1   720 135 CALPAIN-14 AND ITS ASSOCIATION WITH EOSINOPHILIC ESOPHAGITIS. CALPAINS ARE A FAMILY OF INTRACELLULAR, CALCIUM-DEPENDENT CYSTEINE PROTEASES INVOLVED IN A VARIETY OF REGULATORY PROCESSES, INCLUDING CYTOSKELETAL DYNAMICS, CELL-CYCLE PROGRESSION, SIGNAL TRANSDUCTION, GENE EXPRESSION, AND APOPTOSIS. THESE ENZYMES HAVE BEEN IMPLICATED IN A NUMBER OF DISEASE PROCESSES, NOTABLY FOR THIS REVIEW INVOLVING EOSINOPHILIC TISSUE INFLAMMATION, SUCH AS EOSINOPHILIC ESOPHAGITIS (EOE), A CHRONIC INFLAMMATORY DISORDER TRIGGERED BY ALLERGIC HYPERSENSITIVITY TO FOOD AND ASSOCIATED WITH GENETIC VARIANTS IN CALPAIN 14 (CAPN14). HEREIN WE REVIEW THE GENETIC, STRUCTURAL, AND BIOCHEMICAL PROPERTIES OF CAPN14 AND ITS GENE PRODUCT CAPN14, AND ITS EMERGING ROLE IN PATIENTS WITH EOE. THE CAPN14 GENE IS LOCALIZED AT CHROMOSOME 2P23.1-P21 AND IS MOST HOMOLOGOUS TO CAPN13 (36% SEQUENCE IDENTITY), WHICH IS LOCATED 365 KB DOWNSTREAM OF CAPN14. STRUCTURALLY, CAPN14 HAS CLASSICAL CALPAIN MOTIFS, INCLUDING A CYSTEINE PROTEASE CORE. IN COMPARISON WITH OTHER HUMAN CALPAINS, CAPN14 HAS A UNIQUE EXPRESSION PATTERN, WITH THE HIGHEST LEVELS IN THE UPPER GASTROINTESTINAL TRACT, PARTICULARLY IN THE SQUAMOUS EPITHELIUM OF THE ESOPHAGUS. THE CAPN14 GENE IS POSITIONED IN AN EPIGENETIC HOTSPOT REGULATED BY IL-13, A T(H)2 CYTOKINE WITH INCREASED LEVELS IN PATIENTS WITH EOE THAT HAS BEEN SHOWN TO BE A MEDIATOR OF THE DISEASE. CAPN14 INDUCES DISRUPTIVE EFFECTS ON THE ESOPHAGEAL EPITHELIUM BY IMPAIRING EPITHELIAL BARRIER FUNCTION IN ASSOCIATION WITH LOSS OF DESMOGLEIN-1 EXPRESSION AND HAS A REGULATORY ROLE IN REPAIRING EPITHELIAL CHANGES INDUCED BY IL-13. THUS CAPN14 IS A UNIQUE PROTEASE WITH DISTINCT TISSUE-SPECIFIC EXPRESSION AND FUNCTION IN PATIENTS WITH EOE AND IS A POTENTIAL THERAPEUTIC TARGET FOR EOE AND RELATED EOSINOPHILIC AND ALLERGIC DISEASES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
2  5437  33 REMOTE HIND-LIMB ISCHEMIA MECHANISM OF PRESERVED EJECTION FRACTION DURING HEART FAILURE. DURING ACUTE HEART FAILURE (HF), REMOTE ISCHEMIC CONDITIONING (RIC) HAS PROVEN TO BE BENEFICIAL; HOWEVER, IT IS CURRENTLY UNCLEAR WHETHER IT ALSO EXTENDS BENEFITS FROM CHRONIC CONGESTIVE, CARDIOPULMONARY HEART FAILURE (CHF). PREVIOUS STUDIES FROM OUR LABORATORY HAVE SHOWN THREE PHASES DESCRIBING CHF VIZ. (1) HF WITH PRESERVED EJECTION FRACTION (HFPEF), (2) HF WITH REDUCED EF (HFREF), AND (3) HF WITH REVERSED EF. ALTHOUGH RECIPROCAL ORGAN INTERACTION, ABLATION OF SYMPATHETIC, AND CALCIUM SIGNALING GENES ARE ASSOCIATED WITH HFPEF TO HFREF, THE MECHANISM IS UNCLEAR. THE HFREF ENSUES, IN PART, DUE TO REDUCED ANGIOGENESIS, CORONARY RESERVE, AND LEAKAGE OF ENDOCARDIAL ENDOTHELIAL (EE) AND FINALLY BREAKDOWN OF THE BLOOD-HEART BARRIER (BHB) INTEGRITY. IN FACT, OUR HYPOTHESIS STATES THAT A CHANGE IN PHENOTYPE FROM COMPENSATORY HFPEF TO DECOMPENSATORY HFREF IS DETERMINED BY A POTENTIAL DECREASE IN REGENERATIVE, PROANGIOGENIC FACTORS ALONG WITH A CONCOMITANT INCREASE IN EPIGENETIC MEMORY, INFLAMMATION THAT COMBINEDLY CAUSES OXIDATIVE, AND PROTEOLYTIC STRESS RESPONSE. TO TEST THIS HYPOTHESIS, WE CREATED CHF BY AORTA-VENA-CAVA (AV) FISTULA IN A GROUP OF MICE THAT WERE SUBSEQUENTLY TREATED WITH THAT OF HIND-LIMB RIC. HFPEF VS. HFREF TRANSITION WAS DETERMINED BY SERIAL/LONGITUDINAL ECHO MEASUREMENTS. RESULTS REVEALED AN INCREASE IN SKELETAL MUSCLE MUSCLIN CONTENTS, BONE-MARROW (CD71), AND SYMPATHETIC ACTIVATION (BETA2-AR) BY RIC. WE ALSO OBSERVED A DECREASE IN VASCULAR DENSITY AND ATTENUATION OF EE-BHB FUNCTION DUE TO A CORRESPONDING INCREASE IN THE ACTIVITY OF MMP-2, VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), CASPASE, AND CALPAIN. THIS DECREASE WAS SUCCESSFULLY MITIGATED BY RIC-RELEASED SKELETAL MUSCLE EXOSOMES THAT CONTAIN MUSCLIN, THE MYOKINE ALONG WITH BONE MARROW, AND SYMPATHETIC ACTIVATION. IN SHORT, BASED ON PROTEOME (OMICS) ANALYSIS, APPROXIMATELY 20 PROTEINS THAT APPEAR TO BE INVOLVED IN SIGNALING PATHWAYS RESPONSIBLE FOR THE SYNTHESIS, CONTRACTION, AND RELAXATION OF CARDIAC MUSCLE WERE FOUND TO BE THE DOMINANT FEATURES. THUS, OUR RESULTS SUPPORT THAT THE CHF PHENOTYPE CAUSES DYSFUNCTION OF CARDIAC METABOLISM, ITS CONTRACTION, AND RELAXATION. INTERESTINGLY, RIC WAS ABLE TO MITIGATE MANY OF THE DELETERIOUS CHANGES, AS REVEALED BY OUR MULTI-OMICS FINDINGS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                 
3  2537  22 EPIGENETICS IN HEART FAILURE PHENOTYPES. CHRONIC HEART FAILURE (HF) IS A LEADING CLINICAL AND PUBLIC PROBLEM POSING A HIGHER RISK OF MORBIDITY AND MORTALITY IN DIFFERENT POPULATIONS. HF APPEARS TO BE IN BOTH PHENOTYPIC FORMS: HF WITH REDUCED LEFT VENTRICULAR EJECTION FRACTION (HFREF) AND HF WITH PRESERVED LEFT VENTRICULAR EJECTION FRACTION (HFPEF). ALTHOUGH BOTH HF PHENOTYPES CAN BE DISTINGUISHED THROUGH CLINICAL FEATURES, CO-MORBIDITY STATUS, PREDICTION SCORE, AND TREATMENT, THE CLINICAL OUTCOMES IN PATIENTS WITH HFREF AND HFPEF ARE SIMILAR. IN THIS CONTEXT, INVESTIGATION OF VARIOUS MOLECULAR AND CELLULAR MECHANISMS LEADING TO THE DEVELOPMENT AND PROGRESSION OF BOTH HF PHENOTYPES IS VERY IMPORTANT. THERE IS EMERGING EVIDENCE THAT EPIGENETIC REGULATION MAY HAVE A CLUE IN THE PATHOGENESIS OF HF. THIS REVIEW REPRESENTS CURRENT AVAILABLE EVIDENCE REGARDING THE IMPLICATION OF EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF DIFFERENT HF PHENOTYPES AND PERSPECTIVES OF EPIGENETIC-BASED THERAPIES OF HF.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
4  3051  42 GENOME-WIDE ASSOCIATION ANALYSIS OF EOSINOPHILIC ESOPHAGITIS PROVIDES INSIGHT INTO THE TISSUE SPECIFICITY OF THIS ALLERGIC DISEASE. EOSINOPHILIC ESOPHAGITIS (EOE) IS A CHRONIC INFLAMMATORY DISORDER ASSOCIATED WITH ALLERGIC HYPERSENSITIVITY TO FOOD. WE INTERROGATED >1.5 MILLION GENETIC VARIANTS IN EOE CASES OF EUROPEAN ANCESTRY AND SUBSEQUENTLY IN A MULTI-SITE COHORT WITH LOCAL AND OUT-OF-STUDY CONTROL SUBJECTS. IN ADDITION TO REPLICATING ASSOCIATION OF THE 5Q22 LOCUS (META-ANALYSIS P=1.9X10(-16)), WE IDENTIFIED AN ASSOCIATION AT 2P23 SPANNING CAPN14 (P=2.5X10(-10)). CAPN14 WAS SPECIFICALLY EXPRESSED IN THE ESOPHAGUS, WAS DYNAMICALLY UPREGULATED AS A FUNCTION OF DISEASE ACTIVITY AND GENETIC HAPLOTYPE AND AFTER EXPOSURE OF EPITHELIAL CELLS TO INTERLEUKIN (IL)-13, AND WAS LOCATED IN AN EPIGENETIC HOTSPOT MODIFIED BY IL-13. GENES NEIGHBORING THE TOP 208 EOE-ASSOCIATED SEQUENCE VARIANTS WERE ENRICHED FOR ESOPHAGEAL EXPRESSION, AND MULTIPLE LOCI FOR ALLERGIC SENSITIZATION WERE ASSOCIATED WITH EOE SUSCEPTIBILITY (4.8X10(-2)<P<5.1X10(-11)). WE PROPOSE A MODEL TO EXPLAIN THE TISSUE-SPECIFIC NATURE OF EOE THAT INVOLVES THE INTERPLAY OF ALLERGIC SENSITIZATION WITH AN EOE-SPECIFIC, IL-13-INDUCIBLE ESOPHAGEAL RESPONSE INVOLVING CAPN14.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5  5891  23 SYSTEMS BIOLOGY IN CHRONIC HEART FAILURE-IDENTIFICATION OF POTENTIAL MIRNA REGULATORS. HEART FAILURE (HF) IS A COMPLEX DISEASE ENTITY WITH HIGH CLINICAL IMPACT, POORLY UNDERSTOOD PATHOPHYSIOLOGY AND SCANTLY KNOWN MIRNA-MEDIATED EPIGENETIC REGULATION. WE HAVE ANALYSED MIRNA PATTERNS IN PATIENTS WITH CHRONIC HF (CHF) AND A SEX- AND AGE-MATCHED REFERENCE GROUP AND PURSUED AN IN SILICO SYSTEM BIOLOGY ANALYSIS TO DISCERN PATHWAYS INVOLVED IN CHF PATHOPHYSIOLOGY. TWENTY-EIGHT MIRNAS WERE IDENTIFIED IN CHF THAT WERE UP-REGULATED IN THE REFERENCE GROUP, AND EIGHT OF THEM WERE VALIDATED BY RT-QPCR. IN SILICO ANALYSIS OF PREDICTED TARGETS BY STRING PROTEIN-PROTEIN INTERACTION NETWORKS REVEALED EIGHT CLUSTER NETWORKS (INVOLVING SEVEN OF THE IDENTIFIED MIRNAS) ENRICHED IN PATHWAYS RELATED TO CELL CYCLE, RAS, CHEMOKINE, PI3K-AKT AND TGF-BETA SIGNALING. BY ROC CURVE ANALYSIS, COMBINED PROBABILITIES OF THESE SEVEN MIRNAS (LET-7A-5P, MIR-107, MIR-125A-5P, MIR-139-5P, MIR-150-5P, MIR-30B-5P AND MIR-342-3P; CLUSTERS 1-4 [C:1-4]), DISCRIMINATED BETWEEN HF WITH PRESERVED EJECTION FRACTION (HFPEF) AND HF WITH REDUCED EJECTION FRACTION (HFREF), AND ISCHAEMIC AND NON-ISCHAEMIC AETIOLOGY. A COMBINATION OF MIR-107, MIR-139-5P AND MIR-150-5P, INVOLVED IN CLUSTERS 5 AND 7 (C:5+7), DISCRIMINATED HFPEF FROM HFREF. PATHWAY ENRICHMENT ANALYSIS OF MIRNAS PRESENT IN C:1-4 (LET-7A-5P, MIR-125A-5P, MIR-30B-5P AND MIR-342-3P) REVEALED PATHWAYS RELATED TO HF PATHOGENESIS. IN CONCLUSION, WE HAVE IDENTIFIED A DIFFERENTIAL SIGNATURE OF DOWN-REGULATED MIRNAS IN THE PLASMA OF HF PATIENTS AND PROPOSE NOVEL CELLULAR MECHANISMS INVOLVED IN CHF PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6  6569  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  5716  31 SIRT6 PROTECTS VASCULAR SMOOTH MUSCLE CELLS FROM OSTEOGENIC TRANSDIFFERENTIATION VIA RUNX2 IN CHRONIC KIDNEY DISEASE. VASCULAR CALCIFICATION (VC) IS REGARDED AS AN IMPORTANT PATHOLOGICAL CHANGE LACKING EFFECTIVE TREATMENT AND ASSOCIATED WITH HIGH MORTALITY. SIRTUIN 6 (SIRT6) IS A MEMBER OF THE SIRTUIN FAMILY, A CLASS III HISTONE DEACETYLASE AND A KEY EPIGENETIC REGULATOR. SIRT6 HAS A PROTECTIVE ROLE IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD). HOWEVER, THE EXACT ROLE AND MOLECULAR MECHANISM OF SIRT6 IN VC IN PATIENTS WITH CKD REMAIN UNCLEAR. HERE, WE DEMONSTRATED THAT SIRT6 WAS MARKEDLY DOWNREGULATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND IN THE RADIAL ARTERY TISSUE OF PATIENTS WITH CKD WITH VC. SIRT6-TRANSGENIC (SIRT6-TG) MICE SHOWED ALLEVIATED VC, WHILE VASCULAR SMOOTH MUSCLE CELL-SPECIFIC (VSMC-SPECIFIC) SIRT6 KNOCKED-DOWN MICE SHOWED SEVERE VC IN CKD. SIRT6 SUPPRESSED THE OSTEOGENIC TRANSDIFFERENTIATION OF VSMCS VIA REGULATION OF RUNT-RELATED TRANSCRIPTION FACTOR 2 (RUNX2). COIMMUNOPRECIPITATION (CO-IP) AND IMMUNOPRECIPITATION (IP) ASSAYS CONFIRMED THAT SIRT6 BOUND TO RUNX2. MOREOVER, RUNX2 WAS DEACETYLATED BY SIRT6 AND FURTHER PROMOTED NUCLEAR EXPORT VIA EXPORTIN 1 (XPO1), WHICH IN TURN CAUSED DEGRADATION OF RUNX2 THROUGH THE UBIQUITIN-PROTEASOME SYSTEM. THESE RESULTS DEMONSTRATED THAT SIRT6 PREVENTED VC BY SUPPRESSING THE OSTEOGENIC TRANSDIFFERENTIATION OF VSMCS, AND AS SUCH TARGETING SIRT6 MAY BE AN APPEALING THERAPEUTIC TARGET FOR VC IN CKD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8   465  37 ARE TARGETED THERAPIES FOR DIABETIC CARDIOMYOPATHY ON THE HORIZON? DIABETES INCREASES THE RISK OF HEART FAILURE APPROXIMATELY 2.5-FOLD, INDEPENDENT OF CORONARY ARTERY DISEASE AND OTHER COMORBIDITIES. THIS PROCESS, TERMED DIABETIC CARDIOMYOPATHY, IS CHARACTERIZED BY INITIAL IMPAIRMENT OF LEFT VENTRICULAR (LV) RELAXATION FOLLOWED BY LV CONTRACTILE DYSFUNCTION. POST-MORTEM EXAMINATION REVEALS THAT HUMAN DIASTOLIC DYSFUNCTION IS CLOSELY ASSOCIATED WITH LV DAMAGE, INCLUDING CARDIOMYOCYTE HYPERTROPHY, APOPTOSIS AND FIBROSIS, WITH IMPAIRED CORONARY MICROVASCULAR PERFUSION. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERPINNING THE CHARACTERISTIC FEATURES OF DIABETIC CARDIOMYOPATHY REMAIN POORLY UNDERSTOOD, ALTHOUGH MULTIPLE FACTORS INCLUDING ALTERED LIPID METABOLISM, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM (ER) STRESS, INFLAMMATION, AS WELL AS EPIGENETIC CHANGES, ARE IMPLICATED. DESPITE A RECENT RISE IN RESEARCH INTERROGATING THESE MECHANISMS AND AN INCREASED UNDERSTANDING OF THE CLINICAL IMPORTANCE OF DIABETIC CARDIOMYOPATHY, THERE REMAINS A LACK OF SPECIFIC TREATMENT STRATEGIES. HOW THE CHRONIC METABOLIC DISTURBANCES OBSERVED IN DIABETES LEAD TO STRUCTURAL AND FUNCTIONAL CHANGES REMAINS A PERTINENT QUESTION, AND IT IS HOPED THAT RECENT ADVANCES, PARTICULARLY IN THE AREA OF EPIGENETICS, AMONG OTHERS, MAY PROVIDE SOME ANSWERS. THIS REVIEW HENCE EXPLORES THE TEMPORAL ONSET OF THE PATHOLOGICAL FEATURES OF DIABETIC CARDIOMYOPATHY, AND THEIR RELATIVE CONTRIBUTION TO THE RESULTANT DISEASE PHENOTYPE, AS WELL AS BOTH CURRENT AND POTENTIAL THERAPEUTIC OPTIONS. THE EMERGENCE OF GLUCOSE-OPTIMIZING AGENTS, NAMELY GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS AND SODIUM/GLUCOSE CO-TRANSPORTER (SGLT)2 INHIBITORS THAT CONFER BENEFITS ON CARDIOVASCULAR OUTCOMES, TOGETHER WITH NOVEL EXPERIMENTAL APPROACHES, HIGHLIGHT A NEW AND EXCITING ERA IN DIABETES RESEARCH, WHICH IS LIKELY TO RESULT IN MAJOR CLINICAL IMPACT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9   444  33 AORTIC AND CAROTID ARTERIAL STIFFNESS AND EPIGENETIC REGULATOR GENE EXPRESSION CHANGES PRECEDE BLOOD PRESSURE RISE IN STROKE-PRONE DAHL SALT-SENSITIVE HYPERTENSIVE RATS. MULTIPLE CLINICAL STUDIES SHOW THAT ARTERIAL STIFFNESS, MEASURED AS PULSE WAVE VELOCITY (PWV), PRECEDES HYPERTENSION AND IS AN INDEPENDENT PREDICTOR OF HYPERTENSION END ORGAN DISEASES INCLUDING STROKE, CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASE. RISK FACTOR STUDIES FOR ARTERIAL STIFFNESS IMPLICATE AGE, HYPERTENSION AND SODIUM. HOWEVER, CAUSAL MECHANISMS LINKING RISK FACTOR TO ARTERIAL STIFFNESS REMAIN TO BE ELUCIDATED. HERE, WE STUDIED THE CAUSAL RELATIONSHIP OF ARTERIAL STIFFNESS AND HYPERTENSION IN THE NA-INDUCED, STROKE-PRONE DAHL SALT-SENSITIVE (S) HYPERTENSIVE RAT MODEL, AND ANALYZED PUTATIVE MOLECULAR MECHANISMS. STROKE-PRONE AND NON-STROKE-PRONE MALE AND FEMALE RATS WERE STUDIED AT 3- AND 6-WEEKS OF AGE FOR ARTERIAL STIFFNESS (PWV, STRAIN), BLOOD PRESSURE, VESSEL WALL HISTOLOGY, AND GENE EXPRESSION CHANGES. STUDIES SHOWED THAT INCREASED LEFT CAROTID AND AORTIC ARTERIAL STIFFNESS PRECEDED HYPERTENSION, PULSE PRESSURE WIDENING, AND STRUCTURAL WALL CHANGES AT THE 6-WEEK TIME-POINT. INSTEAD, DIFFERENTIAL GENE INDUCTION WAS DETECTED IMPLICATING MOLECULAR-FUNCTIONAL CHANGES IN EXTRACELLULAR MATRIX (ECM) STRUCTURAL CONSTITUENTS, MODIFIERS, CELL ADHESION, AND MATRICELLULAR PROTEINS, AS WELL AS IN ENDOTHELIAL FUNCTION, APOPTOSIS BALANCE, AND EPIGENETIC REGULATORS. IMMUNOSTAINING TESTING HISTONE MODIFIERS EP300, HDAC3, AND PRMT5 LEVELS CONFIRMED CAROTID ARTERY-UPREGULATION IN ALL THREE LAYERS: ENDOTHELIAL, SMOOTH MUSCLE AND ADVENTITIAL CELLS. OUR STUDY RECAPITULATES OBSERVATIONS IN HUMANS THAT GIVEN SALT-SENSITIVITY, INCREASED NA-INTAKE INDUCED ARTERIAL STIFFNESS BEFORE HYPERTENSION, INCREASED PULSE PRESSURE, AND STRUCTURAL VESSEL WALL CHANGES. DIFFERENTIAL GENE EXPRESSION CHANGES ASSOCIATED WITH ARTERIAL STIFFNESS SUGGEST A MOLECULAR MECHANISM LINKING SODIUM TO FULL-VESSEL WALL RESPONSE AFFECTING GENE-NETWORKS INVOLVED IN VASCULAR ECM STRUCTURE-FUNCTION, APOPTOSIS BALANCE, AND EPIGENETIC REGULATION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10   169  28 ABNORMALITIES OF AMPK ACTIVATION AND GLUCOSE UPTAKE IN CULTURED SKELETAL MUSCLE CELLS FROM INDIVIDUALS WITH CHRONIC FATIGUE SYNDROME. BACKGROUND: POST EXERTIONAL MUSCLE FATIGUE IS A KEY FEATURE IN CHRONIC FATIGUE SYNDROME (CFS). ABNORMALITIES OF SKELETAL MUSCLE FUNCTION HAVE BEEN IDENTIFIED IN SOME BUT NOT ALL PATIENTS WITH CFS. TO TRY TO LIMIT POTENTIAL CONFOUNDERS THAT MIGHT CONTRIBUTE TO THIS CLINICAL HETEROGENEITY, WE DEVELOPED A NOVEL IN VITRO SYSTEM THAT ALLOWS COMPARISON OF AMP KINASE (AMPK) ACTIVATION AND METABOLIC RESPONSES TO EXERCISE IN CULTURED SKELETAL MUSCLE CELLS FROM CFS PATIENTS AND CONTROL SUBJECTS. METHODS: SKELETAL MUSCLE CELL CULTURES WERE ESTABLISHED FROM 10 SUBJECTS WITH CFS AND 7 AGE-MATCHED CONTROLS, SUBJECTED TO ELECTRICAL PULSE STIMULATION (EPS) FOR UP TO 24H AND EXAMINED FOR CHANGES ASSOCIATED WITH EXERCISE. RESULTS: IN THE BASAL STATE, CFS CULTURES SHOWED INCREASED MYOGENIN EXPRESSION BUT DECREASED IL6 SECRETION DURING DIFFERENTIATION COMPARED WITH CONTROL CULTURES. CONTROL CULTURES SUBJECTED TO 16 H EPS SHOWED A SIGNIFICANT INCREASE IN BOTH AMPK PHOSPHORYLATION AND GLUCOSE UPTAKE COMPARED WITH UNSTIMULATED CELLS. IN CONTRAST, CFS CULTURES SHOWED NO INCREASE IN AMPK PHOSPHORYLATION OR GLUCOSE UPTAKE AFTER 16 H EPS. HOWEVER, GLUCOSE UPTAKE REMAINED RESPONSIVE TO INSULIN IN THE CFS CELLS POINTING TO AN EXERCISE-RELATED DEFECT. IL6 SECRETION IN RESPONSE TO EPS WAS SIGNIFICANTLY REDUCED IN CFS COMPARED WITH CONTROL CULTURES AT ALL TIME POINTS MEASURED. CONCLUSION: EPS IS AN EFFECTIVE MODEL FOR ELICITING MUSCLE CONTRACTION AND THE METABOLIC CHANGES ASSOCIATED WITH EXERCISE IN CULTURED SKELETAL MUSCLE CELLS. WE FOUND FOUR MAIN DIFFERENCES IN CULTURED SKELETAL MUSCLE CELLS FROM SUBJECTS WITH CFS; INCREASED MYOGENIN EXPRESSION IN THE BASAL STATE, IMPAIRED ACTIVATION OF AMPK, IMPAIRED STIMULATION OF GLUCOSE UPTAKE AND DIMINISHED RELEASE OF IL6. THE RETENTION OF THESE DIFFERENCES IN CULTURED MUSCLE CELLS FROM CFS SUBJECTS POINTS TO A GENETIC/EPIGENETIC MECHANISM, AND PROVIDES A SYSTEM TO IDENTIFY NOVEL THERAPEUTIC TARGETS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11   312  26 ALCOHOL FEEDING IN MICE PROMOTES COLONIC HYPERPERMEABILITY AND CHANGES IN COLONIC ORGANOID STEM CELL FATE. BACKGROUND: ALCOHOL INCREASES INTESTINAL PERMEABILITY TO PROINFLAMMATORY MICROBIAL PRODUCTS THAT PROMOTE LIVER DISEASE, EVEN AFTER A PERIOD OF SOBRIETY. WE SOUGHT TO TEST THE HYPOTHESIS THAT ALCOHOL AFFECTS INTESTINAL STEM CELLS USING AN IN VIVO MODEL AND EX VIVO ORGANOIDS GENERATED FROM JEJUNUM AND COLON FROM MICE FED CHRONIC ALCOHOL. METHODS: MICE WERE FED A CONTROL OR AN ALCOHOL DIET. INTESTINAL PERMEABILITY, LIVER STEATOSIS-INFLAMMATION, AND STOOL SHORT-CHAIN FATTY ACIDS (SCFAS) WERE MEASURED. JEJUNUM AND COLONIC ORGANOIDS AND TISSUE WERE STAINED FOR STEM CELL, CELL LINEAGE, AND APICAL JUNCTION MARKERS WITH ASSESSMENT OF MRNA BY PCR AND RNA-SEQ. CHIP-PCR ANALYSIS WAS CARRIED OUT FOR NOTCH1 USING AN ANTIBODY SPECIFIC FOR ACETYLATED HISTONE 3. RESULTS: ALCOHOL-FED MICE EXHIBITED COLONIC (BUT NOT SMALL INTESTINAL) HYPERPERMEABILITY, STEATOHEPATITIS, AND DECREASED BUTYRATE/TOTAL SCFA RATIO IN STOOL. STEM CELL, CELL LINEAGE, AND APICAL JUNCTION MARKER STAINING IN TISSUE OR ORGANOIDS FROM JEJUNUM TISSUE WERE NOT IMPACTED BY ALCOHOL. ONLY CHROMOGRANIN A (CHGA) WAS INCREASED IN JEJUNUM ORGANOIDS BY QPCR. HOWEVER, COLONIC TISSUE AND ORGANOID STAINING EXHIBITED AN ALCOHOL-INDUCED SIGNIFICANT DECREASE IN CYTOKERATIN 20+ (KRT20+) ABSORPTIVE LINEAGE ENTEROCYTES, A DECREASE IN OCCLUDIN AND E-CADHERIN APICAL JUNCTION PROTEINS, AN INCREASE IN CHGA, AND AN INCREASE IN THE LGR5 STEM CELL MARKER. QPCR REVEALED AN ALCOHOL-INDUCED DECREASE IN COLONIC ORGANOID AND TISSUE NOTCH1, HES1, AND KRT20 AND INCREASED CHGA, SUPPORTING AN ALTERATION IN STEM CELL FATE DUE TO DECREASED NOTCH1 EXPRESSION. COLONIC TISSUE CHIP-PCR REVEALED ALCOHOL FEEDING SUPPRESSED NOTCH1 MRNA EXPRESSION (VIA DEACETYLATION OF HISTONE H3) AND DECREASED NOTCH1 TISSUE STAINING. CONCLUSIONS: DATA SUPPORT A MODEL FOR ALCOHOL-INDUCED COLONIC HYPERPERMEABILITY VIA EPIGENETIC EFFECTS ON NOTCH1, AND THUS HES1, SUPPRESSION THROUGH A MECHANISM INVOLVING HISTONE H3 DEACETYLATION AT THE NOTCH1 LOCUS. THIS DECREASED ENTEROCYTE AND INCREASED ENTEROENDOCRINE CELL COLONIC STEM CELL FATE AND DECREASED APICAL JUNCTIONAL PROTEINS LEADING TO HYPERPERMEABILITY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12  5054  34 PHARMACOPROTEOMICS REVEAL NOVEL PROTECTIVE ACTIVITY OF BROMODOMAIN CONTAINING 4 INHIBITORS ON VASCULAR HOMEOSTASIS IN TLR3-MEDIATED AIRWAY REMODELING. SMALL MOLECULE INHIBITORS OF THE EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) ARE POTENTIAL THERAPEUTICS FOR VIRAL AND ALLERGEN-INDUCED AIRWAY REMODELING. A LIMITATION OF THEIR PRECLINICAL ADVANCEMENT IS THE LACK OF DETAILED UNDERSTANDING OF MECHANISMS OF ACTION AND BIOMARKERS OF EFFECT. WE REPORT A SYSTEMS-LEVEL PHARMACOPROTEOMICS IN A STANDARDIZED MURINE MODEL OF TOLL-LIKE RECEPTOR TLR3-NFKAPPAB/RELA INNATE INFLAMMATION IN THE ABSENCE OR PRESENCE OF A HIGHLY SELECTIVE BRD4 INHIBITOR (ZL0454) OR NONSELECTIVE BROMODOMAIN AND EXTRATERMINAL DOMAIN INHIBITOR (JQ1). PROTEOMICS OF BRONCHOALVEOLAR LAVAGE FLUID (BALF) SECRETOME AND EXOSOMAL PROTEINS FROM THIS MURINE MODEL REVEALED INCREASED, SELECTIVE, CAPILLARY LEAK ASSOCIATED WITH PERICYTE-MYOFIBROBLAST TRANSITION, A PHENOMENON BLOCKED BY BRD4 INHIBITORS. BALF PROTEOMICS ALSO SUGGESTED THAT ZL0454 BETTER REDUCED THE VASCULAR LEAKAGE AND EXTRACELLULAR MATRIX DEPOSITION THAN JQ1. A SIGNIFICANT SUBSET OF INFLAMMATION-MEDIATED REMODELING FACTORS WAS ALSO IDENTIFIED IN A MOUSE MODEL OF IDIOPATHIC PULMONARY FIBROSIS PRODUCED BY BLEOMYCIN. BALF EXOSOME ANALYSIS INDICATED THAT BRD4 INHIBITORS REDUCED THE INDUCTION OF EXOSOMES ENRICHED IN COAGULATION FACTORS WHOSE PRESENCE CORRELATED WITH INTERSTITIAL FIBRIN DEPOSITION. FINALLY, BALF SAMPLES FROM HUMANS WITH SEVERE ASTHMA DEMONSTRATED SIMILAR UPREGULATIONS OF ORM2, APCS, SPARCL1, FGA, AND FN1, SUGGESTING THEIR POTENTIAL AS BIOMARKERS FOR EARLY DETECTION OF AIRWAY REMODELING AND/OR MONITORING OF THERAPY RESPONSE. SIGNIFICANCE: REPETITIVE AND CHRONIC VIRAL UPPER RESPIRATORY TRACT INFECTIONS TRIGGER TOLL-LIKE RECEPTOR (TLR)3-NFKAPPAB/RELA MEDIATED AIRWAY REMODELING WHICH IS LINKED TO A PROGRESSIVE DECLINE IN PULMONARY FUNCTION IN PATIENTS WITH ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. SMALL MOLECULE INHIBITORS OF THE EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) ARE POTENTIAL THERAPEUTICS FOR VIRAL AND ALLERGEN-INDUCED AIRWAY REMODELING. A LIMITATION OF THEIR PRECLINICAL ADVANCEMENT IS THE LACK OF DETAILED UNDERSTANDING OF MECHANISMS OF ACTION AND BIOMARKERS OF EFFECT. OUR STUDY REVEALED THAT THE ACTIVATION OF (TLR)3-NFKAPPAB/RELA PATHWAY IN THE LUNG INDUCED AN ELEVATION IN COAGULATION, COMPLEMENT, AND PLATELET FACTORS, INDICATING THE INCREASED VASCULAR LEAK DURING AIRWAY REMODELING. THE MECHANISM OF VASCULAR LEAKAGE WAS CHRONIC INFLAMMATION-INDUCED PERICYTE-MYOFIBROBLAST TRANSITION, WHICH WAS BLOCKED BY BRD4 INHIBITORS. FINALLY, PROTEOMICS ANALYSIS OF THE BRONCHOALVEOLAR LAVAGE FLUID SAMPLES FROM HUMANS WITH SEVERE ASTHMA DEMONSTRATED SIMILAR FINDINGS THAT WE OBSERVED IN THE ANIMAL MODEL.	2019	

13  4041  30 MACROPHAGE PLASTICITY IN DUCHENNE MUSCULAR DYSTROPHY: A NEXUS OF PATHOLOGICAL REMODELLING WITH THERAPEUTIC IMPLICATIONS. DUCHENNE MUSCULAR DYSTROPHY (DMD) IS CHARACTERIZED BY CHRONIC SKELETAL MUSCLE NECROSIS, LEADING TO MUSCLE REGENERATION FAILURE AND FIBROSIS. ALTHOUGH MACROPHAGES (MPS) ARE NORMALLY ESSENTIAL FOR MUSCLE REGENERATION, DYSREGULATED MP FUNCTION PROMOTES PATHOLOGICAL MUSCLE REMODELLING. INFILTRATING MPS CAN BE PREDOMINANTLY PRO-INFLAMMATORY (M1 BIASED), ANTI-INFLAMMATORY (M2 BIASED) OR OF A MIXED PHENOTYPE AND CAN ORIGINATE FROM THE ADULT BONE MARROW (MONOCYTE DEPENDENT) OR EMBRYONIC PRECURSORS (MONOCYTE INDEPENDENT). IN MDX MICE (GENETIC MODEL OF DMD) LACKING EITHER TOLL-LIKE RECEPTOR (TLR) 2 OR TLR4, IT IS FOUND THAT MP INFILTRATION OF DYSTROPHIC MUSCLE IS SIGNIFICANTLY REDUCED AND THAT THE MP PHENOTYPE IS SHIFTED TOWARD A MORE ANTI-INFLAMMATORY PROFILE. THIS IS ACCOMPANIED BY SIGNIFICANT IMPROVEMENTS IN MUSCLE HISTOLOGY AND FORCE PRODUCTION. LACK OF THE CHEMOKINE RECEPTOR CCR2, WHICH IMPEDES MONOCYTE RELEASE FROM THE BONE MARROW, LEADS TO SIMILAR BENEFICIAL EFFECTS IN MDX MICE. EVIDENCE WAS ALSO FOUND FOR TLR4-REGULATED INDUCTION OF TRAINED INNATE IMMUNITY IN MPS CULTURED FROM THE BONE MARROW OF MDX MICE BEFORE THEIR ENTRY INTO THE MUSCLE. THESE MPS EXHIBIT EPIGENETIC AND METABOLIC ALTERATIONS, ACCOMPANIED BY NON-SPECIFIC HYPER-RESPONSIVENESS TO MULTIPLE STIMULI, WHICH IS MANIFESTED BY POTENTIATED UPREGULATION OF BOTH PRO- AND ANTI-INFLAMMATORY GENES. IN SUMMARY, EXAGGERATED RECRUITMENT OF MONOCYTE-DERIVED MPS AND SIGNS OF TRAINED INNATE IMMUNITY AT THE LEVEL OF THE BONE MARROW ARE FEATURES OF THE IMMUNOPHENOTYPE ASSOCIATED WITH DYSTROPHIC MUSCLE DISEASE. THESE PHENOMENA ARE REGULATED BY TOLL-LIKE RECEPTORS THAT BIND ENDOGENOUS DAMAGE-ASSOCIATED MOLECULAR PATTERN (DAMP) MOLECULES, SUGGESTING THAT DAMP RELEASE FROM DYSTROPHIC MUSCLES MODULATES MP PLASTICITY AT THE BONE MARROW LEVEL THROUGH TOLL-LIKE RECEPTOR-DRIVEN MECHANISMS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
14    83  32 A NOVEL EPIGENETIC MARKER, TEN-ELEVEN TRANSLOCATION FAMILY MEMBER 2 (TET2), IS IDENTIFIED IN THE INTRACTABLE EPILEPTIC BRAIN AND REGULATES ATP BINDING CASSETTE SUBFAMILY B MEMBER 1 (ABCB1) IN THE BLOOD-BRAIN BARRIER. DRUG-RESISTANT EPILEPSY (DRE) IS A CHRONIC CONDITION DERIVED FROM SPONTANEOUS CHANGES AND REGULATORY EFFECTS IN THE EPILEPTIC BRAIN. AS DEMETHYLATION FACTORS, TEN-ELEVEN TRANSLOCATION (TET) FAMILY MEMBERS HAVE BECOME A FOCUS IN RECENT STUDIES OF NEUROLOGICAL DISORDERS. HERE, WE QUANTIFIED AND LOCALIZED TET1, TET2 AND 5-HYDROXYMETHYLCYTOSINE (5-HMC) IN THE TEMPORAL LOBE CORTEX OF DRE PATIENTS (N = 27) AND TRAUMATIC BRAIN HEMORRHAGE CONTROLS (N = 10) BY IMMUNOCHEMICAL STAINING. TET2 AND ATP BINDING CASSETTE SUBFAMILY B MEMBER 1 (ABCB1) EXPRESSION PATTERNS WERE DETERMINED IN THE ISOLATED BRAIN CAPILLARIES OF DRE PATIENTS. TET2 EXPRESSION WAS SIGNIFICANTLY INCREASED IN THE TEMPORAL CORTICAL TISSUE OF DRE PATIENTS WITH OR WITHOUT HIPPOCAMPAL SCLEROSIS (HS) COMPARED TO CONTROL PATIENTS, WHILE TET1 AND 5-HMC SHOWED NO DIFFERENCES IN EXPRESSION. WE ALSO FOUND THAT A PARTICULARLY STRONG EXPRESSION OF TET2 IN THE VASCULAR TISSUE OF DRE PATIENTS. ABCB1 AND TET2 HAVE EVIDENTLY HIGHER EXPRESSION IN THE VASCULAR ENDOTHELIUM FROM THE NEOCORTEX OF DRE PATIENTS. IN BLOOD-BRAIN BARRIER (BBB) MODEL, TET2 DEPLETION CAN CAUSE ATTENUATED EXPRESSION AND FUNCTION OF ABCB1. DATA FROM A COHORT STUDY AND EXPERIMENTS IN A BBB MODEL SUGGEST THAT TET2 HAS A SPECIFIC REGULATORY EFFECT ON ABCB1, WHICH MAY SERVE AS A POTENTIAL MECHANISM AND TARGET IN DRE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15  4303  31 MICRORNA-223 INHIBITS TISSUE FACTOR EXPRESSION IN VASCULAR ENDOTHELIAL CELLS. OBJECTIVE: ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY PROCESS, IN WHICH VASCULAR ENDOTHELIAL CELLS (ECS) BECOME DYSFUNCTIONAL OWING TO THE EFFECTS OF CHEMICAL SUBSTANCES, SUCH AS INFLAMMATORY FACTOR AND GROWTH FACTORS. TISSUE FACTOR (TF) EXPRESSION IS INDUCED BY THE ABOVE CHEMICAL SUBSTANCES IN ACTIVATED ECS. TF INITIATES THROMBOSIS ON DISRUPTED ATHEROSCLEROTIC PLAQUES WHICH PLAYS AN ESSENTIAL ROLE DURING THE ONSET OF ACUTE CORONARY SYNDROMES (ACS). INCREASING EVIDENCES SUGGEST THE IMPORTANT ROLE OF MICRORNAS AS EPIGENETIC REGULATORS OF ATHEROSCLEROTIC DISEASE. THE AIM OF OUR STUDY IS TO IDENTIFY IF MICRORNA-223 (MIR-223) TARGETS TF IN ECS. METHODS AND RESULTS: BIOINFORMATIC ANALYSIS SHOWED THAT TF IS A TARGET CANDIDATE OF MIR-223. WESTERN BLOTTING ANALYSIS REVEALED THAT TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) INCREASED TF EXPRESSION IN AORTA OF C57BL/6J MICE AND CULTURED ECS (EA.HY926 CELLS AND HUVEC) AFTER 4 H TREATMENT. IN TNF-ALPHA TREATED ECS, TF MRNA WAS ALSO INCREASED MEASURED BY REAL-TIME PCR. REAL-TIME PCR RESULTS SHOWED THAT MIR-223 LEVELS WERE DOWNREGULATED IN TNF-ALPHA-TREATED AORTA OF C57BL/6J MICE AND CULTURED ECS. TRANSFECTION OF ECS WITH MIR-223 MIMIC OR MIR-223 INHIBITOR MODIFIED TF EXPRESSION BOTH IN MRNA AND PROTEIN LEVELS. LUCIFERASE ASSAYS CONFIRMED THAT MIR-223 SUPPRESSED TF EXPRESSION BY BINDING TO THE SEQUENCE OF TF 3'-UNTRANSLATED REGIONS (3'UTR). TF PROCOAGULANT ACTIVITY WAS INHIBITED BY OVEREXPRESSING MIR-223 WITH OR WITHOUT TNF-ALPHA STIMULATION. CONCLUSIONS: MIR-223-MEDIATED SUPPRESSION OF TF EXPRESSION PROVIDES A NOVEL MOLECULAR MECHANISM FOR THE REGULATION OF COAGULATION CASCADE, AND SUGGESTS A CLUE AGAINST THROMBOGENESIS DURING THE PROCESS OF ATHEROSCLEROTIC PLAQUE RUPTURE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16  2239  23 EPIGENETIC MODULATION BY APABETALONE COUNTERS CYTOKINE-DRIVEN ACUTE PHASE RESPONSE IN VITRO, IN MICE AND IN PATIENTS WITH CARDIOVASCULAR DISEASE. CHRONIC SYSTEMIC INFLAMMATION CONTRIBUTES TO CARDIOVASCULAR DISEASE (CVD) AND CORRELATES WITH THE ABUNDANCE OF ACUTE PHASE RESPONSE (APR) PROTEINS IN THE LIVER AND PLASMA. BROMODOMAIN AND EXTRATERMINAL (BET) PROTEINS ARE EPIGENETIC READERS THAT REGULATE INFLAMMATORY GENE TRANSCRIPTION. WE SHOW THAT BET INHIBITION BY THE SMALL MOLECULE APABETALONE REDUCES APR GENE AND PROTEIN EXPRESSION IN HUMAN HEPATOCYTES, MOUSE MODELS, AND PLASMA FROM CVD PATIENTS. STEADY-STATE EXPRESSION OF SERUM AMYLOID P, PLASMINOGEN ACTIVATOR INHIBITOR 1, AND CERULOPLASMIN, APR PROTEINS LINKED TO CVD RISK, IS REDUCED BY APABETALONE IN CULTURED HEPATOCYTES AND IN HUMANIZED MOUSE LIVER. IN CYTOKINE-STIMULATED HEPATOCYTES, APABETALONE REDUCES THE EXPRESSION OF C-REACTIVE PROTEIN (CRP), ALPHA-2-MACROGLOBULIN, AND SERUM AMYLOID P. THE LATTER TWO ARE ALSO REDUCED BY APABETALONE IN THE LIVER OF ENDOTOXEMIC MICE. BET KNOCKDOWN IN VITRO ALSO COUNTERS CYTOKINE-MEDIATED INDUCTION OF THE CRP GENE. MECHANISTICALLY, APABETALONE REDUCES THE CYTOKINE-DRIVEN INCREASE IN BRD4 BET OCCUPANCY AT THE CRP PROMOTER, CONFIRMING THAT TRANSCRIPTION OF CRP IS BET-DEPENDENT. IN PATIENTS WITH STABLE CORONARY DISEASE, PLASMA APR PROTEINS CRP, IL-1 RECEPTOR ANTAGONIST, AND FIBRINOGEN GAMMA DECREASE AFTER APABETALONE TREATMENT VERSUS PLACEBO, RESULTING IN A PREDICTED DOWNREGULATION OF THE APR PATHWAY AND CYTOKINE TARGETS. WE CONCLUDE THAT CRP AND COMPONENTS OF THE APR PATHWAY ARE REGULATED BY BET PROTEINS AND THAT APABETALONE COUNTERS CHRONIC CYTOKINE SIGNALING IN PATIENTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17   201  37 ACTIVATING TRANSCRIPTION FACTOR 3 PROTECTS AGAINST PRESSURE-OVERLOAD HEART FAILURE VIA THE AUTOPHAGY MOLECULE BECLIN-1 PATHWAY. ACTIVATING TRANSCRIPTION FACTOR 3 (ATF3), A CAMP RESPONSE ELEMENT-BINDING PROTEIN/ATF FAMILY TRANSCRIPTION FACTORS MEMBER, HAS BEEN IMPLICATED IN THE CARDIOVASCULAR AND INFLAMMATORY SYSTEM AND IS RAPIDLY INDUCED BY ISCHEMIC-REPERFUSION INJURIES. WE PERFORMED TRANSVERSE AORTIC BANDING (TAB) EXPERIMENTS USING ATF3 GENE-DELETED MICE (ATF3(-/-)) AND WILD-TYPE (WT) MICE TO DETERMINE WHAT EFFECT IT MIGHT HAVE ON HEART FAILURE INDUCED BY PRESSURE OVERLOADING. COMPARED WITH THE WT MICE, ATF3(-/-) MICE WERE FOUND BY ECHOCARDIOGRAPHY TO HAVE DECREASED LEFT VENTRICULAR CONTRACTILITY WITH LOSS OF NORMAL CARDIAC HYPERTROPHIC REMODELING. THE ATF3(-/-) MICE HAD GREATER NUMBERS OF TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE-MEDIATED DIGOXIGENIN-DEOXYURIDINE NICK-END LABELING-POSITIVE CELLS AND HIGHER LEVELS OF ACTIVATED CASPASE-3, AS WELL AS MORE APOPTOSIS. RESTORATION OF ATF3 EXPRESSION IN THE HEART OF ATF3(-/-) MICE BY ADENOVIRUS-INDUCED ATF3 TREATMENT SIGNIFICANTLY IMPROVED CARDIAC CONTRACTILITY AFTER TAB. THE RESULTS FROM MOLECULAR AND BIOCHEMICAL ANALYSES, INCLUDING CHROMATIN IMMUNE-PRECIPITATION AND IN VITRO /IN VIVO PROMOTER ASSAYS, SHOWED THAT ATF3 BOUND TO THE ATF/CAMP RESPONSE ELEMENT OF THE BECLIN-1 PROMOTER AND THAT ATF3 REDUCED AUTOPHAGY VIA SUPPRESSION OF THE BECLIN-1-DEPENDENT PATHWAY. FURTHERMORE, INFUSION OF TERT-BUTYLHYDROQUINONE (TBHQ), A SELECTIVE ATF3 INDUCER, INCREASED THE EXPRESSION OF ATF3 VIA THE NUCLEAR FACTOR ERYTHROID 2-RELATED TRANSCRIPTIONAL FACTOR, INHIBITED TAB-INDUCED CARDIAC DILATATION, AND INCREASED LEFT VENTRICULAR CONTRACTILITY, THEREBY RESCUING HEART FAILURE. OUR STUDY IDENTIFIED A NEW EPIGENETIC REGULATION MEDIATED BY THE STRESS-INDUCIBLE GENE ATF3 ON TAB-INDUCED CARDIAC DYSFUNCTION. THESE FINDINGS SUGGEST THAT THE ATF3 ACTIVATOR TBHQ MAY HAVE THERAPEUTIC POTENTIAL FOR THE TREATMENT OF PRESSURE-OVERLOAD HEART FAILURE INDUCED BY CHRONIC HYPERTENSION OR OTHER PRESSURE OVERLOAD MECHANISMS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18  6669  36 URIC ACID IN METABOLIC SYNDROME: DOES URIC ACID HAVE A DEFINITIVE ROLE? INCREASED SERUM URIC ACID (SUA) LEVELS ARE COMMONLY SEEN IN PATIENTS WITH METABOLIC SYNDROME AND ARE WIDELY ACCEPTED AS RISK FACTORS FOR HYPERTENSION, GOUT, NON-ALCOHOLIC FATTY LIVER DISEASE, CHRONIC KIDNEY DISEASE (CKD), AND CARDIOVASCULAR DISEASES. ALTHOUGH SOME AMBIGUITY FOR THE EXACT ROLE OF URIC ACID (UA) IN THESE DISEASES IS STILL PRESENT, SEVERAL PATHOPHYSIOLOGICAL MECHANISMS HAVE BEEN IDENTIFIED SUCH AS INCREASED OXIDATIVE STRESS, INFLAMMATION, AND APOPTOSIS. ACCUMULATING EVIDENCE IN GENOMICS ENLIGHTENS GENETIC VARIABILITIES AND SOME EPIGENETIC CHANGES THAT CAN CONTRIBUTE TO HYPERURICEMIA. HERE WE DISCUSS THE ROLE OF UA WITHIN METABOLISM AND THE CONSEQUENCES OF ASYMPTOMATIC HYPERURICEMIA WHILE PROVIDING NEWFOUND EVIDENCE FOR THE ASSOCIATIONS BETWEEN UA AND GUT MICROBIOTA AND VITAMIN D. INCREASED SUA LEVELS AND BENEFICIAL EFFECTS OF LOWERING SUA LEVELS NEED TO BE ELUCIDATED MORE TO UNDERSTAND ITS COMPLICATED FUNCTION WITHIN DIFFERENT METABOLIC PATHWAYS AND SET OPTIMAL TARGET LEVELS FOR SUA FOR REDUCING RISKS FOR METABOLIC AND CARDIOVASCULAR DISEASES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19  4337  36 MICROTUBULES AS MAJOR REGULATORS OF ENDOTHELIAL FUNCTION: IMPLICATION FOR LUNG INJURY. ENDOTHELIAL DYSFUNCTION HAS BEEN ATTRIBUTED AS ONE OF THE MAJOR COMPLICATIONS IN COVID-19 PATIENTS, A GLOBAL PANDEMIC THAT HAS ALREADY CAUSED OVER 4 MILLION DEATHS WORLDWIDE. THE DYSFUNCTION OF ENDOTHELIAL BARRIER IS CHARACTERIZED BY AN INCREASE IN ENDOTHELIAL PERMEABILITY AND INFLAMMATORY RESPONSES, AND HAS EVEN BROADER IMPLICATIONS IN THE PATHOGENESIS OF ACUTE RESPIRATORY SYNDROMES SUCH AS ARDS, SEPSIS AND CHRONIC ILLNESSES REPRESENTED BY PULMONARY ARTERIAL HYPERTENSION AND INTERSTITIAL LUNG DISEASE. THE STRUCTURAL INTEGRITY OF ENDOTHELIAL BARRIER IS MAINTAINED BY CYTOSKELETON ELEMENTS, CELL-SUBSTRATE FOCAL ADHESION AND ADHESIVE CELL JUNCTIONS. AGONIST-MEDIATED CHANGES IN ENDOTHELIAL PERMEABILITY ARE DIRECTLY ASSOCIATED WITH REORGANIZATION OF ACTOMYOSIN CYTOSKELETON LEADING TO CELL CONTRACTION AND OPENING OF INTERCELLULAR GAPS OR ENHANCEMENT OF CORTICAL ACTIN CYTOSKELETON ASSOCIATED WITH STRENGTHENING OF ENDOTHELIAL BARRIER. THE ROLE OF ACTIN CYTOSKELETON REMODELING IN ENDOTHELIAL BARRIER REGULATION HAS TAKEN THE CENTRAL STAGE, BUT THE IMPACT OF MICROTUBULES IN THIS PROCESS REMAINS LESS EXPLORED AND UNDER-APPRECIATED. THIS REVIEW WILL SUMMARIZE THE CURRENT KNOWLEDGE ON THE CROSSTALK BETWEEN MICROTUBULES DYNAMICS AND ACTIN CYTOSKELETON REMODELING, DESCRIBE THE SIGNALING MECHANISMS MEDIATING THIS CROSSTALK, DISCUSS EPIGENETIC REGULATION OF MICROTUBULES STABILITY AND ITS NEXUS WITH ENDOTHELIAL BARRIER MAINTENANCE, AND OVERVIEW A ROLE OF MICROTUBULES IN TARGETED DELIVERY OF SIGNALING MOLECULES REGULATING ENDOTHELIAL PERMEABILITY AND INFLAMMATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20  4415  33 MOLECULAR AND CELLULAR MECHANISMS THAT INDUCE ARTERIAL CALCIFICATION BY INDOXYL SULFATE AND P-CRESYL SULFATE. THE PROTEIN-BOUND UREMIC TOXINS, INDOXYL SULFATE (IS) AND P-CRESYL SULFATE (PCS), ARE CONSIDERED TO BE HARMFUL VASCULAR TOXINS. ARTERIAL MEDIA CALCIFICATION, OR THE DEPOSITION OF CALCIUM PHOSPHATE CRYSTALS IN THE ARTERIES, CONTRIBUTES SIGNIFICANTLY TO CARDIOVASCULAR COMPLICATIONS, INCLUDING LEFT VENTRICULAR HYPERTROPHY, HYPERTENSION, AND IMPAIRED CORONARY PERFUSION IN THE ELDERLY AND PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) AND DIABETES. RECENTLY, WE REPORTED THAT BOTH IS AND PCS TRIGGER MODERATE TO SEVERE CALCIFICATION IN THE AORTA AND PERIPHERAL VESSELS OF CKD RATS. THIS REVIEW DESCRIBES THE MOLECULAR AND CELLULAR MECHANISMS BY WHICH THESE UREMIC TOXINS INDUCE ARTERIAL MEDIA CALCIFICATION. A COMPLEX INTERPLAY BETWEEN INFLAMMATION, COAGULATION, AND LIPID METABOLISM PATHWAYS, INFLUENCED BY EPIGENETIC FACTORS, IS CRUCIAL IN IS/PCS-INDUCED ARTERIAL MEDIA CALCIFICATION. HIGH LEVELS OF GLUCOSE ARE LINKED TO THESE EVENTS, SUGGESTING THAT A GOOD BALANCE BETWEEN GLUCOSE AND LIPID LEVELS MIGHT BE IMPORTANT. ON THE CELLULAR LEVEL, EFFECTS ON ENDOTHELIAL CELLS, WHICH ACT AS THE PRIMARY SENSORS OF CIRCULATING PATHOLOGICAL TRIGGERS, MIGHT BE AS IMPORTANT AS THOSE ON VASCULAR SMOOTH MUSCLE CELLS. ENDOTHELIAL DYSFUNCTION, PROVOKED BY IS AND PCS TRIGGERED OXIDATIVE STRESS, MAY BE CONSIDERED A KEY EVENT IN THE ONSET AND DEVELOPMENT OF ARTERIAL MEDIA CALCIFICATION. IN THIS REVIEW A NUMBER OF IMPORTANT OUTSTANDING QUESTIONS SUCH AS THE ROLE OF MIRNA'S, PHENOTYPIC SWITCHING OF BOTH ENDOTHELIAL AND VASCULAR SMOOTH MUSCLE CELLS AND NEW TYPES OF PROGRAMMED CELL DEATH IN ARTERIAL MEDIA CALCIFICATION RELATED TO PROTEIN-BOUND UREMIC TOXINS ARE PUT FORWARD AND DISCUSSED.	2020