCE OF ITS HOMEOSTASIS. DYSREGULATION OF MICROGLIA HAS BEEN ASSOCIATED WITH THE DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, THE RELEVANT MOLECULAR PATHWAYS REMAIN POORLY DEFINED. IN THIS STUDY, WE USED A MASS SPECTROMETRY-BASED PROTEOMIC APPROACH TO SCREEN POTENTIAL CHANGES OF HISTONE PROTEIN MODIFICATIONS IN MICROGLIA ISOLATED FROM THE BRAIN OF CONTROL AND CISPLATIN-INDUCED NEUROPATHIC PAIN ADULT C57BL/6J MALE MICE. WE IDENTIFIED SEVERAL NOVEL MICROGLIAL HISTONE MODIFICATIONS ASSOCIATED WITH PAIN, INCLUDING STATISTICALLY SIGNIFICANTLY DECREASED HISTONE H3.1 LYSINE 27 MONO-METHYLATION (H3.1K27ME1, 54.8% OF CONTROL) AND H3 LYSINE 56 TRI-METHYLATION (7.5% OF CONTROL), AS WELL AS A TREND SUGGESTING INCREASED H3 TYROSINE 41 NITRATION. WE FURTHER INVESTIGATED THE FUNCTIONAL ROLE OF H3.1K27ME1 AND FOUND THAT TREATMENT OF CULTURED MICROGLIAL CELLS FOR 4 CONSECUTIVE DAYS WITH 1-10 MUM OF NCDM-64, A POTENT AND SELECTIVE INHIBITOR OF LYSINE DEMETHYLASE 7A, AN ENZYME RESPONSIBLE FOR THE DEMETHYLATION OF H3K27ME1, DOSE-DEPENDENTLY ELEVATED ITS LEVELS WITH A GREATER THAN A TWO-FOLD INCREASE OBSERVED AT 10 MUM COMPARED TO VEHICLE-TREATED CONTROL CELLS. MOREOVER, PRETREATMENT OF MICE WITH NCDM-64 (10 OR 25 MG/KG/DAY, I.P.) PRIOR TO CISPLATIN TREATMENT PREVENTED THE DEVELOPMENT OF NEUROPATHIC PAIN IN MICE. THE IDENTIFICATION OF SPECIFIC CHROMATIN MARKS IN MICROGLIA ASSOCIATED WITH CHRONIC PAIN MAY YIELD CRITICAL INSIGHT INTO THE CONTRIBUTION OF MICROGLIA TO THE DEVELOPMENT AND MAINTENANCE OF PAIN, AND OPENS NEW AVENUES FOR THE DEVELOPMENT OF NOVEL NONOPIOID THERAPEUTICS FOR THE EFFECTIVE MANAGEMENT OF CHRONIC PAIN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6 1762  36 EARLY TRANSCRIPTIONAL ALTERATION OF HISTONE DEACETYLASES IN A MURINE MODEL OF DOXORUBICIN-INDUCED CARDIOMYOPATHY. DOXORUBICIN IS A POTENT CHEMOTHERAPEUTIC AGENT THAT IS WIDELY-USED TO TREAT A VARIETY OF CANCERS BUT CAUSES ACUTE AND CHRONIC CARDIAC INJURY, SEVERELY LIMITING ITS USE. CLINICALLY, THE ACUTE SIDE EFFECTS OF DOXORUBICIN ARE MOSTLY MANAGEABLE, WHEREAS THE DELAYED CONSEQUENCES CAN LEAD TO LIFE-THREATENING HEART FAILURE, EVEN DECADES AFTER CANCER TREATMENT. THE CARDIOTOXICITY OF DOXORUBICIN IS SUBJECT TO A CRITICAL CUMULATIVE DOSE AND SO DOSAGE LIMITATION IS CONSIDERED TO BE THE BEST WAY TO REDUCE THESE EFFECTS. HENCE, A NUMBER OF STUDIES HAVE DEFINED A "SAFE DOSE" OF THE DRUG, BOTH IN ANIMAL MODELS AND CLINICAL SETTINGS, WITH THE AIM OF AVOIDING LONG-TERM CARDIAC EFFECTS. HERE WE SHOW THAT A DOSE GENERALLY CONSIDERED AS SAFE IN A MOUSE MODEL CAN INDUCE HARMFUL CHANGES IN THE MYOCARDIUM, AS EARLY AS 2 WEEKS AFTER INFUSION. THE ADVERSE CHANGES INCLUDE THE DEVELOPMENT OF FIBROTIC LESIONS, DISARRAY OF CARDIOMYOCYTES AND A MAJOR TRANSCRIPTION DYSREGULATION. IMPORTANTLY, LOW-DOSE DOXORUBICIN CAUSED SPECIFIC CHANGES IN THE TRANSCRIPTIONAL PROFILE OF SEVERAL HISTONE DEACETYLASES (HDACS) WHICH ARE EPIGENETIC REGULATORS OF CARDIAC REMODELLING. THIS SUGGESTS THAT CARDIOPROTECTIVE THERAPIES, AIMED AT MODULATING HDACS DURING DOXORUBICIN TREATMENT, DESERVE FURTHER EXPLORATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7 2442  34 EPIGENETIC STABILITY IN THE ADULT MOUSE CORTEX UNDER CONDITIONS OF PHARMACOLOGICALLY INDUCED HISTONE ACETYLATION. HISTONE ACETYLATION IS CONSIDERED A MAJOR EPIGENETIC PROCESS THAT AFFECTS BRAIN DEVELOPMENT AND SYNAPTIC PLASTICITY, AS WELL AS LEARNING AND MEMORY. THE TRANSCRIPTIONAL EFFECTORS AND MORPHOLOGICAL CHANGES RESPONSIBLE FOR PLASTICITY AS A RESULT OF LONG-TERM MODIFICATIONS TO HISTONE ACETYLATION ARE NOT FULLY UNDERSTOOD. TO THIS END, WE PHARMACOLOGICALLY INHIBITED HISTONE DEACETYLATION USING TRICHOSTATIN A IN ADULT (6-MONTH-OLD) MICE AND FOUND SIGNIFICANT INCREASES IN THE LEVELS OF THE ACETYLATED HISTONE MARKS H3LYS9, H3LYS14 AND H4LYS12. HIGH-RESOLUTION TRANSCRIPTOME ANALYSIS OF DIVERSE BRAIN REGIONS UNCOVERED FEW DIFFERENCES IN GENE EXPRESSION BETWEEN TREATED AND CONTROL ANIMALS, NONE OF WHICH WERE PLASTICITY RELATED. INSTEAD, AFTER INCREASED HISTONE ACETYLATION, WE DETECTED A LARGE NUMBER OF NOVEL TRANSCRIPTIONALLY ACTIVE REGIONS, WHICH CORRESPOND TO LONG NON-CODING RNAS (LNCRNAS). WE ALSO SURPRISINGLY FOUND NO SIGNIFICANT CHANGES IN DENDRITIC SPINE PLASTICITY IN LAYERS 1 AND 2/3 OF THE VISUAL CORTEX USING LONG-TERM IN VIVO TWO-PHOTON IMAGING. OUR RESULTS INDICATE THAT CHRONIC PHARMACOLOGICALLY INDUCED HISTONE ACETYLATION CAN BE DECOUPLED FROM GENE EXPRESSION AND INSTEAD, MAY POTENTIALLY EXERT A POST-TRANSCRIPTIONAL EFFECT THROUGH THE DIFFERENTIAL PRODUCTION OF LNCRNAS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8 3341  30 HISTONE DEACETYLASE-2 IS INVOLVED IN STRESS-INDUCED COGNITIVE IMPAIRMENT VIA HISTONE DEACETYLATION AND PI3K/AKT SIGNALING PATHWAY MODIFICATION. EXPOSURE TO CHRONIC STRESS UPREGULATES BLOOD GLUCOCORTICOID LEVELS AND IMPAIRS COGNITION VIA DIVERSE EPIGENETIC MECHANISMS, SUCH AS HISTONE DEACETYLATION. HISTONE DEACETYLATION CAN LEAD TO TRANSCRIPTIONAL SILENCING OF MANY PROTEINS INVOLVED IN COGNITION AND MAY ALSO CAUSE LEARNING AND MEMORY DYSFUNCTION. HISTONE DEACETYLASE?2 (HDAC2) HAS BEEN DEMONSTRATED TO EPIGENETICALLY BLOCK COGNITION VIA A REDUCTION IN THE HISTONE ACETYLATION LEVEL; HOWEVER, IT IS UNKNOWN WHETHER HDAC2 IS INVOLVED IN THE COGNITIVE DECLINE INDUCED BY CHRONIC STRESS. TO THE BEST OF AUTHORS' KNOWLEDGE, THIS IS THE FIRST STUDY TO DEMONSTRATE THAT THE STRESS HORMONE CORTICOSTEROID UPREGULATE HDAC2 PROTEIN LEVELS IN NEURO?2A CELLS AND CAUSE CELL INJURIES. HDAC2 KNOCKDOWN RESULTED IN A SIGNIFICANT AMELIORATION OF THE PATHOLOGICAL CHANGES IN N2A CELLS VIA THE UPREGULATION OF HISTONE ACETYLATION AND MODIFICATIONS IN THE PHOSPHOINOSITIDE 3?KINASE/PROTEIN KINASE B SIGNALING PATHWAY. IN ADDITION, THE HDAC2 PROTEIN LEVELS WERE UPREGULATED IN 12?MONTH?OLD FEMALE C57BL/6J MICE UNDER CHRONIC STRESS IN VIVO. TAKEN TOGETHER, THESE FINDINGS SUGGESTED THAT HDAC2 MAY BE AN IMPORTANT NEGATIVE REGULATOR INVOLVED IN CHRONIC STRESS?INDUCED COGNITIVE IMPAIRMENT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
9 3348  37 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 6564  36 TRANSIENT EXPOSURE TO ELEVATED GLUCOSE LEVELS CAUSES PERSISTENT CHANGES IN DERMAL MICROVASCULAR ENDOTHELIAL CELL RESPONSES TO INJURY. BACKGROUND: THE PURPOSE OF THIS STUDY WAS TO DETERMINE WHETHER ELEVATED GLUCOSE CAN INDUCE A DERMAL MICROVASCULAR ENDOTHELIAL CELL METABOLIC MEMORY, THUS AFFECTING ANGIOGENESIS IN THE REPAIR PROCESS OF MAMMALIAN CUTANEOUS WOUND. WE HYPOTHESIZED THAT TRANSIENT ELEVATED GLUCOSE LEVELS CAUSE SUSTAINED ALTERATION OF ENDOTHELIAL CELL RESPONSES TO INJURY AND PERSISTENT EPIGENETIC CHANGES IN GENE EXPRESSION. METHODS: HUMAN DERMAL MICROVASCULAR ENDOTHELIAL CELLS WERE EXPOSED TO EXPERIMENTAL CONDITIONS WITH OR WITHOUT 30 MM D-GLUCOSE. THE CONTROL GROUP WAS MAINTAINED AT 5 MM D-GLUCOSE; WHILE IN THE TRANSIENT GLUCOSE GROUP, AFTER BEING EXPOSED TO 30 MM D-GLUCOSE FOR TWO DAYS, THEN BEING PUT UNDER THE CONTROL CONDITIONS DURING THE EXPERIMENT. BESIDES, IN THE WHOLE PROCESS OF THE EXPERIMENT, THE CHRONIC GLUCOSE GROUP WAS KEPT IN THE CONDITION WITH 30 MM D-GLUCOSE. PROLIFERATION, MIGRATION, TUBE FORMATION, GENE EXPRESSION AND HISTONE METHYLATION WERE ASSESSED FOR INDIVIDUAL CONDITIONS. RESULTS: TRANSIENT ELEVATED GLUCOSE CAUSED SUSTAINED EFFECTS ON ENDOTHELIAL CELL MIGRATION, TUBE FORMATION AND TIMP3 GENE EXPRESSION. THE EFFECTS ON TIMP3 EXPRESSION WERE ASSOCIATED WITH PERSISTENT CHANGES IN HISTONE MODIFICATION AT THE 5' END OF THE TIMP3 GENE, SUGGESTING AN EPIGENETIC EFFECT. CONCLUSIONS: HYPERGLYCEMIA INDUCED METABOLIC MEMORY COULD PROMOTE THE REGULATION OF TIMP3, AND IT CAN BE USED AS A POSSIBLE INNOVATIVE MOLECULAR TARGET FOR THERAPEUTIC INTERVENTION IN THE TREATMENT OF CHRONIC NON-HEALING DIABETIC WOUNDS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11 6765  35 ZINC DEFICIENCY LEADS TO REDUCED INTERLEUKIN-2 PRODUCTION BY ACTIVE GENE SILENCING DUE TO ENHANCED CREMALPHA EXPRESSION IN T CELLS. BACKGROUND & AIMS: THE MICRONUTRIENT ZINC IS ESSENTIAL FOR PROPER IMMUNE FUNCTION. CONSEQUENTLY, ZINC DEFICIENCY LEADS TO IMPAIRED IMMUNE FUNCTION, AS SEEN IN DECREASED SECRETION OF INTERLEUKIN (IL)-2 BY T CELLS. ALTHOUGH THIS ASSOCIATION HAS BEEN KNOWN SINCE THE LATE 1980S, THE UNDERLYING MOLECULAR MECHANISMS ARE STILL UNKNOWN. ZINC DEFICIENCY AND REDUCED IL-2 LEVELS ARE ESPECIALLY FOUND IN THE ELDERLY, WHICH IN TURN ARE PRONE TO CHRONIC DISEASES. HERE, WE DESCRIBE A NEW MOLECULAR LINK BETWEEN ZINC DEFICIENCY AND REDUCED IL-2 EXPRESSION IN T CELLS. METHODS: THE EFFECTS OF ZINC DEFICIENCY WERE FIRST INVESTIGATED IN VITRO IN THE HUMAN T CELL LINES JURKAT AND HUT-78 AND COMPLEMENTED BY IN VIVO DATA FROM ZINC-SUPPLEMENTED PIGS. A SHORT- AND LONG-TERM MODEL FOR ZINC DEFICIENCY WAS ESTABLISHED. ZINC LEVELS WERE DETECTED BY FLOW CYTOMETRY AND EXPRESSION PROFILES WERE INVESTIGATED ON THE MRNA AND PROTEIN LEVEL. RESULTS: THE EXPRESSION OF THE TRANSCRIPTION FACTOR CAMP-RESPONSIVE-ELEMENT MODULATOR ALPHA (CREMALPHA) IS INCREASED DURING ZINC DEFICIENCY IN VITRO, DUE TO INCREASED PROTEIN PHOSPHATASE 2A (PP2A) ACTIVITY, RESULTING IN DECREASED IL-2 PRODUCTION. ADDITIONALLY, ZINC SUPPLEMENTATION IN VIVO REDUCED CREMALPHA LEVELS CAUSING INCREASED IL-2 EXPRESSION. ON EPIGENETIC LEVELS INCREASED CREMALPHA BINDING TO THE IL-2 PROMOTER IS MEDIATED BY HISTONE DEACETYLASE 1 (HDAC1). THE HDAC1 ACTIVITY IS INHIBITED BY ZINC. MOREOVER, DEACETYLATION OF THE ACTIVATING HISTONE MARK H3K9 WAS INCREASED UNDER ZINC DEFICIENCY, RESULTING IN REDUCED IL-2 EXPRESSION. CONCLUSIONS: WITH THE TRANSCRIPTION FACTOR CREMALPHA A MOLECULAR LINK WAS UNCOVERED, CONNECTING ZINC DEFICIENCY WITH REDUCED IL-2 PRODUCTION DUE TO ENHANCED PP2A AND HDAC1 ACTIVITY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                 
12 3857  30 ISCHEMIA- REPERFUSION INJURY AND ITS INFLUENCE ON THE EPIGENETIC MODIFICATION OF THE DONOR KIDNEY GENOME. BACKGROUND: IN CLINICAL TRANSPLANTATION, ISCHEMIA-REPERFUSION INJURY (I/RI) CAUSES DAMAGE TO DNA. WE HYPOTHESIZE THAT ONE FORM OF DAMAGE IS THE DEMETHYLATION OF METHYLATED CYTOSINES IN THE DONOR GENOME CAUSED BY THE OXIDATIVE ENVIRONMENT CREATED FIRST BY ISCHEMIA, AND SUBSEQUENTLY BY REPERFUSION ON TRANSPLANTATION. THIS STUDY CONTRIBUTES TO THE UNDERSTANDING OF HOW THE SHORT-LIVED AND TRANSIENT ISCHEMIC INSULT MAY INFLUENCE CHRONIC PATHOLOGICAL CHANGES THAT OCCUR IN CLINICAL TRANSPLANTATION IN THE LONG TERM. METHODS: A MODEL OF I/RI AND CHRONIC REJECTION; FISHER TO FISHER KIDNEY TRANSPLANT RENDERED COLD-ISCHEMIC FOR 4 HR BEFORE TRANSPLANTATION, TO INDUCE ANTIGEN-INDEPENDENT CHRONIC NEPHROPATHY OVER A 6-MONTH PERIOD, WAS USED. TISSUE WAS ASSESSED BY HISTOPATHOLOGY AND METHYLATION BY PYROSEQUENCING ANALYSIS. RESULTS: AN EPIGENETIC MAP OF THE RAT RENAL C3 PROMOTER WAS PRODUCED, WHICH IDENTIFIED METHYLATED CYTOSINE PHOSPHO GUANINE (CPG) SITES COINCIDENT TO CYTOKINE RESPONSE ELEMENTS AND NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB) BINDING SITES. PYROSEQUENCING ANALYSIS SHOWED THAT THE TISSUE THAT HAD UNDERGONE 4 HR ISCHEMIA AND REPERFUSION DEVELOPED ABERRANT DEMETHYLATION OF CYTOSINES IN PUTATIVE REGULATORY SITES WITHIN THE C3 PROMOTER. CONCLUSION: THESE FINDINGS MAY DESCRIBE A NEWLY RECOGNIZED PHENOMENA IN THE FIELD OF TRANSPLANTATION. ABERRANT DEMETHYLATION HAS LONG BEEN LINKED TO THE DEVELOPMENT OF TUMORS, AND OUR DATA SUGGEST A SIMILAR MECHANISM OF GENE DYSREGULATION THAT MAY BE INITIATED BY I/RI WITH ACUTE AND CHRONIC EFFECTS. THESE DATA MAY CONTRIBUTE TO A FURTHER UNDERSTANDING OF HOW THE SHORT LIVED AND TRANSIENT ISCHEMIC INSULT INFLUENCES CHRONIC PATHOLOGICAL CHANGES THAT OCCUR EVEN IN THE ABSENCE OF MAJOR HISTOCOMPATIBILITY COMPLEX DISPARITY IN TRANSPLANTATION.	2008	
                                                                                                                                                                                                                                                                                                                                                                      
13 3527  26 IL-6 ENHANCES THE NUCLEAR TRANSLOCATION OF DNA CYTOSINE-5-METHYLTRANSFERASE 1 (DNMT1) VIA PHOSPHORYLATION OF THE NUCLEAR LOCALIZATION SEQUENCE BY THE AKT KINASE. THE EPIGENETIC PROGRAMMING OF GENOMIC DNA IS ACCOMPLISHED, IN PART, BY SEVERAL DNA CYTOSINE-5-METHYLTRANSFERASES THAT ACT BY COVALENTLY MODIFYING CYTOSINES WITH THE ADDITION OF A METHYL GROUP. THIS COVALENT MODIFICATION IS MAINTAINED BY THE DNA CYTOSINE-5-METHYLTRANSFERASE-1 ENZYME (DNMT1), WHICH IS CAPABLE OF ACTING IN CONCERT WITH OTHER SIMILAR ENZYMES TO SILENCE IMPORTANT TUMOR SUPPRESSOR GENES. IL-6 IS A MULTIFUNCTIONAL MEDIATOR OF INFLAMMATION, ACTING THROUGH SEVERAL MAJOR SIGNALING CASCADES, INCLUDING THE PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY (PI-3-K), WHICH ACTIVATES PROTEIN KINASE B (AKT/PKB) DOWNSTREAM. HERE, WE SHOW THAT THE SUBCELLULAR LOCALIZATION OF DNMT1 CAN BE ALTERED BY THE ADDITION OF IL-6, INCREASING THE RATE OF NUCLEAR TRANSLOCATION OF THE ENZYME FROM THE CYTOSOLIC COMPARTMENT. THE MECHANISM OF NUCLEAR TRANSLOCATION OF DNMT1 IS GREATLY ENHANCED BY PHOSPHORYLATION OF THE DNMT1 NUCLEAR LOCALIZATION SIGNAL (NLS) BY PKB/AKT KINASE. MUTAGENIC ALTERATION OF THE TWO AKT TARGET AMINO ACIDS WITHIN THE NLS RESULTS IN A MAJOR LOSS OF DNMT1 NUCLEAR TRANSLOCATION, WHILE THE CREATION OF A "PHOSPHO-MIMIC" AMINO ACID (MUTATION TO ACIDIC RESIDUES) RESTORES THIS COMPARTMENTATION ABILITY. THESE OBSERVATIONS SUGGEST AN INTERESTING HYPOTHESIS REGARDING HOW MEDIATORS OF CHRONIC INFLAMMATION MAY DISTURB THE DELICATE BALANCE OF CELLULAR COMPARTMENTALIZATION OF IMPORTANT PROTEINS, AND REVEALS A POTENTIAL MECHANISM FOR THE INDUCTION OR ENHANCEMENT OF TUMOR GROWTH VIA ALTERATION OF THE COMPONENTS INVOLVED IN THE EPIGENETIC PROGRAMMING OF A CELL.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14 2297  29 EPIGENETIC REGULATION OF ACUTE INFLAMMATORY PAIN. ACUTE PAIN IS ASSOCIATED WITH TISSUE DAMAGE, WHICH RESULTS IN THE RELEASE OF INFLAMMATORY MEDIATORS. RECENT STUDIES POINT TO THE INVOLVEMENT OF EPIGENETIC MECHANISMS (DNA METHYLATION) IN THE DEVELOPMENT OF PAIN. WE HAVE FOUND THAT DURING ACUTE INFLAMMATORY PAIN INDUCED BY THE APPLICATION OF 10% MUSTARD OIL ON THE TONGUES OF RATS, LEVELS OF DNMT3A AND 3B WERE ELEVATED MARKEDLY (36 AND 42 % RESPECTIVELY), WHEREAS THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY. PREVIOUS INJECTION OF XEFOCAM WITH 0,4 MG/KG DOSE DECREASED LEVELS OF DNMT3A AND 3B (25 AND 24% RESPECTIVELY). THE LEVEL OF DNMT1 WAS NOT CHANGED SIGNIFICANTLY COMPARED TO THE CONTROL GROUP. THE FINDINGS SUPPORT THE IDEA THAT INHIBITORS OF DNA-METHYLTRANSFERASES COULD BE USEFUL FOR PAIN MANAGEMENT. OUR DATA SUGGEST THAT NSAIDS (ALONE OR IN COMBINATION WITH DNMT INHIBITORS) MAY BE PROPOSED AS POSSIBLE EPIGENETIC REGULATORY AGENTS, WHICH MAY PLAY A ROLE IN EPIGENETIC MECHANISMS INDIRECTLY THROUGH ALTERING THE ACTIVITY OF INFLAMMATORY MEDIATORS INVOLVED IN PAIN DEVELOPMENT.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15 2590  34 EPIGENETICS OF PROTEASOME INHIBITION IN THE LIVER OF RATS FED ETHANOL CHRONICALLY. AIM: TO EXAMINE THE EFFECTS OF ETHANOL-INDUCED PROTEASOME INHIBITION, AND THE EFFECTS OF PROTEASOME INHIBITION IN THE REGULATION OF EPIGENETIC MECHANISMS. METHODS: RATS WERE FED ETHANOL FOR 1 MO USING THE TSUKAMOTO-FRENCH MODEL AND WERE COMPARED TO RATS GIVEN THE PROTEASOME INHIBITOR PS-341 (BORTEZOMIB, VELCADE(TM)) BY INTRAPERITONEAL INJECTION. MICROARRAY ANALYSIS AND REAL TIME PCR WERE PERFORMED AND PROTEASOME ACTIVITY ASSAYS AND WESTERN BLOT ANALYSIS WERE PERFORMED USING ISOLATED NUCLEI. RESULTS: CHRONIC ETHANOL FEEDING CAUSED A SIGNIFICANT INHIBITION OF THE UBIQUITIN PROTEASOME PATHWAY IN THE NUCLEUS, WHICH LED TO CHANGES IN THE TURNOVER OF TRANSCRIPTIONAL FACTORS, HISTONE-MODIFYING ENZYMES, AND, THEREFORE, AFFECTED EPIGENETIC MECHANISMS. CHRONIC ETHANOL FEEDING WAS RELATED TO AN INCREASE IN HISTONE ACETYLATION, AND IT IS HYPOTHESIZED THAT THE PROTEASOME PROTEOLYTIC ACTIVITY REGULATED HISTONE MODIFICATIONS BY CONTROLLING THE STABILITY OF HISTONE MODIFYING ENZYMES, AND, THEREFORE, REGULATED THE CHROMATIN STRUCTURE, ALLOWING EASY ACCESS TO CHROMATIN BY RNA POLYMERASE, AND, THUS, PROPER GENE EXPRESSION. PROTEASOME INHIBITION BY PS-341 INCREASED HISTONE ACETYLATION SIMILAR TO CHRONIC ETHANOL FEEDING. IN ADDITION, PROTEASOME INHIBITION CAUSED DRAMATIC CHANGES IN HEPATIC REMETHYLATION REACTIONS AS THERE WAS A SIGNIFICANT DECREASE IN THE ENZYMES RESPONSIBLE FOR THE REGENERATION OF S-ADENOSYLMETHIONINE, AND, IN PARTICULAR, A SIGNIFICANT DECREASE IN THE BETAINE-HOMOCYSTEINE METHYLTRANSFERASE ENZYME. THIS SUGGESTED THAT HYPOMETHYLATION WAS ASSOCIATED WITH PROTEASOME INHIBITION, AS INDICATED BY THE DECREASE IN HISTONE METHYLATION. CONCLUSION: THE ROLE OF PROTEASOME INHIBITION IN REGULATING EPIGENETIC MECHANISMS, AND ITS LINK TO LIVER INJURY IN ALCOHOLIC LIVER DISEASE, IS THUS A PROMISING APPROACH TO STUDY LIVER INJURY DUE TO CHRONIC ETHANOL CONSUMPTION.	2009	
                                                                                                                                                                                                                                                                                                                                         
16  164  37 ABNORMAL HISTONE METHYLATION IS RESPONSIBLE FOR INCREASED VASCULAR ENDOTHELIAL GROWTH FACTOR 165A SECRETION FROM AIRWAY SMOOTH MUSCLE CELLS IN ASTHMA. VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), A KEY ANGIOGENIC MOLECULE, IS ABERRANTLY EXPRESSED IN SEVERAL DISEASES INCLUDING ASTHMA WHERE IT CONTRIBUTES TO BRONCHIAL VASCULAR REMODELING AND CHRONIC INFLAMMATION. ASTHMATIC HUMAN AIRWAY SMOOTH MUSCLE CELLS HYPERSECRETE VEGF, BUT THE MECHANISM IS UNCLEAR. IN THIS STUDY, WE DEFINED THE MECHANISM IN HUMAN AIRWAY SMOOTH MUSCLE CELLS FROM NONASTHMATIC AND ASTHMATIC PATIENTS. WE FOUND THAT ASTHMATIC CELLS LACKED A REPRESSION COMPLEX AT THE VEGF PROMOTER, WHICH WAS PRESENT IN NONASTHMATIC CELLS. RECRUITMENT OF G9A, TRIMETHYLATION OF HISTONE H3 AT LYSINE 9 (H3K9ME3), AND A RESULTANT DECREASE IN RNA POLYMERASE II AT THE VEGF PROMOTER WAS CRITICAL TO REPRESSION OF VEGF SECRETION IN NONASTHMATIC CELLS. AT THE ASTHMATIC PROMOTER, H3K9ME3 WAS ABSENT BECAUSE OF FAILED RECRUITMENT OF G9A; RNA POLYMERASE II BINDING, IN ASSOCIATION WITH TATA-BINDING PROTEIN-ASSOCIATED FACTOR 1, WAS INCREASED; H3K4ME3 WAS PRESENT; AND SP1 BINDING WAS EXAGGERATED AND SUSTAINED. IN CONTRAST, DNA METHYLATION AND HISTONE ACETYLATION WERE SIMILAR IN ASTHMATIC AND NONASTHMATIC CELLS. THIS IS THE FIRST STUDY, TO OUR KNOWLEDGE, TO SHOW THAT AIRWAY CELLS IN ASTHMA HAVE ALTERED EPIGENETIC REGULATION OF REMODELING GENE(S). HISTONE METHYLATION AT GENES SUCH AS VEGF MAY BE AN IMPORTANT NEW THERAPEUTIC TARGET.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17 3193  40 HDAC INHIBITION REGULATES OXIDATIVE STRESS IN CD4(+)THELPER CELLS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND NON-SMALL CELL LUNG CANCER PATIENTS VIA MITOCHONDRIAL TRANSCRIPTION FACTOR A (MTTFA) MODULATING NF-KAPPAB/HIF1ALPHA AXIS. HISTONE DEACETYLASES (HDACS) PLAY A CRUCIAL ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION BY REMODELLING CHROMATIN. ISOENZYMES OF THE HDAC FAMILY EXHIBIT ABERRANT REGULATION IN A WIDE VARIETY OF CANCERS AS WELL AS SEVERAL INFLAMMATORY LUNG DISORDERS LIKE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). INHIBITION OF HDACS IS A POTENTIAL THERAPEUTIC STRATEGY THAT COULD BE USED TO REVERSE EPIGENETIC MODIFICATION. TRICHOSTATIN A (TSA), A POWERFUL HISTONE DEACETYLASE (HDAC) INHIBITOR, HAS ANTI-CANCER EFFECTS IN NUMEROUS CANCER TYPES. HOWEVER, IT IS NOT YET APPARENT HOW HDAC INHIBITORS AFFECT HUMAN NON-SMALL CELL LUNG CANCER CELLS (NSCLC) AND COPD. THIS STUDY AIMS TO INVESTIGATE TSA'S ROLE IN RESTORING MITOCHONDRIAL DYSFUNCTION AND ITS EFFECT ON HYPOXIA AND INFLAMMATION IN CD4(+)T CELLS OBTAINED FROM PATIENTS WITH COPD AND LUNG CANCER. AS A RESULT OF TREATMENT WITH TSA, THERE IS A REDUCTION IN THE EXPRESSION OF INFLAMMATORY CYTOKINES AND A DECREASED ENRICHMENT OF TRANSCRIPTIONAL FACTORS ASSOCIATED WITH INFLAMMATION AT VEGFA GENE LOCI. WE HAVE SEEN A SUBSTANTIAL DECREASE IN THE EXPRESSION OF NF-KAPPAB AND HIF1ALPHA, WHICH ARE THE CRITICAL MEDIATORS OF INFLAMMATION AND HYPOXIA, RESPECTIVELY. FOLLOWING TSA TREATMENT, MTTFA EXPRESSION WAS INCREASED, FACILITATING PATIENTS WITH COPD AND NSCLC IN THE RECOVERY OF THEIR DYSFUNCTIONAL MITOCHONDRIA. FURTHERMORE, WE HAVE DISCOVERED THAT TSA TREATMENT IN PATIENTS WITH COPD AND NSCLC MAY LEAD TO IMMUNOPROTECTIVE NESS BY INDUCING TH1NESS. OUR FINDING GIVES A NEW INSIGHT INTO THE EXISTING BODY OF KNOWLEDGE REGARDING TSA-BASED THERAPEUTIC METHODS AND HIGHLIGHTS THE NECESSITY OF EPIGENETIC THERAPY FOR THESE DEVASTATING LUNG DISORDERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                           
18 2119  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19 5947  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20 1709  20 DYSFUNCTIONAL ERG SIGNALING DRIVES PULMONARY VASCULAR AGING AND PERSISTENT FIBROSIS. VASCULAR DYSFUNCTION IS A HALLMARK OF CHRONIC DISEASES IN ELDERLY. THE CONTRIBUTION OF THE VASCULATURE TO LUNG REPAIR AND FIBROSIS IS NOT FULLY UNDERSTOOD. HERE, WE PERFORMED AN EPIGENETIC AND TRANSCRIPTIONAL ANALYSIS OF LUNG ENDOTHELIAL CELLS (ECS) FROM YOUNG AND AGED MICE DURING THE RESOLUTION OR PROGRESSION OF BLEOMYCIN-INDUCED LUNG FIBROSIS. WE IDENTIFIED THE TRANSCRIPTION FACTOR ETS-RELATED GENE (ERG) AS PUTATIVE ORCHESTRATOR OF LUNG CAPILLARY HOMEOSTASIS AND REPAIR, AND WHOSE FUNCTION IS DYSREGULATED IN AGING. ERG DYSREGULATION IS ASSOCIATED WITH REDUCED CHROMATIN ACCESSIBILITY AND MALADAPTIVE TRANSCRIPTIONAL RESPONSES TO INJURY. LOSS OF ENDOTHELIAL ERG ENHANCES PARACRINE FIBROBLAST ACTIVATION IN VITRO, AND IMPAIRS LUNG FIBROSIS RESOLUTION IN YOUNG MICE IN VIVO. SCRNA-SEQ OF ERG DEFICIENT MOUSE LUNGS REVEALES TRANSCRIPTIONAL AND FIBROGENIC ABNORMALITIES RESEMBLING THOSE ASSOCIATED WITH AGING AND HUMAN LUNG FIBROSIS, INCLUDING REDUCED NUMBER OF GENERAL CAPILLARY (GCAP) ECS. OUR FINDINGS DEMONSTRATE THAT LUNG ENDOTHELIAL CHROMATIN REMODELING DETERIORATES WITH AGING LEADING TO ABNORMAL TRANSCRIPTION, VASCULAR DYSREPAIR, AND PERSISTENT FIBROSIS FOLLOWING INJURY.	2022