1  3726 141 INHIBITION OF HISTONE METHYLTRANSFERASE EZH2 SUPPRESSES ENDOMETRIOTIC VESICLE DEVELOPMENT IN A RAT MODEL OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A PAINFUL GYNECOLOGICAL DISEASE WITH NO CURE AND LIMITED THERAPEUTIC OPTIONS. IT HAS BEEN HYPOTHESIZED THAT EPIGENETIC DRUGS CAN BE USED AS A NONHORMONAL TREATMENT FOR ENDOMETRIOSIS. THIS STUDY WAS CONDUCTED TO STUDY THE EFFICACY OF AN INHIBITOR OF THE HISTONE METHYLTRANSFERASE EZH2 USING AN ESTABLISHED RAT MODEL OF ENDOMETRIOSIS. WE HYPOTHESIZED THAT TREATMENT WILL BLOCK OR REDUCE THE NUMBER OF ENDOMETRIOTIC VESICLES IN THIS MODEL. WE CONDUCTED A PRECLINICAL DRUG STUDY IN FEMALE RATS WITH EXPERIMENTAL ENDOMETRIOSIS (UTERINE TISSUE TRANSPLANTED NEXT TO THE INTESTINAL MESENTERY) OR CONTROL SHAM (SUTURES ONLY). RATS WITH ENDOMETRIOSIS OR SHAM SURGERY RECEIVED EITHER TREATMENT WITH EZH2 INHIBITOR (5 MG/KG OR 10 MG/KG) OR VEHICLE (0.1%, 67% DMSO) EVERY OTHER DAY DURING 4 WEEKS. AFTER TREATMENT COMPLETION, THE NUMBER, AREA, VOLUME, AND WEIGHT OF VESICLES WERE EVALUATED. RT [2] PROFILER ARRAYS FOR NEUROPATHIC AND INFLAMMATION, EPITHELIAL TO MESENCHYMAL TRANSITION, INFLAMMATORY RESPONSE, AND AUTOIMMUNITY PATHWAYS WERE USED TO EXAMINE GENE EXPRESSION CHANGES IN THE VESICLES THAT DEVELOPED. TREATMENT WITH EZH2 INHIBITOR (10 MG/KG) SUPPRESSED THE DEVELOPMENT OF VESICLES, BY SIGNIFICANTLY DECREASING THE TOTAL VESICLE NUMBER, AREA, VOLUME, AND WEIGHT. IN ADDITION, EZH2 INHIBITION SIGNIFICANTLY INCREASED THE EXPRESSION OF CACNA1B AND FKBP1A GENES, INVOLVED IN PAIN AND PROLIFERATION, RESPECTIVELY. EZH2 INHIBITION SUPPRESSES THE GROWTH OF VESICLES WITHOUT APPARENT DETRIMENTAL EFFECTS TO OTHER ORGANS. TREATMENT WITH THIS EPIGENETIC INHIBITOR LEADS TO UPREGULATION OF A LIMITED NUMBER OF GENES RELATED TO ENDOMETRIOSIS-RELEVANT PATHWAYS. IN CONCLUSION, THESE DATA SUPPORT FOLLOW-UP STUDIES TO EVALUATE ITS POTENTIAL AS A THERAPEUTIC APPROACH FOR ENDOMETRIOSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  5418  40 REGULATION OF DNA METHYLATION SIGNATURES ON NF-KAPPAB AND STAT3 PATHWAY GENES AND TET ACTIVITY IN CIGARETTE SMOKE EXTRACT-CHALLENGED CELLS/COPD EXACERBATION MODEL IN VITRO. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A GLOBAL HEALTH PROBLEM. CURRENTLY, THERE IS A LACK OF KNOWLEDGE ABOUT THE PATHOBIOLOGY OF THIS DISEASE AND AVAILABLE THERAPIES ARE INEFFECTIVE. CIGARETTE SMOKING IS THE LEADING CAUSE OF COPD; HOWEVER, NOT ALL SMOKERS DEVELOP COPD. EXACERBATIONS OF COPD CAUSED BY MICROBES ARE COMMON AND DETRIMENTAL. APPROXIMATELY 20-50% OF PATIENT EXACERBATIONS ARE CAUSED BY BACTERIAL COLONIZATION IN THE LOWER AIRWAYS. IT IS GENERALLY ACCEPTED THAT EPIGENETIC MECHANISMS, ESPECIALLY DNA METHYLATION, PLAY AN IMPORTANT ROLE DURING PROGRESSION OF COPD. THUS, WE HYPOTHESIZED THAT DNA METHYLATION PATTERNS VARY SIGNIFICANTLY FOLLOWING SMOKE EXPOSURE AND DURING EXACERBATIONS CAUSED BY BACTERIAL INFECTIONS. TO TEST OUR HYPOTHESIS, WE USED AN IN VITRO STUDY MODEL THAT MIMICS COPD EXACERBATIONS AND PERFORMED EXTENSIVE STUDIES TO UNDERSTAND THE ROLE OF CPG PROMOTER METHYLATION OF NF-KAPPAB AND STAT3-MEDIATED PATHWAY GENES. BOTH NF-KAPPAB AND STAT3 TRANSCRIPTION FACTORS PLAY CRITICAL ROLES IN ORCHESTRATING INFLAMMATORY RESPONSES DURING CIGARETTE SMOKE EXPOSURE. IN BRIEF, HUMAN LUNG ADENOCARCINOMA CELLS WITH TYPE II ALVEOLAR EPITHELIUM CHARACTERISTICS (A549) WERE CHALLENGED WITH CIGARETTE SMOKE EXTRACT (CSE) OR DMSO (CONTROL) FOLLOWED BY A 3-H CHALLENGE WITH BACTERIAL LIPOPOLYSACCHARIDE (LPS; FROM PSEUDOMONAS AERUGINOSA) PRIOR TO THE TERMINATION OF CSE EXPOSURE (COPD EXACERBATION GROUP). THE PRODUCTION OF CYTOKINES/CHEMOKINES, REGULATION OF TRANSCRIPTION FACTORS, AND DNA METHYLATION OF SPECIFIC GENES WERE THEN ASSESSED. WE ALSO STUDIED CHANGES IN THE EXPRESSION AND ACTIVITY OF TEN-ELEVEN TRANSLOCASES (TETS), THE ENZYMES RESPONSIBLE FOR DNA DEMETHYLATION, AND ASSESSED THEIR ROLE IN REGULATING DNA METHYLATION IN THE CSE-CHALLENGED GROUP. RESULTS: THERE WAS A SIGNIFICANT INCREASE IN THE RELEASE OF CYTOKINES/CHEMOKINES (IL-8, MCP-1, IL-6 AND CCL5) IN THE COPD EXACERBATION GROUP AS COMPARED TO THE CONTROL GROUP. HYPOMETHYLATION OF NF-KAPPAB-MEDIATED PATHWAY GENES CORRELATED WITH THEIR INDUCTION IN OUR COPD EXACERBATION STUDY MODEL. FURTHER, WE OBSERVED AN IMPORTANT ROLE OF TET1/2 IN REGULATING THE DNA METHYLATION OF NF-KAPPAB, STAT3, IKK, AND NIK GENES AND CYTOKINE/CHEMOKINE PRODUCTION BY A549 CELLS DURING CSE CHALLENGE. CONCLUSIONS: STUDIES TO FURTHER DEFINE THE ROLE OF TETS IN CSE-MEDIATED EPIGENETIC REGULATION MAY LEAD TO THE DEVELOPMENT OF BETTER AND MORE EFFECTIVE THERAPEUTIC INTERVENTION STRATEGIES FOR COPD.	2020	

3  5227  35 PRMT6 MEDIATES INFLAMMATION VIA ACTIVATION OF THE NF-KAPPAB/P65 PATHWAY ON A CIGARETTE SMOKE EXTRACT-INDUCED MURINE EMPHYSEMA MODEL. INTRODUCTION: SMOKE-DRIVEN LUNG INFLAMMATION IS CONSIDERED TO BE THE MAJOR PATHOPHYSIOLOGY MECHANISM OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA. PROTEIN ARGININE METHYLTRANSFERASE 6 (PRMT6) IS A KEY EPIGENETIC ENZYME, WHICH IS RELATED TO PROTECTING THE TRI-METHYLATION OF H3K4 (H3K4ME3). WE HYPOTHESIZED THAT PTMT6 PROTECTS LUNG INFLAMMATION THROUGH THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY. METHODS: MICE WERE INJECTED WITH CIGARETTE SMOKE EXTRACT (CSE) OR PBS TO ESTABLISH A MICE MODEL, INTRATRACHEALLY INSTILLED WITH OVEREXPRESSED PRMT6 OR NEGATIVE CONTROL VECTOR. MORPHOMETRY OF LUNG SLIDES AND LUNG FUNCTION WERE MEASURED. WE DETERMINED THE PROTEIN EXPRESSION OF PRMT6 AND ITS RELATED HISTONE TARGETS, THE ACTIVATION OF NF-KAPPAB PATHWAY, THE LEVEL OF TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) AND INTERLEUKIN-1BETA (IL-1BETA). RESULTS: AFTER PRMT6 OVEREXPRESSION, THE MORPHOMETRY INDEXES AND LUNG FUNCTION WERE IMPROVED. ALSO, THE EXPRESSION OF H3K4ME3 WAS DECREASED. OVEREXPRESSED PRMT6 COULD SUPPRESS CSE-INDUCED NF-KAPPAB ACTIVATION AND PRO-INFLAMMATION GENES EXPRESSION. CONCLUSIONS: THE OVEREXPRESSED PRMT6 COULD SERVE AS AN INFLAMMATION INHIBITOR, POTENTIALLY THROUGH BLOCKING THE NF-KAPPAB/P65 PATHWAY IN THE MURINE EMPHYSEMA MODEL.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  1194  38 CORRELATION OF EPIGENETIC CHANGE AND IDENTIFICATION OF RISK FACTORS FOR ORAL SUBMUCOUS FIBROSIS. BACKGROUND: DNA METHYLATION OF CERTAIN GENES IS AN EPIGENETIC CHANGE THAT IS ESSENTIAL FOR TUMORIGENESIS. ORAL SUBMUCOUS FIBROSIS (OSF) IS A PRECANCEROUS CONDITION OF ORAL MUCOSA WITH INFLAMMATION AND PROGRESSIVE FIBROSIS OF THE LAMINA PROPRIA AND DEEPER CONNECTIVE TISSUE. THE HYPERMETHYLATION OF E-CADHERIN AND CYCLOOXYGENASE 2 (COX-2) IN CHRONIC INFLAMMATION MAY DEMONSTRATE A MILD LESION/MUTATION AT EPIGENETIC LEVELS. THIS STUDY COMPARES THE HYPERMETHYLATION STATUS OF E-CADHERIN AND COX-2 GENES IN PATIENTS WITH ORAL CANCER AND PATIENTS WITH OSF AND ALSO AIMS TO IDENTIFY RISK FACTORS FOR THE DEVELOPMENT OF OSF. METHODS: DNA WAS EXTRACTED FROM BLOOD SAMPLES OF 50 HEALTHY SUBJECTS, 50 PATIENTS WITH OSF AND 60 PATIENTS WITH ORAL CANCER. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION FOR E-CADHERIN AND COX-2 WAS PERFORMED ON THESE SAMPLES AND THE PRODUCTS WERE ANALYZED ON 2% AGAROSE GEL. SURVEYS ABOUT ORAL HEALTH HABITS AND CLINICAL PERIODONTAL EXAMINATIONS IN PATIENTS WITH OSF AND HEALTHY SUBJECTS WERE ALSO CONDUCTED BY WELL-TRAINED DENTISTS, AND LOGISTIC REGRESSION WAS PERFORMED TO IDENTIFY RISK FACTORS FOR OSF. RESULTS: HYPERMETHYLATION OF E-CADHERIN AND COX-2 WAS OBSERVED IN 36% AND 22% OF ORAL CANCER SAMPLES, RESPECTIVELY. IN PATIENTS WITH OSF, THE RATES WERE 52% AND 30%, AND IN HEALTHY CONTROLS THE RATES WERE 4% AND 6%. HYPERMETHYLATION WAS SHOWN TO BE CORRELATED BETWEEN THE 3 GROUPS WITH STATISTICAL SIGNIFICANCE (P<0.01). METHYLATION OF CPG ISLANDS IN E-CADHERIN AND COX-2 OCCURRED MORE FREQUENTLY IN PATIENTS WITH OSF THAN IN THE CONTROL GROUP, BUT LESS FREQUENTLY THAN IN PATIENTS WITH ORAL CANCER. IN THE LOGISTIC REGRESSION ANALYSIS, SMOKING, BRUSHING MORE THAN TWICE DAILY, PERIODONTAL PROBING DEPTH AND PLAQUE INDEX WERE IDENTIFIED AS 4 MAJOR RISK FACTORS FOR OSF. CONCLUSIONS: THESE DATA CONFIRM THAT E-CADHERIN AND COX-2 EXPRESSIONS ARE RELATED TO OSF. THE EPIGENETIC CHANGES PRESENTED IN PATIENTS WITH CHRONIC INFLAMMATION MIGHT DEMONSTRATE AN IRREVERSIBLE DESTRUCTION IN THE TISSUES OR ORGANS SIMILAR TO THE EFFECTS OF CANCER. CHRONIC OSF WAS SIGNIFICANTLY ASSOCIATED WITH HYPERMETHYLATION, A CANCER RISK FACTOR.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                        
5  3983  35 LONG-TERM EXPOSURE TO CIGARETTE SMOKE EXTRACT INDUCES HYPOMETHYLATION AT THE RUNX3 AND IGF2-H19 LOCI IN IMMORTALIZED HUMAN UROTHELIAL CELLS. CIGARETTE SMOKING IS THE SINGLE MOST IMPORTANT EPIDEMIOLOGICAL RISK FACTOR FOR BLADDER CANCER BUT IT IS NOT KNOWN WHETHER EXPOSURE OF UROTHELIAL CELLS TO THE SYSTEMIC SOLUBLE CONTENTS OF CIGARETTE SMOKE IS DIRECTLY CAUSATIVE TO BLADDER CANCER AND THE ASSOCIATED EPIGENETIC CHANGES SUCH AS TUMOR SUPPRESSOR GENE HYPERMETHYLATION. WE UNDERTOOK THIS STUDY TO INVESTIGATE IF LONG-TERM TREATMENT OF HUMAN UROTHELIAL CELLS WITH CIGARETTE SMOKE EXTRACT (CSE) RESULTS IN TUMOR SUPPRESSOR GENE HYPERMETHYLATION, A PHENOTYPE THAT WAS PREVIOUSLY ASSOCIATED WITH LONG-TERM CONSTANT CSE TREATMENT OF AIRWAY EPITHELIAL CELLS. WE CHRONICALLY TREATED AN IMMORTALIZED HUMAN UROTHELIAL CELL LINE UROTSA WITH CSE USING A CYCLIC DAILY REGIMEN BUT THE CELLS WERE CULTURED IN CSE-FREE MEDIUM BETWEEN DAILY TREATMENTS. BISULFITE SEQUENCING AND REAL-TIME PCR ARRAY-BASED METHYLATION PROFILING WERE EMPLOYED TO EVALUATE METHYLATION CHANGES AT TUMOR SUPPRESSOR GENE LOCI IN THE CHRONICALLY CSE-TREATED CELLS VERSUS THE PASSAGE-MATCHED UNTREATED CONTROL CELLS. THE RUNX3 TUMOR SUPPRESSOR GENE PROMOTER WAS HYPOMETHYLATED WITH A SIGNIFICANT INCREASE IN PROPORTION OF THE COMPLETELY UNMETHYLATED HAPLOTYPE AFTER THE LONG-TERM CSE TREATMENT; WHEREAS RUNX3 PROMOTER HYPERMETHYLATION WAS PREVIOUSLY REPORTED FOR BLADDER CANCERS OF SMOKERS. HYPOMETHYLATION INDUCED BY THE LONG-TERM CSE TREATMENT WAS ALSO OBSERVED FOR THE IGF2-H19 LOCUS. THE METHYLATION STATUS AT THE PRSS8/PROSTASIN AND 16 ADDITIONAL LOCI HOWEVER, WAS UNAFFECTED BY THE CHRONIC CSE TREATMENT. TRANSIENT CSE TREATMENT OVER 1 DAILY REGIMEN RESULTED IN TRANSCRIPTIONAL DOWN-REGULATION OF RUNX3 AND H19, BUT ONLY THE H19 TRANSCRIPTION WAS DOWN-REGULATED IN THE CHRONICALLY CSE-TREATED UROTHELIAL CELLS. TRANSCRIPTION OF A KEY ENZYME IN ONE-CARBON METABOLISM, DIHYDROFOLATE REDUCTASE (DHFR) WAS GREATLY REDUCED BY THE LONG-TERM CSE TREATMENT, POTENTIALLY SERVING AS A MECHANISM FOR THE HYPOMETHYLATION PHENOTYPE VIA A REDUCED SUPPLY OF METHYL DONOR. IN CONCLUSION, CHRONIC CYCLIC CSE TREATMENT OF UROTHELIAL CELLS INDUCED HYPOMETHYLATION RATHER THAN HYPERMETHYLATION AT SPECIFIC LOCI.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                               
6  5479  29 RESVERATROL ATTENUATES CIGARETTE SMOKE EXTRACT INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY ACCELERATED LUNG AGING. SMOKING IS THE CRITICAL RISK FACTOR FOR COPD. CELLULAR SENESCENCE OF AIRWAY EPITHELIAL CELLS IS THE CYTOLOGICAL BASIS OF ACCELERATED LUNG AGING IN COPD, AND THE REGULATION OF MICRORNAS (MIRNAS) IS THE CENTRAL EPIGENETIC MECHANISM OF CELLULAR SENESCENCE. RESVERATROL (RES) IS A POLYPHENOL WITH ANTI-AGING PROPERTIES. THIS STUDY INVESTIGATED WHETHER RES ATTENUATES CIGARETTE SMOKE EXTRACT (CSE)-INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS (BEAS-2B) THROUGH THE MIR-34A/SIRT1/NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) PATHWAY. BEAS-2B CELLS WERE TREATED WITH RES, CSE AND TRANSFECTED WITH MIR-34A-5P MIMICS. CELLULAR SENESCENCE WAS EVALUATED BY SENESCENCE -RELATED BETA-GALACTOSIDASE (SA-BETA-GAL) STAINING AND EXPRESSION OF SENESCENCE-RELATED GENES (P16, P21, AND P53). THE EXPRESSIONS OF MIR-34A-5P, SIRT1, AND NF-KAPPAB P65 WERE EXAMINED USING QUANTITATIVE REAL TIME POLYMERASE CHAIN REACTION AND WESTERN BLOTTING. THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) WERE ASSESSED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. THE BINDING BETWEEN MIR-34A-5P AND SIRT1 WAS CONFIRMED BY DUAL-LUCIFERASE REPORTER ASSAY. THE RESULTS SHOWED THAT CSE DOSE-DEPENDENTLY DECREASED CELL VIABILITY AND ELEVATED CELLULAR SENESCENCE, CHARACTERIZED BY INCREASED SA-BETA-GAL STAINING AND SENESCENCE-RELATED GENE EXPRESSIONS (P16, P21, AND P53). FURTHER, CSE DOSE-DEPENDENTLY INCREASED THE EXPRESSION OF MIR-34A-5P AND SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN BEAS-2B CELLS. PRETREATMENT WITH RES INHIBITED CSE-INDUCED CELLULAR SENESCENCE AND SECRETION OF SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN A DOSE-DEPENDENT MANNER. MOREOVER, RES REVERSED THE CSE-INDUCED DOWN-REGULATION OF SIRT1 AND UP-REGULATION OF MIR-34A-5P AND NF-KAPPAB P65. SIRT1 IS A TARGET OF MIR-34A-5P. OVEREXPRESSION OF MIR-34A-5P VIA TRANSFECTION WITH MIR-34A-5P MIMIC IN BEAS-2B CELLS ATTENUATED THE INHIBITORY EFFECT OF RES ON CELLULAR SENESCENCE, ACCOMPANIED BY REVERSING THE EXPRESSION OF SIRT1 AND NF-KAPPAB P65. IN CONCLUSION, RES ATTENUATED CSE-INDUCED CELLULAR SENESCENCE IN BEAS-2B CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY, WHICH MAY PROVIDE A NEW APPROACH FOR COPD TREATMENT.	2022	
                                                                                                                                                                                         
7  4703  22 NIK AS A DRUGGABLE MEDIATOR OF TISSUE INJURY. NF-KAPPAB-INDUCING KINASE (NIK, MAP3K14) IS BEST KNOWN AS THE APICAL KINASE THAT TRIGGERS NON-CANONICAL NF-KAPPAB ACTIVATION AND BY ITS ROLE IN THE IMMUNE SYSTEM. RECENT DATA INDICATE A ROLE FOR NIK EXPRESSED BY NON-LYMPHOID CELLS IN CANCER, KIDNEY DISEASE, LIVER INJURY, GLUCOSE HOMEOSTASIS, OSTEOSARCOPENIA, VASCULAR CALCIFICATION, HEMATOPOIESIS, AND ENDOTHELIAL FUNCTION. THE SPECTRUM OF NIK-ASSOCIATED DISEASE NOW RANGES FROM IMMUNODEFICIENCY (WHEN NIK IS DEFECTIVE) TO AUTOIMMUNITY, CANCER, STERILE INFLAMMATION, FIBROSIS, AND METABOLIC DISEASE WHEN NIK IS OVERACTIVE. THE DEVELOPMENT OF NOVEL SMALL-MOLECULE NIK INHIBITORS HAS PAVED THE WAY TO TEST NIK TARGETING TO TREAT DISEASE IN VIVO, AND MAY EVENTUALLY LEAD TO NIK TARGETING IN THE CLINIC. IN ADDITION, NIK ACTIVATORS ARE BEING EXPLORED FOR SPECIFIC CONDITIONS SUCH AS MYELOID LEUKEMIA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8  6368  30 THE ROLE OF MICRORNAS IN CHRONIC PSEUDOMONAS LUNG INFECTION IN CYSTIC FIBROSIS. BACKGROUND: CYSTIC FIBROSIS (CF) IS THE MOST COMMON LIFE LIMITING GENETIC DISORDER, CHARACTERIZED BY CHRONIC RESPIRATORY FAILURE SECONDARY TO INFLAMMATION AND CHRONIC BACTERIAL LUNG INFECTION. PSEUDOMONAS AERUGINOSA LUNG INFECTION IS ASSOCIATED WITH MORE SEVERE LUNG DISEASE AND RAPID PROGRESSION OF RESPIRATORY FAILURE WHEN COMPARED TO STAPHYLOCOCCUS AUREUS INFECTION. WE HYPOTHESIZED THAT A SPECIFIC SIGNATURE OF EPIGENETIC FACTORS TARGETING SPECIFIC GENE TRANSCRIPTS CONTRIBUTES TO THE INCREASED MORBIDITY SEEN IN CF PATIENTS WITH CHRONIC PSEUDOMONAS INFECTION. METHODS: WE COLLECTED EXHALED BREATH CONDENSATE (EBC) FROM 27 SUBJECTS AND EVALUATED MIRNA SIGNATURES IN THESE SAMPLES USING COMMERCIAL PCR ARRAY. WE IDENTIFIED PREDICTED MRNA TARGETS AND ASSOCIATED SIGNALING PATHWAYS USING INGENUITY PATHWAY ANALYSIS. RESULTS: WE FOUND 11 DIFFERENTIALLY EXPRESSED MIRNAS IN EBC OF PATIENTS INFECTED WITH PSEUDOMONAS AERUGINOSA COMPARED TO EBC FROM CF PATIENTS WHO WERE NOT CHRONICALLY INFECTED WITH PSEUDOMONAS AERUGINOSA (P < 0.05). SIX OF THESE MIRNAS (HSA-MIRNA-1247, HSA-MIRNA-1276, HSA-MIRNA-449C, HSA-MIRNA-3170, HSA-MIRNA-432-5P AND HSA-MIR-548) WERE SIGNIFICANTLY DIFFERENT IN THE CF PSEUDOMONAS POSITIVE GROUP WHEN COMPARED TO BOTH THE CF PSEUDOMONAS NEGATIVE GROUP AND HEALTHY CONTROL GROUP. INGENUITY PATHWAY ANALYSIS (IPA) REVEALED ORGANISMAL INJURY AND ABNORMALITIES, REPRODUCTIVE SYSTEM DISEASE AND CANCER AS THE TOP DISEASES AND BIO FUNCTIONS ASSOCIATED WITH THESE MIRNAS. IPA ALSO DETECTED RELA, JUN, TNF, IL-10, CTNNB1, IL-13, SERPINB8, CALM1, STARD3NL, SFI1, CD55, RPS6KA4, TTC36 AND HIST1H3D AS THE TOP TARGET GENES FOR THESE MIRNAS. CONCLUSION: OUR STUDY IDENTIFIED 6 MIRNAS AS EPIGENETIC FACTORS SPECIFICALLY ASSOCIATED WITH CHRONIC PSEUDOMONAS INFECTION IN PATIENTS WITH CF.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9  3722  42 INHIBITION OF DNA METHYLATION DURING CHRONIC OBSTRUCTIVE BLADDER DISEASE (COBD) IMPROVES FUNCTION, PATHOLOGY AND EXPRESSION. PARTIAL BLADDER OUTLET OBSTRUCTION DUE TO PROSTATE HYPERPLASIA OR POSTERIOR URETHRAL VALVES, IS A WIDESPREAD CAUSE OF URINARY DYSFUNCTION, PATIENT DISCOMFORT AND ALSO RESPONSIBLE FOR IMMENSE HEALTH CARE COSTS. EVEN AFTER REMOVAL OR RELIEF OF OBSTRUCTION, THE FUNCTIONAL AND PATHOLOGIC ASPECTS OF OBSTRUCTION REMAIN AS A CHRONIC OBSTRUCTIVE BLADDER DISEASE (COBD). EPIGENETIC CHANGES, SUCH AS DNA METHYLATION, CONTRIBUTE TO THE PERSISTENT CHARACTER OF MANY CHRONIC DISEASES, AND MAY BE ALTERED IN COBD. WE TESTED WHETHER CANDIDATE GENES AND PATHWAYS AND THE PATHOPHYSIOLOGY OF COBD WERE AFFECTED BY A HYPOMETHYLATING AGENT, DECITABINE (DAC). COBD WAS CREATED IN FEMALE SPRAGUE-DAWLEY RATS BY SURGICAL LIGATION OF THE URETHRA FOR 6 WEEKS, FOLLOWED BY REMOVAL OF THE SUTURE. SHAM LIGATIONS WERE PERFORMED BY PASSING THE SUTURE BEHIND THE URETHRA. AFTER REMOVAL OF THE OBSTRUCTION OR SHAM REMOVAL, ANIMALS WERE RANDOMIZED TO DAC TREATMENT (1 MG/KG/3-TIMES/WEEK INTRAPERITONEALLY) OR VEHICLE (NORMAL SALINE). BLADDER FUNCTION WAS NON-INVASIVELY TESTED USING METABOLIC CAGES, BOTH ONE DAY PRIOR TO DE-OBSTRUCTION AT 6 WEEKS AND PRIOR TO SACRIFICE AT 10 WEEKS. RESIDUAL VOLUME AND BLADDER MASS WERE MEASURED FOR EACH BLADDER. BLADDERS WERE EXAMINED BY IMMUNOSTAINING AS WELL AS QPCR. THE EFFECTS OF DNA METHYLTRANSFERASE (DNMT)-3A KNOCKOUT OR OVEREXPRESSION ON SMOOTH MUSCLE CELL (SMC) FUNCTION AND PHENOTYPE WERE ALSO EXAMINED IN BLADDER SMC AND EX VIVO CULTURE. RESIDUAL VOLUMES OF THE DAC TREATED GROUP WERE NOT SIGNIFICANTLY DIFFERENT FROM THE NS GROUP. COMPARED TO COBD NS, COBD DAC TREATMENT HELPED PRESERVE MICTURITION VOLUME WITH A SIGNIFICANT RECOVERY OF THE VOIDING EFFICIENCY (RATIO OF THE MAXIMUM VOIDED VOLUME/MAXIMUM BLADDER CAPACITY) BY ONE THIRD (FIG. 1, P > 0.05). BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) VARIANTS 1 AND 5 WERE UPREGULATED BY COBD AND SIGNIFICANTLY REDUCED BY DAC TREATMENT. DEPOSITION OF COLLAGEN IN THE COBD BLADDER WAS REDUCED BY DAC, BUT GROSS HYPERTROPHY REMAINED. IN BLADDER SMC, DNMT3A OVEREXPRESSION LED TO A LOSS OF CONTRACTILE FUNCTION AND PHENOTYPE. IN BLADDERS, PERSISTENTLY ALTERED BY COBD, INHIBITION OF DNA-METHYLATION ENHANCES FUNCTIONAL RECOVERY, UNLIKE TREATMENT DURING PARTIAL OBSTRUCTION, WHICH EXACERBATES OBSTRUCTIVE PATHOLOGY. THE UNDERLYING MECHANISMS MAY RELATE TO THE GENE EXPRESSION CHANGES IN BDNF AND THEIR EFFECTS ON SIGNALING IN THE BLADDER.	2021	
                                                                                                                                  
10  3939  29 LNC-IL7R ALLEVIATES PM(2.5)-MEDIATED CELLULAR SENESCENCE AND APOPTOSIS THROUGH EZH2 RECRUITMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: LONG-TERM EXPOSURE TO PM(2.5) (PARTICULATE MATTER WITH AN AERODYNAMIC DIAMETER OF </= 2.5 MUM) IS ASSOCIATED WITH PULMONARY INJURY AND EMPHYSEMA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE INVESTIGATED MECHANISMS THROUGH WHICH THE LONG NONCODING RNA LNC-IL7R CONTRIBUTES TO CELLULAR DAMAGE BY INDUCING OXIDATIVE STRESS IN COPD PATIENTS EXPOSED TO PM(2.5). METHODS: ASSOCIATIONS OF SERUM LNC-IL7R LEVELS WITH LUNG FUNCTION, EMPHYSEMA, AND PREVIOUS PM(2.5) EXPOSURE IN COPD PATIENTS WERE ANALYZED. REACTIVE OXYGEN SPECIES AND LNC-IL7R LEVELS WERE MEASURED IN PM(2.5)-TREATED CELLS. THE LEVELS OF LNC-IL7R AND CELLULAR SENESCENCE-ASSOCIATED GENES, NAMELY P16(INK4A) AND P21(CIP1/WAF1), WERE DETERMINED THROUGH LUNG TISSUE SECTION STAINING. THE EFFECTS OF P16(INK4A) OR P21(CIP1/WAF1) REGULATION WERE EXAMINED BY PERFORMING LNC-IL7R OVEREXPRESSION AND KNOCKDOWN ASSAYS. THE FUNCTIONS OF LNC-IL7R-MEDIATED CELL PROLIFERATION, CELL CYCLE, SENESCENCE, COLONY FORMATION, AND APOPTOSIS WERE EXAMINED IN CELLS TREATED WITH PM(2.5). CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE CONDUCTED TO INVESTIGATE THE EPIGENETIC REGULATION OF P21(CIP1/WAF1). RESULTS: LNC-IL7R LEVELS DECREASED IN COPD PATIENTS AND WERE NEGATIVELY CORRELATED WITH EMPHYSEMA OR PM(2.5) EXPOSURE. LNC-IL7R LEVELS WERE UPREGULATED IN NORMAL LUNG EPITHELIAL CELLS BUT NOT IN COPD CELLS EXPOSED TO PM(2.5). LOWER LNC-IL7R EXPRESSION IN PM(2.5)-TREATED CELLS INDUCED P16(INK4A) AND P21(CIP1/WAF1) EXPRESSION BY INCREASING OXIDATIVE STRESS. HIGHER LNC-IL7R EXPRESSION PROTECTED AGAINST CELLULAR SENESCENCE AND APOPTOSIS, WHEREAS LOWER LNC-IL7R EXPRESSION AUGMENTED INJURY IN PM(2.5)-TREATED CELLS. LNC-IL7R AND THE ENHANCER OF ZESTE HOMOLOG 2 (EZH2) SYNERGISTICALLY SUPPRESSED P21(CIP1/WAF1) EXPRESSION THROUGH EPIGENETIC MODULATION. CONCLUSION: LNC-IL7R ATTENUATES PM(2.5)-MEDIATED P21(CIP1/WAF1) EXPRESSION THROUGH EZH2 RECRUITMENT, AND ITS DYSFUNCTION MAY AUGMENT CELLULAR INJURY IN COPD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11  3767  30 INTEGRATIVE EPIGENOMIC ANALYSIS IN DIFFERENTIATED HUMAN PRIMARY BRONCHIAL EPITHELIAL CELLS EXPOSED TO CIGARETTE SMOKE. CIGARETTE SMOKE (CS) IS ONE OF THE MAJOR RISK FACTORS FOR MANY PULMONARY DISEASES, INCLUDING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. THE FIRST LINE OF DEFENSE FOR CS EXPOSURE IS THE BRONCHIAL EPITHELIAL CELLS. ELUCIDATION OF THE EPIGENETIC CHANGES DURING CS EXPOSURE IS KEY TO GAINING A MECHANISTIC UNDERSTANDING INTO HOW MATURE AND DIFFERENTIATED BRONCHIAL EPITHELIAL CELLS RESPOND TO CS. THEREFORE, WE PERFORMED EPIGENOMIC PROFILING IN CONJUNCTION WITH TRANSCRIPTIONAL PROFILING IN WELL-DIFFERENTIATED HUMAN BRONCHIAL EPITHELIAL (HBE) CELLS CULTURED IN AIR-LIQUID INTERFACE (ALI) EXPOSED TO THE VAPOR PHASE OF CS. THE GENOME-WIDE ENRICHMENT OF HISTONE 3 LYSINE 27 ACETYLATION WAS DETECTED BY CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) IN HBE CELLS AND SUGGESTED THE PLAUSIBLE BINDING OF SPECIFIC TRANSCRIPTION FACTORS RELATED TO CS EXPOSURE. ADDITIONALLY, INTERROGATION OF CHIP-SEQ DATA WITH GENE EXPRESSION PROFILING OF HBE CELLS AFTER CS EXPOSURE FOR DIFFERENT DURATIONS (3 HOURS, 2 DAYS, 4 DAYS) SUGGESTED THAT EARLIER EPIGENETIC CHANGES (3 HOURS AFTER CS EXPOSURE) MAY BE ASSOCIATED WITH LATER GENE EXPRESSION CHANGES INDUCED BY CS EXPOSURE (4 DAYS). THE INTEGRATION OF EPIGENETICS AND GENE EXPRESSION DATA REVEALED SIGNALING PATHWAYS RELATED TO CS-INDUCED EPIGENETIC CHANGES IN HBE CELLS THAT MAY IDENTIFY NOVEL REGULATORY PATHWAYS RELATED TO CS-INDUCED COPD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  3460  28 HYPOMETHYLATION OF THE IL8 PROMOTER IN NASAL EPITHELIAL CELLS OF PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND: IL-8 IS AN IMPORTANT CHEMOKINE IMPLICATED IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS (CRS), BUT LITTLE IS KNOWN ABOUT EPIGENETIC REGULATION OF IL8 IN THE PATHOGENESIS OF CRS. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE RELATIONSHIP BETWEEN THE DNA METHYLATION LEVEL IN THE IL8 PROXIMAL PROMOTER AND CRS IN HAN CHINESE SUBJECTS. METHODS: PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP; N = 187), PATIENTS WITH CHRONIC RHINOSINUSITIS WITHOUT NASAL POLYPS (CRSSNP; N = 89), AND CONTROL SUBJECTS (N = 57) WERE ENROLLED IN 2 INDEPENDENT COHORTS. PURIFIED HUMAN NASAL EPITHELIAL CELLS FROM EACH PARTICIPANT WERE ASSESSED FOR PERCENTAGE DNA METHYLATION OF CPG SITES IN THE IL8 PROXIMAL PROMOTER BY USING BISULFITE PYROSEQUENCING AND FOR FUNCTIONAL ASPECTS OF METHYLATION STATUS BY USING IN VITRO ASSAYS. RESULTS: DNA METHYLATION OF CPG SITES 1, 2, AND 3, RESPECTIVELY, IN THE IL8 PROXIMAL PROMOTER WAS SIGNIFICANTLY DECREASED IN HUMAN NASAL EPITHELIAL CELLS OF PATIENTS WITH CRSWNP COMPARED WITH THAT IN PATIENTS WITH CRSSNP (P < .001) AND CONTROL SUBJECTS (P < .001). PERCENTAGE OF DNA METHYLATION OF THE CPG3 SITE WAS CORRELATED NEGATIVELY WITH BOTH TISSUE EOSINOPHILIC CATIONIC PROTEIN (P < .01) AND MYELOPEROXIDASE (P < .05) LEVELS. IL-1BETA (P < .001) AND TNF-ALPHA (P < .01) SIGNIFICANTLY INCREASED IL8 EXPRESSION ACCOMPANIED BY A REDUCTION IN METHYLATION AT THE CPG3 SITE (P < .001). ELECTROPHORETIC MOBILITY SHIFT ASSAYS DEMONSTRATED THAT METHYLATION STATUS OF CPG3 CHANGED THE BINDING OF OCTAMER-BINDING TRANSCRIPTION FACTOR 1 AND NUCLEAR FACTOR KAPPAB. CONCLUSION: DECREASED DNA METHYLATION OF PARTICULARLY CPG SITES IN THE IL8 PROXIMAL PROMOTER MIGHT PLAY A ROLE IN THE PATHOGENESIS OF CRSWNP.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  5868  32 SUPPRESSIVE EFFECTS OF METFORMIN ON T-HELPER 1-RELATED CHEMOKINES EXPRESSION IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. PURPOSE OF THE STUDY: TYPE 1 AND TYPE 2 DIABETES MELLITUS (DM) ARE CHRONIC T-CELL-MEDIATED INFLAMMATORY DISEASES. METFORMIN IS A WIDELY USED DRUG FOR TYPE 2 DM THAT REDUCES THE NEED FOR INSULIN IN TYPE 1 DM. HOWEVER, WHETHER METFORMIN HAS AN ANTI-INFLAMMATORY EFFECT FOR TREATING DM IS UNKNOWN. WE INVESTIGATED THE ANTI-INFLAMMATORY MECHANISM OF METFORMIN IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. MATERIALS AND METHODS: THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1 WAS PRETREATED WITH METFORMIN AND STIMULATED WITH LIPOPOLYSACCHARIDE (LPS). THE PRODUCTION OF T-HELPER (TH)-1-RELATED CHEMOKINES INCLUDING INTERFERON-GAMMA-INDUCED PROTEIN-10 (IP-10) AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), TH2-RELATED CHEMOKINE MACROPHAGE-DERIVED CHEMOKINE, AND THE PROINFLAMMATORY CHEMOKINE TUMOR NECROSIS FACTOR-ALPHA WAS MEASURED USING ENZYME-LINKED IMMUNOSORBENT ASSAY. INTRACELLULAR SIGNALING PATHWAYS WERE INVESTIGATED USING WESTERN BLOT ANALYSIS AND CHROMATIN IMMUNOPRECIPITATION ASSAY. RESULTS: METFORMIN SUPPRESSED LPS-INDUCED IP-10 AND MCP-1 PRODUCTION AS WELL AS LPS-INDUCED PHOSPHORYLATION OF C-JUN N-TERMINAL KINASE (JNK), P38, EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK), AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB). MOREOVER, METFORMIN SUPPRESSED LPS-INDUCED ACETYLATION OF HISTONES H3 AND H4 AT THE IP-10 PROMOTER. CONCLUSIONS: METFORMIN SUPPRESSED THE PRODUCTION OF TH1-RELATED CHEMOKINES IP-10 AND MCP-1 IN THP-1 CELLS. SUPPRESSIVE EFFECTS OF METFORMIN ON IP-10 PRODUCTION MIGHT BE ATTRIBUTED AT LEAST PARTIALLY TO THE JNK, P38, ERK, AND NF-KAPPAB PATHWAYS AS WELL AS TO EPIGENETIC REGULATION THROUGH THE ACETYLATION OF HISTONES H3 AND H4. THESE RESULTS INDICATED THE THERAPEUTIC ANTI-INFLAMMATORY POTENTIAL OF METFORMIN.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  1632  37 DNMTS ARE INVOLVED IN TGF-BETA1-INDUCED EPITHELIAL-MESENCHYMAL TRANSITIONS IN AIRWAY EPITHELIAL CELLS. CHRONIC RHINOSINUSITIS (CRS) PATHOGENESIS IS CLOSELY RELATED TO TISSUE REMODELING, INCLUDING EPITHELIAL-MESENCHYMAL TRANSITION (EMT). EPIGENETIC MECHANISMS PLAY KEY ROLES IN EMT. DNA METHYLATION, MEDIATED BY DNA METHYLTRANSFERASES (DNMTS), IS AN EPIGENETIC MARKER THAT IS CRITICAL TO EMT. THE GOAL OF THIS STUDY WAS TO DETERMINE WHETHER DNMTS WERE INVOLVED IN TGF-BETA1-INDUCED EMT AND ELUCIDATE THE UNDERLYING MECHANISMS IN NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. GLOBAL DNA METHYLATION AND DNMT ACTIVITY WERE QUANTIFIED. DNMT EXPRESSION WAS MEASURED USING REAL-TIME PCR (QRT-PCR) IN HUMAN CRS TISSUES. MRNA AND PROTEIN LEVELS OF DNMTS, E-CADHERIN, VIMENTIN, ALPHA-SMA, AND FIBRONECTIN WERE DETERMINED USING RT-PCR AND WESTERN BLOTTING, RESPECTIVELY. DNMT1, DNMT3A, AND DNMT3B GENE EXPRESSION WERE KNOCKED DOWN USING SIRNA TRANSFECTION. MAPK PHOSPHORYLATION AND EMT-RELATED TRANSCRIPTION FACTOR LEVELS WERE DETERMINED USING WESTERN BLOTTING. SIGNALING PATHWAYS WERE ANALYZED USING SPECIFIC INHIBITORS OF MAPK. WE DEMONSTRATED THESE DATA IN PRIMARY NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. GLOBAL DNA METHYLATION, DNMT ACTIVITY, AND DNMT EXPRESSION INCREASED IN CRS TISSUES. DNMT EXPRESSION WAS POSITIVELY CORRELATED WITH LUND-MCKAY CT SCORES. TGF-BETA1 DOSE-DEPENDENTLY INDUCED DNMT EXPRESSION. FURTHER, 5-AZA INHIBITED TGF-BETA1-INDUCED DNMT, SNAIL, AND SLUG EXPRESSION RELATED TO EMT, AS WELL AS P38 AND JNK PHOSPHORYLATION IN A549 CELLS AND TGF-BETA1-INDUCED DNMT EXPRESSION AND EMT IN PRIMARY NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. TGF-BETA1-INDUCED DNMT EXPRESSION LEADS TO DNA METHYLATION AND EMT VIA P38, JNK, SNAIL, AND SLUG SIGNALING PATHWAYS. INHIBITION OF DNMT SUPPRESSED THE EMT PROCESS AND THEREFORE IS POTENTIALLY A CRS THERAPEUTIC STRATEGY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15  3246  23 HEPATITIS B VIRUS (HBV) INDUCES THE EXPRESSION OF INTERLEUKIN-8 THAT IN TURN REDUCES HBV SENSITIVITY TO INTERFERON-ALPHA. HIGH LEVELS OF SERUM INTERLEUKIN-8 (IL-8) HAVE BEEN DETECTED IN CHRONIC HEPATITIS B (CHB) PATIENTS DURING EPISODES OF HEPATITIS FLARES. WE INVESTIGATED WHETHER HEPATITIS B VIRUS (HBV) MAY DIRECTLY INDUCE IL-8 PRODUCTION AND WHETHER IL-8 MAY ANTAGONIZE INTERFERON-ALPHA (IFN-ALPHA) ANTIVIRAL ACTIVITY AGAINST HBV. WE SHOWED THAT CHB PATIENTS HAD SIGNIFICANTLY HIGHER IL-8 LEVELS BOTH IN SERUM AND IN LIVER TISSUE THAN CONTROLS. IN HBV-REPLICATING HEPG2 CELLS, IL-8 TRANSCRIPTION WAS SIGNIFICANTLY ACTIVATED. AP-1, C/EBP AND NF-KB TRANSCRIPTION FACTORS WERE CONCURRENTLY NECESSARY FOR MAXIMUM IL-8 INDUCTION. MOREOVER, HBX VIRAL PROTEIN WAS RECRUITED ONTO THE IL-8 PROMOTER AND THIS WAS PARALLELED BY IL8-BOUND HISTONE HYPERACETYLATION AND BY ACTIVE RECRUITMENT OF TRANSCRIPTIONAL COACTIVATORS. INHIBITION OF IL-8 INCREASES THE ANTIVIRAL ACTIVITY OF IFN-ALPHA AGAINST HBV. OUR RESULTS INDICATE THAT HBV ACTIVATES IL-8 GENE EXPRESSION BY TARGETING THE EPIGENETIC REGULATION OF THE IL-8 PROMOTER AND THAT IL-8 MAY CONTRIBUTE TO REDUCE HBV SENSITIVITY TO IFN-ALPHA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16   401  32 ANALYSIS OF ABERRANT METHYLATION ON PROMOTER SEQUENCES OF TUMOR SUPPRESSOR GENES AND TOTAL DNA IN SPUTUM SAMPLES: A PROMISING TOOL FOR EARLY DETECTION OF COPD AND LUNG CANCER IN SMOKERS. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A DISORDER ASSOCIATED TO CIGARETTE SMOKE AND LUNG CANCER (LC). SINCE EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES (TSGS) ARE CLEARLY IMPORTANT IN THE DEVELOPMENT OF LC. IN THIS STUDY, WE HYPOTHESIZE THAT TOBACCO SMOKERS ARE SUSCEPTIBLE FOR METHYLATION IN THE PROMOTER REGION OF TSGS IN AIRWAY EPITHELIAL CELLS WHEN COMPARED WITH NON-SMOKER SUBJECTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE USEFULNESS OF DETECTION OF GENES PROMOTER METHYLATION IN SPUTUM SPECIMENS, AS A COMPLEMENTARY TOOL TO IDENTIFY LC BIOMARKERS AMONG SMOKERS WITH EARLY COPD. METHODS: WE DETERMINED THE AMOUNT OF DNA IN INDUCED SPUTUM FROM PATIENTS WITH COPD (N = 23), LC (N = 26), AS WELL AS IN HEALTHY SUBJECTS (CTR) (N = 33), USING A COMMERCIAL KIT FOR DNA PURIFICATION, FOLLOWED BY ABSORBANCE MEASUREMENT AT 260 NM. THE FREQUENCY OF CDKN2A, CDH1 AND MGMT PROMOTER METHYLATION IN THE SAME GROUPS WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP). THE FISHER'S EXACT TEST WAS EMPLOYED TO COMPARE FREQUENCY OF RESULTS BETWEEN DIFFERENT GROUPS. RESULTS: DNA CONCENTRATION WAS 7.4 AND 5.8 TIMES HIGHER IN LC AND COPD COMPARED TO THE (CTR) (P < 0.0001), RESPECTIVELY. METHYLATION STATUS OF CDKN2A AND MGMT WAS SIGNIFICANTLY HIGHER IN COPD AND LC PATIENTS COMPARED WITH CTR GROUP (P < 0.0001). FREQUENCY OF CDH1 METHYLATION ONLY SHOWED A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN LC PATIENTS AND CTR GROUP (P < 0.05). CONCLUSIONS: WE PROVIDE EVIDENCE THAT ABERRANT METHYLATION OF TSGS IN SAMPLES OF INDUCED SPUTUM IS A USEFUL TOOL FOR EARLY DIAGNOSTIC OF LUNG DISEASES (LC AND COPD) IN SMOKER SUBJECTS. VIRTUAL SLIDES: THE ABSTRACT MUST FINISH WITH THE FOLLOWING TEXT: VIRTUAL SLIDES THE VIRTUAL SLIDE(S) FOR THIS ARTICLE CAN BE FOUND HERE: HTTP://WWW.DIAGNOSTICPATHOLOGY.DIAGNOMX.EU/VS/1127865005664160.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17  1826  40 EFFECTS OF HISTONE DEACETYLASE INHIBITOR ON EXTRACELLULAR MATRIX PRODUCTION IN HUMAN NASAL POLYP ORGAN CULTURES. BACKGROUND: NASAL POLYPOSIS IS ASSOCIATED WITH A CHRONIC INFLAMMATORY CONDITION OF THE SINONASAL MUCOSA AND INVOLVES MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX (ECM) ACCUMULATION. EPIGENETIC MODULATION BY HISTONE DEACETYLASE (HDAC) INHIBITORS INCLUDING TRICHOSTATIN A (TSA) HAS BEEN REPORTED TO HAVE INHIBITORY EFFECTS ON MYOFIBROBLAST DIFFERENTIATION IN LUNG AND RENAL FIBROBLASTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE INHIBITORY EFFECT OF TSA ON MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION IN NASAL POLYP ORGAN CULTURES. METHODS: NASAL POLYP TISSUES FROM 18 PATIENTS WERE ACQUIRED DURING ENDOSCOPIC SINUS SURGERY. AFTER ORGAN CULTURE, NASAL POLYPS WERE STIMULATED WITH TGF-BETA1 AND THEN TREATED WITH TSA. ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), FIBRONECTIN, AND COLLAGEN TYPE I EXPRESSION LEVELS WERE EXAMINED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (PCR), REAL-TIME PCR, WESTERN BLOT, AND IMMUNOFLUORESCENT STAINING. HDAC2, HDAC4, AND ACETYLATED H4 EXPRESSION LEVELS WERE ASSAYED BY WESTERN BLOT. CYTOTOXICITY WAS ANALYZED BY THE TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE BIOTIN-DUTP NICK END LABELING ASSAY. RESULTS: THE EXPRESSION LEVELS OF ALPHA-SMA, FIBRONECTIN, AND COLLAGEN TYPE 1 WERE INCREASED IN NASAL POLYP AFTER TRANSFORMING GROWTH FACTOR (TGF) BETA1 TREATMENT. TSA-INHIBITED TGF-BETA1 INDUCED THESE GENE AND PROTEIN EXPRESSION LEVELS. FURTHERMORE, TSA SUPPRESSED PROTEIN EXPRESSION LEVELS OF HDAC2 AND HDAC4. HOWEVER, TSA INDUCED HYPERACETYLATION OF HISTONES H4. TREATMENT WITH TGF-BETA1 WITH OR WITHOUT TSA DID NOT HAVE CYTOTOXIC EFFECT. CONCLUSION: THESE FINDINGS PROVIDE NOVEL INSIGHTS INTO THE EPIGENETIC REGULATION IN MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION OF NASAL POLYP. TSA COULD BE A CANDIDATE OF A THERAPEUTIC AGENT FOR REVERSING THE TGF-BETA1-INDUCED ECM SYNTHESIS THAT LEADS TO NASAL POLYP DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18  5743  33 SMOKING SUPPRESSES THE THERAPEUTIC POTENTIAL OF ADIPOSE STEM CELLS IN CROHN'S DISEASE PATIENTS THROUGH EPIGENETIC CHANGES. PATIENTS WITH CROHN'S DISEASE (CD) WHO SMOKE ARE KNOWN TO HAVE A WORSE PROGNOSIS THAN NEVER-SMOKERS AND A HIGHER RISK FOR POST-SURGICAL RECURRENCE, WHEREAS PATIENTS WHO QUIT SMOKING AFTER SURGERY HAVE SIGNIFICANTLY LOWER POST-OPERATIVE RECURRENCE. THE HYPOTHESIS WAS THAT SMOKING INDUCES EPIGENETIC CHANGES THAT IMPAIR THE CAPACITY OF ADIPOSE STEM CELLS (ASCS) TO SUPPRESS THE IMMUNE SYSTEM. IT WAS ALSO QUESTIONED WHETHER THIS IMPAIRMENT REMAINS IN EX-SMOKERS WITH CD. ASCS WERE ISOLATED FROM NON-SMOKERS, SMOKERS AND EX-SMOKERS WITH CD AND THEIR INTERACTIONS WITH IMMUNE CELLS WERE STUDIED. THE ASCS FROM BOTH SMOKERS AND EX-SMOKERS PROMOTED MACROPHAGE POLARIZATION TO AN M1 PRO-INFLAMMATORY PHENOTYPE, WERE NOT ABLE TO INHIBIT T- AND B-CELL PROLIFERATION IN VITRO AND ENHANCED THE GENE AND PROTEIN EXPRESSION OF INFLAMMATORY MARKERS INCLUDING INTERLEUKIN-1B. GENOME-WIDE EPIGENETIC ANALYSIS USING TWO DIFFERENT BIOINFORMATIC APPROACHES REVEALED SIGNIFICANT CHANGES IN THE METHYLATION PATTERNS OF GENES THAT ARE CRITICAL FOR WOUND HEALING, IMMUNE AND METABOLIC RESPONSE AND P53-MEDIATED DNA DAMAGE RESPONSE IN ASCS FROM SMOKERS AND EX-SMOKERS WITH CD. IN CONCLUSION, CIGARETTE SMOKING INDUCES A PRO-INFLAMMATORY EPIGENETIC SIGNATURE IN ASCS THAT LIKELY COMPROMISES THEIR THERAPEUTIC POTENTIAL.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19   603  41 BETULINIC ACID INHIBITS ENDOMETRIOSIS THROUGH SUPPRESSION OF ESTROGEN RECEPTOR BETA SIGNALING PATHWAY. ENDOMETRIOSIS IS AN INFLAMMATORY GYNECOLOGICAL DISORDER CHARACTERIZED BY ENDOMETRIAL TISSUE GROWTH LOCATED OUTSIDE OF THE UTERINE CAVITY IN ADDITION TO CHRONIC PELVIC PAIN AND INFERTILITY. IN THIS STUDY, WE AIM TO DEVELOP A POTENTIAL THERAPEUTIC TREATMENT BASED ON THE PATHOGENESIS AND MECHANISM OF ENDOMETRIOSIS. OUR PRELIMINARY DATA SHOWED THAT THE EXPRESSION OF ESTROGEN RECEPTOR BETA (ERBETA) WAS SIGNIFICANTLY INCREASED, WHILE ERALPHA WAS SIGNIFICANTLY DECREASED, IN ENDOMETRIOTIC CELLS COMPARED TO NORMAL ENDOMETRIAL CELLS. FURTHER INVESTIGATION SHOWED THAT BETULINIC ACID (BA) TREATMENT SUPPRESSED ERBETA EXPRESSION THROUGH EPIGENETIC MODIFICATION ON THE ERBETA PROMOTER, WHILE HAD NO EFFECT ON ERALPHA EXPRESSION. IN ADDITION, BA TREATMENT SUPPRESSES ERBETA TARGET GENES, INCLUDING SUPEROXIDE DISMUTASE 2 (SOD2), NUCLEAR RESPIRATORY FACTOR-1 (NRF1), CYCLOOXYGENASE 2 (COX2), AND MATRIX METALLOPROTEINASE-1 (MMP1), SUBSEQUENTLY INCREASING OXIDATIVE STRESS, TRIGGERING MITOCHONDRIAL DYSFUNCTION, DECREASING ELEVATED PROINFLAMMATORY CYTOKINES, AND EVENTUALLY SUPPRESSING ENDOMETRIOTIC CELL PROLIFERATION, MIMICKING THE EFFECT OF ERBETA KNOCKDOWN. ON THE OTHER HAND, GAIN OF ERBETA BY LENTIVIRUS INFECTION IN NORMAL ENDOMETRIAL CELLS RESULTED IN INCREASED CELL PROLIFERATION AND PROINFLAMMATORY CYTOKINE RELEASE, WHILE BA TREATMENT DIMINISHED THIS EFFECT THROUGH ERBETA SUPPRESSION WITH SUBSEQUENT OXIDATIVE STRESS AND APOPTOSIS. OUR RESULTS INDICATE THAT ERBETA MAY BE A MAJOR DRIVING FORCE FOR THE DEVELOPMENT OF ENDOMETRIOSIS, WHILE BA INHIBITS ENDOMETRIOSIS THROUGH SPECIFIC SUPPRESSION OF THE ERBETA SIGNALING PATHWAY. THIS STUDY PROVIDES A NOVEL THERAPEUTIC STRATEGY FOR ENDOMETRIOSIS TREATMENT THROUGH BA-MEDIATED ERBETA SUPPRESSION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  6216  32 THE INVOLVEMENT OF COPPER, CIRCULAR RNAS, AND INFLAMMATORY CYTOKINES IN CHRONIC RESPIRATORY DISEASE. EXPOSURE TO HIGH CONCENTRATIONS OF COPPER IS ASSOCIATED WITH PULMONARY INFLAMMATION AND CHRONIC RESPIRATORY DISEASE (CRD). EPIGENETIC MODULATION OF NONCODING RNAS CONTRIBUTES TO THE DEVELOPMENT OF SEVERAL CRDS. IT IS UNKNOWN WHETHER EPIGENETIC MODULATION IS INVOLVED IN COPPER MEDIATED PULMONARY INFLAMMATION AND CRD. WE CONDUCTED A CASE-CONTROL STUDY OF 101 CRD CASES AND 161 CONTROL SUBJECTS IN SHIJIAZHUANG, CHINA, AND EVALUATED CIRCRNAS AND CYTOKINE LEVELS (IL-6 AND IL-8) BY QPCR AND ELISA. URINARY COPPER CONCENTRATION WAS DETERMINED BY INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY. LINEAR MIXED MODELS AND GENERALIZED LINEAR MIXED MODELS WERE USED TO ASSESS THE ASSOCIATIONS OF CIRCRNAS WITH CRD, URINARY COPPER, AND CYTOKINES. WE EXPOSED THE HUMAN BRONCHIAL EPITHELIAL CELL LINE, 16HBE, TO COPPER AND ASSESSED THE FUNCTIONAL ROLE OF A CIRCRNA, CIRC_0008882, BY RNA OVEREXPRESSION. CELLULAR LOCATION OF CIRC_0008882 WAS ASSESSED BY SEPARATION OF NUCLEAR AND CYTOPLASMIC RNAS. NINE CIRCRNAS WERE ASSOCIATED WITH AN INCREASED RISK FOR CRDS, WHILE THE RELATIVE EXPRESSION OF CIRC_0008882 WAS DECREASED AFTER COPPER EXPOSURE IN VITRO AND IN VIVO. COPPER EXPOSURE STIMULATED 16HBE CELLS TO RELEASE PROINFLAMMATORY IL-6 AND IL-8. THE RELEASE OF THE CYTOKINES WAS INHIBITED BY OVEREXPRESSION OF CIRC_0008882. THESE RESULTS SUGGEST A ROLE FOR CIRC_0008882 IN THE REGULATION OF CRD ASSOCIATED INFLAMMATION FOLLOWING COPPER EXPOSURE.	2022