1 1494 123 DNA HYPERMETHYLATION IN HYPERHOMOCYSTEINEMIA CONTRIBUTES TO ABNORMAL EXTRACELLULAR MATRIX METABOLISM IN THE KIDNEY. HYPERHOMOCYSTEINEMIA (HHCY) IS PREVALENT IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) AND END-STAGE RENAL DISEASE (ESRD). EMERGING STUDIES SUGGEST THAT EPIGENETIC MECHANISMS CONTRIBUTE TO THE DEVELOPMENT AND PROGRESSION OF FIBROSIS IN CKD. HHCY AND ITS INTERMEDIATES ARE KNOWN TO ALTER THE DNA METHYLATION PATTERN, WHICH IS A CRITICAL REGULATOR OF EPIGENETIC INFORMATION. IN THIS STUDY, WE HYPOTHESIZED THAT HHCY CAUSES RENOVASCULAR REMODELING BY DNA HYPERMETHYLATION, LEADING TO GLOMERULOSCLEROSIS. WE ALSO EVALUATED WHETHER THE DNA METHYLATION INHIBITOR, 5-AZA-2'-DEOXYCYTIDINE (5-AZA) COULD MODULATE EXTRACELLULAR MATRIX (ECM) METABOLISM AND REDUCE RENOVASCULAR FIBROSIS. C57BL/6J (WILD-TYPE) AND CYSTATHIONINE-BETA-SYNTHASE (CBS(+/-)) MICE, TREATED WITHOUT OR WITH 5-AZA (0.5 MG/KG BODY WEIGHT, I.P.), WERE USED. CBS(+/-) MICE SHOWED HIGH PLASMA HCY LEVELS, HYPERTENSION, AND SIGNIFICANT GLOMERULAR AND ARTERIOLAR INJURY. 5-AZA TREATMENT NORMALIZED BLOOD PRESSURE AND REVERSED RENAL INJURY. CBS(+/-) MICE SHOWED GLOBAL HYPERMETHYLATION AND UP-REGULATION OF DNA METHYLTRANSFERASE-1 AND -3A. METHYLATION-SPECIFIC PCR SHOWED AN IMBALANCE BETWEEN MATRIX METALLOPROTEINASE (MMP)-9 AND TISSUE INHIBITOR OF METALLOPROTEINASE (TIMP)-1 AND -2 AND ALSO INCREASED COLLAGEN AND GALECTIN-3 EXPRESSION. 5-AZA REDUCED ABNORMAL DNA METHYLATION AND RESTORED THE MMP-9/TIMP-1, -2 BALANCE. IN CONCLUSION, OUR DATA SUGGEST THAT DURING HHCY, ABNORMAL DNA METHYLATION AND AN IMBALANCE BETWEEN MMP-9 AND TIMP-1 AND -2 LEAD TO ECM REMODELING AND RENAL FIBROSIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2 3431  50 HYDROGEN SULFIDE ALLEVIATES HYPERTENSIVE KIDNEY DYSFUNCTION THROUGH AN EPIGENETIC MECHANISM. HYPERTENSION IS A MAJOR RISK FACTOR FOR CHRONIC KIDNEY DISEASE (CKD), AND RENAL INFLAMMATION IS AN INTEGRAL PART IN THIS PATHOLOGY. HYDROGEN SULFIDE (H(2)S) HAS BEEN SHOWN TO MITIGATE RENAL DAMAGE THROUGH REDUCTION IN BLOOD PRESSURE AND ROS; HOWEVER, THE EXACT MECHANISMS ARE NOT CLEAR. WHILE SEVERAL STUDIES HAVE UNDERLINED THE ROLE OF EPIGENETICS IN RENAL INFLAMMATION AND DYSFUNCTION, THE MECHANISMS THROUGH WHICH EPIGENETIC REGULATORS PLAY A ROLE IN HYPERTENSION ARE NOT WELL DEFINED. IN THIS STUDY, WE SOUGHT TO IDENTIFY WHETHER MICRORNAS ARE DYSREGULATED IN RESPONSE TO ANGIOTENSIN II (ANG II)-INDUCED HYPERTENSION IN THE KIDNEY AND WHETHER A H(2)S DONOR, GYY4137, COULD REVERSE THE MICRORNA ALTERATION AND KIDNEY FUNCTION. WILD-TYPE (C57BL/6J) MICE WERE TREATED WITHOUT OR WITH ANG II AND GYY4137 FOR 4 WK. BLOOD PRESSURE, RENAL BLOOD FLOW, AND RESISTIVE INDEX (RI) WERE MEASURED. MICRORNA MICROARRAYS WERE CONDUCTED AND SUBSEQUENT TARGET PREDICTION REVEALED GENES ASSOCIATED WITH A PROINFLAMMATORY RESPONSE. ANG II TREATMENT SIGNIFICANTLY INCREASED BLOOD PRESSURE, DECREASED BLOOD FLOW IN THE RENAL CORTEX, INCREASED RI, AND REDUCED RENAL FUNCTION. THESE EFFECTS WERE AMELIORATED IN MICE TREATED WITH GYY4137. MICROARRAY ANALYSIS REVEALED DOWNREGULATION OF MIR-129 IN ANG II-TREATED MICE AND UPREGULATION AFTER GYY4137 TREATMENT. QUANTITATION OF PROTEINS INVOLVED IN THE INFLAMMATORY RESPONSE AND DNA METHYLATION REVEALED UPREGULATION OF IL-17A AND DNA METHYLTRANSFERASE 3A, WHEREAS H(2)S PRODUCTION ENZYMES AND ANTI-INFLAMMATORY IL-10 WERE REDUCED. TAKEN TOGETHER, OUR DATA SUGGEST THAT DOWNREGULATION OF MIR-129 PLAYS A SIGNIFICANT ROLE IN ANG II-INDUCED RENAL INFLAMMATION AND FUNCTIONAL OUTCOMES AND THAT GYY4137 IMPROVES RENAL FUNCTION BY REVERSING MIR-129 EXPRESSION.NEW & NOTEWORTHY WE INVESTIGATED EPIGENETIC CHANGES THAT OCCUR IN THE HYPERTENSIVE KIDNEY AND HOW H(2)S SUPPLEMENTATION REVERSES ADVERSE EFFECTS. INFLAMMATION, ABERRANT METHYLATION, AND DYSFUNCTION WERE OBSERVED IN THE HYPERTENSIVE KIDNEY, AND THESE EFFECTS WERE ALLEVIATED WITH H(2)S SUPPLEMENTATION. WE IDENTIFY MIR-129 AS A POTENTIAL REGULATOR OF BLOOD PRESSURE AND H(2)S REGULATION.	2017	

3 2710  33 EXERCISE MITIGATES ALCOHOL INDUCED ENDOPLASMIC RETICULUM STRESS MEDIATED COGNITIVE IMPAIRMENT THROUGH ATF6-HERP SIGNALING. CHRONIC ETHANOL/ALCOHOL (AL) DOSING CAUSES AN ELEVATION IN HOMOCYSTEINE (HCY) LEVELS, WHICH LEADS TO THE CONDITION KNOWN AS HYPERHOMOCYSTEINEMIA (HHCY). HHCY ENHANCES OXIDATIVE STRESS AND BLOOD-BRAIN-BARRIER (BBB) DISRUPTION THROUGH MODULATION OF ENDOPLASMIC RETICULUM (ER) STRESS; IN PART BY EPIGENETIC ALTERNATION, LEADING TO COGNITIVE IMPAIRMENT. CLINICIANS HAVE RECOMMENDED EXERCISE AS A THERAPY; HOWEVER, ITS PROTECTIVE EFFECT ON COGNITIVE FUNCTIONS HAS NOT BEEN FULLY EXPLORED. THE PRESENT STUDY WAS DESIGNED TO OBSERVE THE PROTECTIVE EFFECTS OF EXERCISE (EX) AGAINST ALCOHOL-INDUCED EPIGENETIC AND MOLECULAR ALTERATIONS LEADING TO CEREBROVASCULAR DYSFUNCTION. WILD-TYPE MICE WERE SUBJECTED TO AL ADMINISTRATION (1.5 G/KG-BW) AND SUBSEQUENT TREADMILL EX FOR 12 WEEKS (5 DAY/WEEK@7-11 M/MIN). AL AFFECTED MOUSE BRAIN THROUGH INCREASES IN OXIDATIVE AND ER STRESS MARKERS, SAHH AND DNMTS ALTERNATION, WHILE DECREASES IN CBS, CSE, MTHFR, TIGHT-JUNCTION PROTEINS AND CELLULAR H(2)S LEVELS. MECHANISTIC STUDY REVEALED THAT AL INCREASED EPIGENETIC DNA HYPOMETHYLATION OF HERP PROMOTER. BBB DYSFUNCTION AND COGNITIVE IMPAIRMENT WERE OBSERVED IN THE AL TREATED MICE. AL MEDIATED TRANSCRIPTIONAL CHANGES WERE ABOLISHED BY ADMINISTRATION OF ER STRESS INHIBITOR DTT. IN CONCLUSION, EXERCISE RESTORED HCY AND H(2)S TO BASAL LEVELS WHILE AMELIORATING AL-INDUCED ER STRESS, DIMINISHING BBB DYSFUNCTION AND IMPROVING COGNITIVE FUNCTION VIA ATF6-HERP-SIGNALING. EX SHOWED ITS PROTECTIVE EFFICACY AGAINST AL-INDUCED NEUROTOXICITY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
4 5972  21 TET REPRESSION AND INCREASED DNMT ACTIVITY SYNERGISTICALLY INDUCE ABERRANT DNA METHYLATION. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN VARIOUS HUMAN DISORDERS, SUCH AS CANCER, NEURODEGENERATIVE DISORDERS, AND METABOLIC DISORDERS. INDUCTION OF EPIGENETIC ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IS ONE OF THE MAJOR MECHANISMS, BUT HOW IT IS INDUCED IS STILL UNCLEAR. HERE, WE FOUND THAT EXPRESSION OF TET GENES, METHYLATION ERASERS, WAS DOWNREGULATED IN INFLAMED MOUSE AND HUMAN TISSUES, AND THAT THIS WAS CAUSED BY UPREGULATION OF TET-TARGETING MIRNAS SUCH AS MIR20A, MIR26B, AND MIR29C, LIKELY DUE TO ACTIVATION OF NF-KAPPAB SIGNALING DOWNSTREAM OF IL-1BETA AND TNF-ALPHA. HOWEVER, TET KNOCKDOWN INDUCED ONLY MILD ABERRANT METHYLATION. NITRIC OXIDE (NO), PRODUCED BY NOS2, ENHANCED ENZYMATIC ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), METHYLATION WRITERS, AND NO EXPOSURE INDUCED MINIMAL ABERRANT METHYLATION. IN CONTRAST, A COMBINATION OF TET KNOCKDOWN AND NO EXPOSURE SYNERGISTICALLY INDUCED ABERRANT METHYLATION, INVOLVING GENOMIC REGIONS NOT METHYLATED BY EITHER ALONE. THE RESULTS SHOWED THAT A VICIOUS COMBINATION OF TET REPRESSION, DUE TO NF-KAPPAB ACTIVATION, AND DNMT ACTIVATION, DUE TO NO PRODUCTION, IS RESPONSIBLE FOR ABERRANT METHYLATION INDUCTION IN HUMAN TISSUES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5 3388  40 HOMOCYSTEINE INDUCES PODOCYTE APOPTOSIS BY REGULATING MIR-1929-5P EXPRESSION THROUGH C-MYC, DNMT1 AND EZH2. CHRONIC KIDNEY DISEASE (CKD) IS A COMMON AND COMPLEX DISEASE IN KIDNEYS WHICH HAS BEEN ASSOCIATED WITH AN INCREASED RISK OF RENAL CELL CARCINOMA. ELEVATED HOMOCYSTEINE (HCY) LEVELS ARE KNOWN TO INFLUENCE THE DEVELOPMENT AND PROGRESSION OF CKD BY REGULATING PODOCYTE INJURY AND APOPTOSIS. TO INVESTIGATE THE MOLECULAR MECHANISMS TRIGGERED IN PODOCYTES BY HCY, WE USED CBS(+/-) MICE AND OBSERVED THAT HIGHER HCY LEVELS INCREASED THE APOPTOSIS RATE OF PODOCYTES WITH ACCOMPANYING GLOMERULAR DAMAGE. HCY-INDUCED PODOCYTE INJURY AND APOPTOSIS IN CBS(+/-) MICE WAS REGULATED BY INHIBITION OF MICRORNA (MIR)-1929-5P EXPRESSION. OVEREXPRESSION OF MIR-1929-5P IN PODOCYTES INHIBITED APOPTOSIS BY UPREGULATING BCL-2. FURTHERMORE, THE EXPRESSION OF MIR-1929-5P WAS REGULATED BY EPIGENETIC MODIFICATIONS OF ITS PROMOTER. HCY UPREGULATED DNA METHYLTRANSFERASE 1 (DNMT1) AND ENHANCER OF ZESTE HOMOLOG 2 (EZH2) LEVELS, RESULTING IN INCREASED DNA METHYLATION AND H3K27ME3 LEVELS ON THE MIR-1929-5P PROMOTER. ADDITIONALLY, WE OBSERVED THAT C-MYC RECRUITED DNMT1 AND EZH2 TO THE MIR-1929-5P PROMOTER AND SUPPRESSED THE EXPRESSION OF MIR-1929-5P. IN SUMMARY, WE DEMONSTRATED THAT HCY PROMOTES PODOCYTE APOPTOSIS THROUGH THE REGULATION OF THE EPIGENETIC MODIFIERS DNMT1 AND EZH2, WHICH ARE RECRUITED BY C-MYC TO THE PROMOTER OF MIR-1929-5P TO SILENCE MIR-1929-5P EXPRESSION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6  141  35 ABERRANT DNA METHYLATION OF MTOR PATHWAY GENES PROMOTES INFLAMMATORY ACTIVATION OF IMMUNE CELLS IN DIABETIC KIDNEY DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE (DKD), BUT THE UNDERLYING MECHANISMS REMAIN UNCLEAR. IN THIS STUDY, WE TESTED THE HYPOTHESIS THAT ABERRANT DNA METHYLATION IN PERIPHERAL IMMUNE CELLS CONTRIBUTES TO DKD PROGRESSION. WE SHOWED THAT LEVELS OF DNA METHYLTRANSFERASE 1 (DNMT1), A KEY ENZYME FOR DNA METHYLATION, WERE INCREASED ALONG WITH INFLAMMATORY ACTIVITY OF PERIPHERAL BLOOD MONONUCLEAR CELLS IN DKD PATIENTS. INHIBITION OF DNMT1 WITH 5-AZA-2'-DEOXYCYTIDINE (5-AZA) MARKEDLY INCREASED THE PROPORTION OF CD4(+)CD25(+) REGULATORY T CELLS IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN CULTURE AND IN DIABETIC ANIMALS. ADOPTIVE TRANSFER OF IMMUNE CELLS FROM 5-AZA-TREATED ANIMALS SHOWED BENEFICIAL EFFECTS ON THE HOST IMMUNE SYSTEM, RESULTING IN A SIGNIFICANT IMPROVEMENT OF DKD. USING GENOME-WIDE DNA METHYLATION ASSAYS, WE IDENTIFIED THE DIFFERENTIALLY METHYLATED CYTOSINES IN THE PROMOTER REGIONS OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR) REGULATORS IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF DIABETIC PATIENTS. FURTHER, MRNA ARRAYS CONFIRMED THE CONSISTENT INDUCTION OF GENES EXPRESSED IN THE MTOR PATHWAY. IMPORTANTLY, DOWN-REGULATION OF DNMT1 EXPRESSION VIA RNA INTERFERENCE RESULTED IN PROMINENT CYTOSINE DEMETHYLATION OF MTOR NEGATIVE REGULATORS AND SUBSEQUENT DECREASE OF MTOR ACTIVITY. LASTLY, MODULATION OF MTOR RESULTED IN CHANGES IN THE EFFECT OF 5-AZA ON DIABETIC IMMUNE CELLS. THUS, UP-REGULATION OF DNMT1 IN DIABETIC IMMUNE CELLS INDUCES ABERRANT CYTOSINE METHYLATION OF THE UPSTREAM REGULATORS OF MTOR, LEADING TO PATHOGENIC ACTIVATION OF THE MTOR PATHWAY AND CONSEQUENT INFLAMMATION IN DIABETIC KIDNEYS. HENCE, THIS STUDY HIGHLIGHTS THERAPEUTIC POTENTIAL OF TARGETING EPIGENETIC EVENTS IN IMMUNE SYSTEM FOR TREATING DKD.	2019	
                                                                                                                                                                                                                                                                                                                                                                         
7 2297  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8 1615  31 DNA METHYLTRANSFERASE 3B PLAYS A PROTECTIVE ROLE AGAINST HEPATOCARCINOGENESIS CAUSED BY CHRONIC INFLAMMATION VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS. MOST HEPATOCELLULAR CARCINOMAS (HCCS) DEVELOP ON THE BASIS OF CHRONIC HEPATITIS, BUT THE MECHANISM OF EPIGENETIC REGULATION IN INFLAMMATORY HEPATOCARCINOGENESIS HAS YET TO BE ELUCIDATED. AMONG DE NOVO DNA METHYLTRANSFERASES (DNMTS), DNMT3B HAS LATELY BEEN REPORTED TO ACT SPECIFICALLY ON ACTIVELY TRANSCRIBED GENES, SUGGESTING THE POSSIBILITY THAT IT PLAYS A ROLE IN THE PATHOGENESIS OF CANCER. WE CONFIRMED THAT DNMT3B ISOFORMS LACKING ITS CATALYTIC DOMAIN WERE HIGHLY EXPRESSED IN HCCS COMPARED WITH NON-TUMOROUS LIVER TISSUE. TO ELUCIDATE THE ROLE OF DNMT3B IN HEPATOCARCINOGENESIS, WE GENERATED A GENETICALLY ENGINEERED MOUSE MODEL WITH HEPATOCYTE-SPECIFIC DNMT3B DELETION. THE LIVER OF THE DNMT3B-DEFICIENT MICE EXHIBITED AN EXACERBATION OF THIOACETAMIDE-INDUCED HEPATITIS, PROGRESSION OF LIVER FIBROSIS AND A HIGHER INCIDENCE OF HCC COMPARED WITH THE LIVER OF THE CONTROL MICE. WHOLE-GENOME BISULFITE SEQUENCING VERIFIED A LOWER CG METHYLATION LEVEL IN THE DNMT3B-DEFICIENT LIVER, DEMONSTRATING DIFFERENTIALLY METHYLATED REGIONS THROUGHOUT THE GENOME. TRANSCRIPTOME ANALYSIS REVEALED DECREASED EXPRESSION OF GENES RELATED TO OXIDATIVE PHOSPHORYLATION IN THE DNMT3B-DEFICIENT LIVER. MOREOVER, PRIMARY HEPATOCYTES ISOLATED FROM THE DNMT3B-DEFICIENT MICE SHOWED REDUCED MITOCHONDRIAL RESPIRATORY CAPACITY, LEADING TO THE ENHANCEMENT OF OXIDATIVE STRESS IN THE LIVER TISSUE. OUR FINDINGS SUGGEST THE PROTECTIVE ROLE OF DNMT3B AGAINST CHRONIC INFLAMMATION AND HCC DEVELOPMENT VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9 5571  34 ROLE OF MICRORNA 1207-5P AND ITS HOST GENE, THE LONG NON-CODING RNA PVT1, AS MEDIATORS OF EXTRACELLULAR MATRIX ACCUMULATION IN THE KIDNEY: IMPLICATIONS FOR DIABETIC NEPHROPATHY. DIABETIC NEPHROPATHY IS THE MOST COMMON CAUSE OF CHRONIC KIDNEY FAILURE AND END-STAGE RENAL DISEASE IN THE WESTERN WORLD. ONE OF THE MAJOR CHARACTERISTICS OF THIS DISEASE IS THE EXCESSIVE ACCUMULATION OF EXTRACELLULAR MATRIX (ECM) IN THE KIDNEY GLOMERULI. WHILE BOTH ENVIRONMENTAL AND GENETIC DETERMINANTS ARE RECOGNIZED FOR THEIR ROLE IN THE DEVELOPMENT OF DIABETIC NEPHROPATHY, EPIGENETIC FACTORS, SUCH AS DNA METHYLATION, LONG NON-CODING RNAS, AND MICRORNAS, HAVE ALSO RECENTLY BEEN FOUND TO UNDERLIE SOME OF THE BIOLOGICAL MECHANISMS, INCLUDING ECM ACCUMULATION, LEADING TO THE DISEASE. WE PREVIOUSLY FOUND THAT A LONG NON-CODING RNA, THE PLASMACYTOMA VARIANT TRANSLOCATION 1 (PVT1), INCREASES PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) AND TRANSFORMING GROWTH FACTOR BETA 1 (TGF-BETA1) IN MESANGIAL CELLS, THE TWO MAIN CONTRIBUTORS TO ECM ACCUMULATION IN THE GLOMERULI UNDER HYPERGLYCEMIC CONDITIONS, AS WELL AS FIBRONECTIN 1 (FN1), A MAJOR ECM COMPONENT. HERE, WE REPORT THAT MIR-1207-5P, A PVT1-DERIVED MICRORNA, IS ABUNDANTLY EXPRESSED IN KIDNEY CELLS, AND IS UPREGULATED BY GLUCOSE AND TGF-BETA1. WE ALSO FOUND THAT LIKE PVT1, MIR-1207-5P INCREASES EXPRESSION OF TGF-BETA1, PAI-1, AND FN1 BUT IN A MANNER THAT IS INDEPENDENT OF ITS HOST GENE. IN ADDITION, REGULATION OF MIR-1207-5P EXPRESSION BY GLUCOSE AND TGFBETA1 IS INDEPENDENT OF PVT1. THESE RESULTS PROVIDE EVIDENCE SUPPORTING IMPORTANT ROLES FOR MIR-1207-5P AND ITS HOST GENE IN THE COMPLEX PATHOGENESIS OF DIABETIC NEPHROPATHY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10 3527  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11 2774  38 EXTRACELLULAR SUPEROXIDE DISMUTASE (EC-SOD) REGULATES GENE METHYLATION AND CARDIAC FIBROSIS DURING CHRONIC HYPOXIC STRESS. CHRONIC HYPOXIC STRESS INDUCES EPIGENETIC MODIFICATIONS MAINLY DNA METHYLATION IN CARDIAC FIBROBLASTS, INACTIVATING TUMOR SUPPRESSOR GENES (RASSF1A) AND ACTIVATING KINASES (ERK1/2) LEADING TO FIBROBLAST PROLIFERATION AND CARDIAC FIBROSIS. THE RAS/ERK SIGNALING PATHWAY IS AN INTRACELLULAR SIGNAL TRANSDUCTION CRITICALLY INVOLVED IN FIBROBLAST PROLIFERATION. RASSF1A FUNCTIONS THROUGH ITS EFFECT ON DOWNSTREAM ERK1/2. THE ANTIOXIDANT ENZYME, EXTRACELLULAR SUPEROXIDE DISMUTASE (EC-SOD), DECREASES OXIDATIVE STRESS FROM CHRONIC HYPOXIA, BUT ITS EFFECTS ON THESE EPIGENETIC CHANGES HAVE NOT BEEN FULLY EXPLORED. TO TEST OUR HYPOTHESIS, WE USED AN IN-VITRO MODEL: WILD-TYPE C57B6 MALE MICE (WT) AND TRANSGENIC MALES WITH AN EXTRA COPY OF HUMAN HEC-SOD (TG). THE STUDIED ANIMALS WERE HOUSED IN HYPOXIA (10% O(2)) FOR 21 DAYS. THE RIGHT VENTRICULAR TISSUE WAS STUDIED FOR CARDIAC FIBROSIS MARKERS USING RT-PCR AND WESTERN BLOT ANALYSES. PRIMARY C57BL6 MOUSE CARDIAC FIBROBLAST TISSUE CULTURE WAS USED TO STUDY THE IN-VITRO MODEL, THE DOWNSTREAM EFFECTS OF RASSF-1 EXPRESSION AND METHYLATION, AND ITS RELATION TO ERK1/2. OUR FINDINGS SHOWED A SIGNIFICANT INCREASE IN CARDIAC FIBROSIS MARKERS: COLLAGEN 1, ALPHA SMOOTH MUSCLE ACTIN (ASMA), AND SNAIL, IN THE WT HYPOXIC ANIMALS AS COMPARED TO THE TG HYPOXIC GROUP (P < 0.05). THE EXPRESSION OF DNA METHYLATION ENZYMES (DNMT 1&3B) WAS SIGNIFICANTLY INCREASED IN THE WT HYPOXIC MICE AS COMPARED TO THE HYPOXIC TG MICE (P < 0.001). RASSF1A EXPRESSION WAS SIGNIFICANTLY LOWER AND ERK1/2 WAS SIGNIFICANTLY HIGHER IN HYPOXIA WT COMPARED TO THE HYPOXIC TG GROUP (P < 0.05). USE OF SIRNA TO BLOCK RASSF1A GENE EXPRESSION IN MURINE CARDIAC FIBROBLAST TISSUE CULTURE LED TO INCREASED FIBROBLAST PROLIFERATION (P < 0.05). METHYLATION OF THE RASSF1A PROMOTER REGION WAS SIGNIFICANTLY REDUCED IN THE TG HYPOXIC GROUP COMPARED TO THE WT HYPOXIC GROUP (0.59 VS. 0.75, RESPECTIVELY). BASED ON OUR FINDINGS, WE CAN SPECULATE THAT EC-SOD SIGNIFICANTLY ATTENUATES RASSF1A GENE METHYLATION AND CAN ALLEVIATE CARDIAC FIBROSIS INDUCED BY HYPOXIA.	2021	
                                                                       
12 2926  27 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  273  40 AGE-INDUCED SUPPRESSION OF EZH2 MEDIATES INJURY OF PODOCYTES BY REDUCING H3K27ME3. BACKGROUND: CHRONIC HYPERGLYCEMIA, A PIVOTAL FEATURE OF DIABETES MELLITUS (DM), INITIATES THE FORMATION OF ADVANCED GLYCATION END PRODUCTS (AGES) AND THE DYSREGULATION OF EPIGENETIC MECHANISMS, WHICH MAY CAUSE INJURY TO RENAL PODOCYTES, A CENTRAL FEATURE OF DIABETIC KIDNEY DISEASE (DKD). PREVIOUS DATA OF OUR GROUP SHOWED THAT AGES SIGNIFICANTLY REDUCE THE EXPRESSION OF NIPP1 (NUCLEAR INHIBITOR OF PROTEIN PHOSPHATASE 1) IN PODOCYTES IN VITRO AS WELL AS IN HUMAN AND MURINE DKD. NIPP1 WAS SHOWN BY OTHERS TO INTERACT WITH ENHANCER OF ZESTE HOMOLOG 2 (EZH2), WHICH CATALYZES THE REPRESSIVE METHYLATION OF H3K27ME3 ON HISTONE 3. THEREFORE, WE HYPOTHESIZED THAT AGES CAN DIRECTLY INDUCE EPIGENETIC CHANGES IN PODOCYTES. METHODS: WE ANALYZED THE RELEVANCE OF AGES ON EZH2 EXPRESSION AND ACTIVITY IN A MURINE PODOCYTE CELL LINE. CELLS WERE TREATED WITH 5 MG/ML GLYCATED BSA FOR 24 H. TO DETERMINE THE MEANING OF EZH2 SUPPRESSION, EZH2 ACTIVITY WAS INHIBITED BY INCUBATING THE CELLS WITH THE PHARMACOLOGICAL METHYLTRANSFERASE INHIBITOR 3-DEAZANEPLANOCIN A; EZH2 EXPRESSION WAS REPRESSED WITH SIRNA. MRNA EXPRESSION WAS ANALYZED WITH REAL-TIME PCR, AND PROTEIN EXPRESSION WITH WESTERN BLOT. EZH2 EXPRESSION AND LEVEL OF H3K27 TRIMETHYLATION IN PODOCYTES OF DIABETIC DB/DB MICE, A MOUSE MODEL FOR TYPE 2 DM, WERE ANALYZED USING IMMUNOFLUORESCENCE. RESULTS: OUR DATA DEMONSTRATED THAT AGES DECREASE EZH2 EXPRESSION IN PODOCYTES AND CONSEQUENTLY REDUCE H3K27ME3. THIS SUPPRESSION OF EZH2 MIMICKED THE AGE EFFECTS AND CAUSED AN UPREGULATED EXPRESSION OF PATHOLOGICAL FACTORS THAT CONTRIBUTE TO PODOCYTE INJURY IN DKD. IN ADDITION, ANALYSES OF DB/DB MICE SHOWED SIGNIFICANTLY REDUCED H3K27ME3 AND EZH2 EXPRESSION IN PODOCYTES. MOREOVER, THE SUPPRESSION OF NIPP1 AND EZH2 SHOWED SIMILAR EFFECTS REGARDING PODOCYTE INJURY. CONCLUSIONS: OUR STUDIES PROVIDE A NOVEL PATHWAY HOW AGES CONTRIBUTE TO PODOCYTE INJURY AND THE FORMATION OF THE SO-CALLED METABOLIC MEMORY IN DKD.	2020	
                                                                                                                                                                                                                          
14 6431  33 THE USE OF TARGETED NEXT GENERATION SEQUENCING TO EXPLORE CANDIDATE REGULATORS OF TGF-BETA1'S IMPACT ON KIDNEY CELLS. AIMS/HYPOTHESIS: TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA1) PLAYS AN IMPORTANT REGULATORY ROLE IN THE PROGRESSION OF CHRONIC KIDNEY FAILURE. FURTHER, DAMAGE TO KIDNEY GLOMERULAR MESANGIAL CELLS IS CENTRAL TO THE PROGRESSION OF DIABETIC NEPHROPATHY. THE AIM OF THIS STUDY WAS TO EXPLORE THE GENETIC ASSOCIATIONS BETWEEN MRNA, MICRORNA, AND EPIGENETICS IN MESANGIAL CELLS IN RESPONSE TO TGF-BETA1. METHODS: THE REGULATORY EFFECTS OF TGF-BETA1 ON MESANGIAL CELLS WERE INVESTIGATED AT DIFFERENT MOLECULAR LEVELS BY TREATING MESANGIAL CELLS WITH TGF-BETA1 FOR 3 DAYS FOLLOWED BY GENOME-WIDE MIRNA, RNA, DNA METHYLATION, AND H3K27ME3 EXPRESSION PROFILING USING NEXT GENERATION SEQUENCING (NGS). RESULTS: OUR RESULTS PROVIDE THE FIRST COMPREHENSIVE, COMPUTATIONALLY INTEGRATED REPORT OF RNA-SEQ, MIRNA-SEQ, AND EPIGENOMIC ANALYSES ACROSS ALL GENETIC VARIATIONS, CONFIRMING THE OCCURRENCE OF DNA METHYLATION AND H3K27ME3 IN RESPONSE TO TGF-BETA1. OUR FINDINGS SHOW THAT THE EXPRESSION OF KLF7 AND GJA4 ARE INVOLVED IN TGF-BETA1 REGULATED DNA METHYLATION. OUR DATA ALSO PROVIDE EVIDENCE OF THE ASSOCIATION BETWEEN EPIGENETIC CHANGES AND THE EXPRESSION OF GENES CLOSELY RELATED TO TGF-BETA1 REGULATION. CONCLUSION: THIS STUDY HAS ADVANCED OUR CURRENT KNOWLEDGE OF MECHANISMS THAT CONTRIBUTE TO THE EXPRESSION OF TGF-BETA1-REGULATED GENES INVOLVED IN THE PATHOGENESIS OF KIDNEY DISEASE. THE MOLECULAR UNDERPINNINGS OF TGF-BETA1 STIMULATION OF KIDNEY CELLS WAS DETERMINED, THEREBY PROVIDING A ROBUST PLATFORM FOR FURTHER TARGET EXPLORATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15 1117  29 COMPARATIVE AND EXPERIMENTAL STUDIES ON THE GENES ALTERED BY CHRONIC HYPOXIA IN HUMAN BRAIN MICROENDOTHELIAL CELLS. BACKGROUND : HYPOXIA INDUCIBLE FACTOR 1 ALPHA (HIF1A) IS A MASTER REGULATOR OF ACUTE HYPOXIA; HOWEVER, WITH CHRONIC HYPOXIA, HIF1A LEVELS RETURN TO THE NORMOXIC LEVELS. IMPORTANTLY, THE GENES THAT ARE INVOLVED IN THE CELL SURVIVAL AND VIABILITY UNDER CHRONIC HYPOXIA ARE NOT KNOWN. THEREFORE, WE TESTED THE HYPOTHESIS THAT CHRONIC HYPOXIA LEADS TO THE UPREGULATION OF A CORE GROUP OF GENES WITH ASSOCIATED CHANGES IN THE PROMOTER DNA METHYLATION THAT MEDIATES THE CELL SURVIVAL UNDER HYPOXIA. RESULTS : WE EXAMINED THE EFFECT OF CHRONIC HYPOXIA (3 DAYS; 0.5% OXYGEN) ON HUMAN BRAIN MICRO ENDOTHELIAL CELLS (HBMEC) VIABILITY AND APOPTOSIS. HYPOXIA CAUSED A SIGNIFICANT REDUCTION IN CELL VIABILITY AND AN INCREASE IN APOPTOSIS. NEXT, WE EXAMINED CHRONIC HYPOXIA ASSOCIATED CHANGES IN TRANSCRIPTOME AND GENOME-WIDE PROMOTER METHYLATION. THE DATA OBTAINED WAS COMPARED WITH 16 OTHER MICROARRAY STUDIES ON CHRONIC HYPOXIA. NINE GENES WERE ALTERED IN RESPONSE TO CHRONIC HYPOXIA IN ALL 17 STUDIES. INTERESTINGLY, HIF1A WAS NOT ALTERED WITH CHRONIC HYPOXIA IN ANY OF THE STUDIES. FURTHERMORE, WE COMPARED OUR DATA TO THREE OTHER STUDIES THAT IDENTIFIED HIF-RESPONSIVE GENES BY VARIOUS APPROACHES. ONLY TWO GENES WERE FOUND TO BE HIF DEPENDENT. WE SILENCED EACH OF THESE 9 GENES USING CRISPR/CAS9 SYSTEM. DOWNREGULATION OF EGLN3 SIGNIFICANTLY INCREASED THE CELL DEATH UNDER CHRONIC HYPOXIA, WHEREAS DOWNREGULATION OF ERO1L, ENO2, ADRENOMEDULLIN, AND SPAG4 REDUCED THE CELL DEATH UNDER HYPOXIA. CONCLUSIONS : WE PROVIDE A CORE GROUP OF GENES THAT REGULATES CELLULAR ACCLIMATIZATION UNDER CHRONIC HYPOXIC STRESS, AND MOST OF THEM ARE HIF INDEPENDENT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16 3348  38 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	
                                                               
17  476  45 ARSENIC INDUCES FIBROGENIC CHANGES IN HUMAN KIDNEY EPITHELIAL CELLS POTENTIALLY THROUGH EPIGENETIC ALTERATIONS IN DNA METHYLATION. ARSENIC CONTAMINATION IS A SIGNIFICANT PUBLIC HEALTH ISSUE, AND KIDNEY IS ONE OF THE TARGET ORGAN FOR ARSENIC-INDUCED ADVERSE EFFECTS. RENAL FIBROSIS IS A WELL-KNOWN PATHOLOGICAL STAGE FREQUENTLY OBSERVED IN PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD). EPIDEMIOLOGICAL STUDIES IMPLICATE ARSENIC EXPOSURE TO CKD, BUT THE ROLE OF ARSENIC IN KIDNEY FIBROSIS AND THE UNDERLYING MECHANISM IS STILL UNCLEAR. IT IS IN THIS CONTEXT THAT THE CURRENT STUDY EVALUATED THE EFFECTS OF LONG-TERM ARSENIC EXPOSURE ON THE CELLULAR RESPONSE IN MORPHOLOGY, AND MARKER GENES EXPRESSION WITH RESPECT TO FIBROSIS USING HUMAN KIDNEY 2 (HK-2) EPITHELIAL CELLS. RESULTS OF THIS STUDY REVEALED THAT IN ADDITION TO INCREASED GROWTH, HK-2 CELLS UNDERWENT PHENOTYPIC, BIOCHEMICAL AND MOLECULAR CHANGES INDICATIVE OF EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IN RESPONSE TO THE EXPOSURE TO ARSENIC. MOST IMPORTANTLY, THE ARSENIC-EXPOSED CELLS ACQUIRED THE PATHOGENIC FEATURES OF FIBROSIS AS SUPPORTED BY INCREASED EXPRESSION OF MARKERS FOR FIBROSIS, SUCH AS COLLAGEN I, FIBRONECTIN, TRANSFORMING GROWTH FACTOR BETA, AND ALPHA-SMOOTH MUSCLE ACTIN. UPREGULATION OF FIBROSIS ASSOCIATED SIGNALING MOLECULES SUCH AS TISSUE INHIBITOR OF METALLOPROTEINASES-3 AND MATRIX METALLOPROTEINASE-2 AS WELL AS ACTIVATION OF AKT WAS ALSO OBSERVED. ADDITIONALLY, THE EXPRESSION OF EPIGENETIC GENES (DNA METHYLTRANSFERASES 3A AND 3B; METHYL-CPG BINDING DOMAIN 4) WAS INCREASED IN ARSENIC-EXPOSED CELLS. TREATMENT WITH DNA METHYLATION INHIBITOR 5-AZA-2'-DC REVERSED THE EMT PROPERTIES AND RESTORED THE LEVEL OF PHOSPHO-AKT. TOGETHER, THESE DATA FOR THE FIRST TIME SUGGEST THAT LONG-TERM EXPOSURE TO ARSENIC CAN INCREASE THE RISK OF KIDNEY FIBROSIS. ADDITIONALLY, OUR DATA SUGGEST THAT THE ARSENIC-INDUCED FIBROTIC CHANGES ARE, AT LEAST IN PART, MEDIATED BY DNA METHYLATION AND THEREFORE POTENTIALLY CAN BE REVERSED BY EPIGENETIC THERAPEUTICS.	2019	
                                                                                                                                                                                                                                                
18 6564  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19 5189  35 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20 2590  31 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