1  1852 207 ELECTRONIC CIGARETTES: THEIR CONSTITUENTS AND POTENTIAL LINKS TO ASTHMA. PURPOSE OF REVIEW: VAPING IS GAINING POPULARITY IN THE USA, PARTICULARLY AMONG TEENS AND YOUNG ADULTS. WHILE E-CIGS ARE COMMONLY REPRESENTED AS SAFER ALTERNATIVES TO TOBACCO CIGARETTES, LITTLE IS KNOWN REGARDING THE HEALTH EFFECTS OF THEIR SHORT- OR LONG-TERM USE, ESPECIALLY IN INDIVIDUALS WITH PRE-EXISTING RESPIRATORY DISEASES SUCH AS ASTHMA. FLAVORED E-CIG LIQUIDS (E-LIQUIDS) AND E-CIG AEROSOLS CONTAIN AIRWAY IRRITANTS AND TOXICANTS THAT HAVE BEEN IMPLICATED IN THE PATHOGENESIS AND WORSENING OF LUNG DISEASES. IN THIS REVIEW, WE WILL SUMMARIZE EXISTING DATA ON POTENTIAL HEALTH EFFECTS OF COMPONENTS PRESENT IN E-CIG AEROSOLS, SUCH AS PROPYLENE GLYCOL, VEGETABLE GLYCERIN, NICOTINE, AND FLAVORINGS, AND DISCUSS THEIR RELEVANCE IN THE CONTEXT OF ASTHMA. RECENT FINDINGS: RECENT SURVEY DATA INDICATE THAT ADOLESCENTS WITH ASTHMA HAD A HIGHER PREVALENCE OF CURRENT E-CIG USE (12.4%) COMPARED TO THEIR NON-ASTHMATICS PEERS (10.2%) AND CONVEYED POSITIVE BELIEFS ABOUT TOBACCO PRODUCTS, ESPECIALLY E-CIGS. SIMILARLY, A STUDY CONDUCTED AMONG HIGH SCHOOL STUDENTS FROM ONTARIO, CANADA, INDICATED A GREATER LIKELIHOOD OF E-CIG USE IN ASTHMATICS AS COMPARED TO THEIR NON-ASTHMATIC PEERS. AVAILABILITY OF DIFFERENT FLAVORINGS IS OFTEN CITED AS THE MAIN REASON AMONG YOUTH/ADOLESCENTS FOR TRYING E-CIGS OR SWITCHING FROM CIGARETTES TO E-CIGS. OCCUPATIONAL INHALATION OF SOME COMMON FOOD-SAFE FLAVORING AGENTS IS REPORTED TO CAUSE OCCUPATIONAL ASTHMA AND WORSEN ASTHMATIC SYMPTOMS. MOREOVER, WORKPLACE INHALATION EXPOSURES TO THE FLAVORING AGENT DIACETYL HAVE CAUSED IRREVERSIBLE OBSTRUCTIVE AIRWAY DISEASE IN HEALTHY WORKERS. ADDITIONALLY, RECENT STUDIES REPORT THAT THERMAL DECOMPOSITION OF PROPYLENE GLYCOL (PG) AND VEGETABLE GLYCERIN (VG), THE BASE CONSTITUENTS OF E-LIQUIDS, PRODUCES REACTIVE CARBONYLS, INCLUDING ACROLEIN, FORMALDEHYDE, AND ACETALDEHYDE, WHICH HAVE KNOWN RESPIRATORY TOXICITIES. FURTHERMORE, RECENT NICOTINE STUDIES IN RODENTS REVEAL THAT PRENATAL NICOTINE EXPOSURES LEAD TO EPIGENETIC REPROGRAMMING IN THE OFFSPRING, ABNORMAL LUNG DEVELOPMENT, AND MULTIGENERATIONAL TRANSMISSION OF ASTHMATIC-LIKE SYMPTOMS. COMPARISONS OF THE TOXICITY AND HEALTH EFFECTS OF E-CIGS AND CONVENTIONAL CIGARETTES OFTEN FOCUS ON TOXICANTS KNOWN TO BE PRESENT IN CIGARETTE SMOKE (CS) (I.E., FORMALDEHYDE, NITROSAMINES, ETC.), AS WELL AS SMOKING-ASSOCIATED CLINICAL ENDPOINTS, SUCH AS CANCER, BRONCHITIS, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). HOWEVER, THIS APPROACH DISREGARDS POTENTIAL TOXICITY OF COMPONENTS UNIQUE TO FLAVORED E-CIGS, SUCH AS PG, VG, AND THE MANY DIFFERENT FLAVORING CHEMICALS, WHICH LIKELY INDUCE RESPIRATORY EFFECTS NOT USUALLY OBSERVED IN CIGARETTE SMOKERS.	2017	

2  3677  22 INFLAMMATION AND PYROPTOSIS MEDIATE MUSCLE EXPANSION IN AN INTERLEUKIN-1BETA (IL-1BETA)-DEPENDENT MANNER. MUSCLE INFLAMMATION IS OFTEN ASSOCIATED WITH ITS EXPANSION. BLADDER SMOOTH MUSCLE INFLAMMATION-INDUCED CELL DEATH IS ACCOMPANIED BY HYPERPLASIA AND HYPERTROPHY AS THE PRIMARY CAUSE FOR POOR BLADDER FUNCTION. IN MICE, DNA DAMAGE INITIATED BY CHEMOTHERAPEUTIC DRUG CYCLOPHOSPHAMIDE ACTIVATED CASPASE 1 THROUGH THE FORMATION OF THE NLRP3 COMPLEX RESULTING IN DETRUSOR HYPERPLASIA. A CYCLOPHOSPHAMIDE METABOLITE, ACROLEIN, CAUSED GLOBAL DNA METHYLATION AND ACCUMULATION OF DNA DAMAGE IN A MOUSE MODEL OF BLADDER INFLAMMATION AND IN CULTURED BLADDER MUSCLE CELLS. IN CORRELATION, GLOBAL DNA METHYLATION AND NLRP3 EXPRESSION WAS UP-REGULATED IN HUMAN CHRONIC BLADDER INFLAMMATORY TISSUES. THE EPIGENETIC SILENCING OF DNA DAMAGE REPAIR GENE, OGG1, COULD BE REVERSED BY THE USE OF DEMETHYLATING AGENTS. IN MICE, DEMETHYLATING AGENTS REVERSED CYCLOPHOSPHAMIDE-INDUCED BLADDER INFLAMMATION AND DETRUSOR EXPANSION. THE TRANSGENIC KNOCK-OUT OF OGG1 IN AS FEW AS 10% OF THE DETRUSOR CELLS TRIPLED THE PROLIFERATION OF THE REMAINING WILD TYPE COUNTERPARTS IN AN IN VITRO CO-CULTURE TITRATION EXPERIMENT. ANTAGONIZING IL-1BETA WITH ANAKINRA, A RHEUMATOID ARTHRITIS THERAPEUTIC, PREVENTED DETRUSOR PROLIFERATION IN CONDITIONED MEDIA EXPERIMENTS AS WELL AS IN A MOUSE MODEL OF BLADDER INFLAMMATION. RADIATION TREATMENT VALIDATED THE ROLE OF DNA DAMAGE IN THE NLRP3-ASSOCIATED CASPASE 1-MEDIATED IL-1BETA SECRETORY PHENOTYPE. A PROTEIN ARRAY ANALYSIS IDENTIFIED IGF1 TO BE DOWNSTREAM OF IL-1BETA SIGNALING. IL-1BETA-INDUCED DETRUSOR PROLIFERATION AND HYPERTROPHY COULD BE REVERSED WITH THE USE OF ANAKINRA AS WELL AS AN IGF1 NEUTRALIZING ANTIBODY. IL-1BETA ANTAGONISTS IN CURRENT CLINICAL PRACTICE CAN EXPLOIT THE REVEALED MECHANISM FOR DNA DAMAGE-MEDIATED MUSCULAR EXPANSION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3  5380  57 RECENT UPDATES ON BIOMARKERS OF EXPOSURE AND SYSTEMIC TOXICITY IN E-CIGARETTE USERS AND EVALI. ELECTRONIC NICOTINE DELIVERY SYSTEMS (ENDS), OR E-CIGARETTES, ARE EMERGING TOBACCO PRODUCTS THAT PRODUCE AEROSOLS BY HEATING E-LIQUIDS, WHICH MOST OFTEN CONSIST OF PROPYLENE GLYCOL AND VEGETABLE GLYCERIN ALONG WITH VARIOUS FLAVORING COMPOUNDS, BYPASSING THE COMBUSTION THAT OCCURS IN THE USE OF TRADITIONAL TOBACCO CIGARETTES. THESE PRODUCTS HAVE SEEN A DRASTIC INCREASE IN POPULARITY IN RECENT YEARS BOTH AS SMOKING CESSATION DEVICES AS WELL AS AMONG YOUNGER GENERATIONS, DUE IN LARGE PART TO THE WIDESPREAD PERCEPTION AMONG CONSUMERS THAT E-CIGS ARE SIGNIFICANTLY LESS HARMFUL TO HEALTH THAN TRADITIONAL TOBACCO CIGARETTES. DUE TO THE NOVELTY OF ENDS AS WELL AS THEIR RAPIDLY INCREASING USE, RESEARCH INTO BIOMARKERS OF E-CIG EXPOSURE AND TOXICITY HAVE LAGGED BEHIND THEIR POPULARITY, LEAVING IMPORTANT QUESTIONS ABOUT THEIR POTENTIAL TOXICITY UNANSWERED. RESEARCH INTO POTENTIAL BIOMARKERS OF ACUTE AND CHRONIC E-CIG USE, AND E-CIGARETTE- OR VAPING-ASSOCIATED LUNG INJURY IS NECESSARY FOR INFORMING BOTH CLINICAL AND REGULATORY DECISION-MAKING. WE AIM TO PROVIDE AN UPDATED REVIEW OF RECENT RESEARCH INTO POTENTIAL CIRCULATING, GENOMIC, TRANSCRIPTOMIC, AND EPIGENETIC BIOMARKERS OF EXPOSURE TO AND TOXICITY OF E-CIGS. WE ADDITIONALLY HIGHLIGHT RESEARCH AREAS THAT WARRANT ADDITIONAL STUDY TO GAIN A BETTER UNDERSTANDING OF HEALTH RISKS ASSOCIATED WITH ENDS USE, AS WELL AS TO PROVIDE VALIDATION OF EXISTING DATA AND METHODS FOR MEASURING AND ANALYZING E-CIG-ASSOCIATED BIOMARKERS IN HUMAN AND ANIMAL BIOFLUIDS, TISSUES, AND CELLS. THIS REVIEW ALSO HIGHLIGHTS ONGOING EFFORTS WITHIN THE WNY CENTER FOR RESEARCH ON FLAVORED TOBACCO FOR RESEARCH INTO NOVEL BIOMARKERS IN EXTRACELLULAR VESICLES THAT MAY BE ASSOCIATED WITH SHORT- AND LONG-TERM ENDS USE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4  5479  27 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	
                                                                                                                                                                                                                                                                                                 
5  5857  30 SUBSTRATE-SPECIFIC BINDING OF 8-OXOGUANINE DNA GLYCOSYLASE 1 (OGG1) REPROGRAMS MUCOSAL ADAPTATIONS TO CHRONIC AIRWAY INJURY. RECENT ADVANCES HAVE UNCOVERED THE NON-RANDOM DISTRIBUTION OF 7, 8-DIHYDRO-8-OXOGUANINE (8-OXOGUA) INDUCED BY REACTIVE OXYGEN SPECIES, WHICH IS BELIEVED TO HAVE EPIGENETIC EFFECTS. ITS COGNATE REPAIR PROTEIN, 8-OXOGUANINE DNA GLYCOSYLASE 1 (OGG1), READS OXIDATIVE SUBSTRATES AND PARTICIPATES IN TRANSCRIPTIONAL INITIATION. WHEN REDOX SIGNALING IS ACTIVATED IN SMALL AIRWAY EPITHELIAL CELLS, THE DNA REPAIR FUNCTION OF OGG1 IS REPURPOSED TO TRANSMIT ACUTE INFLAMMATORY SIGNALS ACCOMPANIED BY CELL STATE TRANSITIONS AND MODIFICATION OF THE EXTRACELLULAR MATRIX. EPITHELIAL-MESENCHYMAL AND EPITHELIAL-IMMUNE INTERACTIONS ACT COOPERATIVELY TO ESTABLISH A LOCAL NICHE THAT INSTRUCTS THE MUCOSAL IMMUNE LANDSCAPE. IF THE TRANSITIONAL CELL STATE GOVERNED BY OGG1 REMAINS RESPONSIVE TO INFLAMMATORY MEDIATORS INSTEAD OF DIFFERENTIATION, THE COLLATERAL DAMAGE PROVIDES POSITIVE FEEDBACK TO INFLAMMATION, ASCRIBING INFLAMMATORY REMODELING TO ONE OF THE DRIVERS IN CHRONIC PATHOLOGIES. IN THIS REVIEW, WE DISCUSS THE SUBSTRATE-SPECIFIC READ THROUGH OGG1 HAS EVOLVED IN REGULATING THE INNATE IMMUNE RESPONSE, CONTROLLING ADAPTATIONS OF THE AIRWAY TO ENVIRONMENTAL AND INFLAMMATORY INJURY, WITH A FOCUS ON THE READER FUNCTION OF OGG1 IN INITIATION AND PROGRESSION OF EPITHELIAL TO MESENCHYMAL TRANSITIONS IN CHRONIC PULMONARY DISEASE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
6  4529  29 MULTIGENERATIONAL GRAPHENE OXIDE INTOXICATION RESULTS IN REPRODUCTION DISORDERS AT THE MOLECULAR LEVEL OF VITELLOGENIN PROTEIN EXPRESSION IN ACHETA DOMESTICUS. THE ANTHROPOGENIC ACTIVITIES MAY LEAD TO ACCUMULATION OF GRAPHENE OXIDE (GO) POLLUTION IN THE ENVIRONMENT. ORGANISMS EXPOSED TO CHRONIC OR MULTIGENERATIONAL GO INTOXICATION CAN PRESENT REPRODUCTION DEPLETION. VITELLOGENIN (VG) HAS BEEN USED AS A PARAMETER FOR EVALUATING FEMALE FERTILITY DUE TO ITS IMPORTANCE IN EMBRYO NUTRITION. IN THIS STUDY, WE USED A PROMISING MODEL ORGANISM, ACHETA DOMESTICUS, WHICH WAS INTOXICATED WITH GO IN FOOD FOR THREE GENERATIONS. THE AIM OF THE STUDY WAS TO INVESTIGATE THE PROCESS OF VG SYNTHESIS IN CRICKETS DEPENDING ON THE EXPOSURE TIME, GO CONCENTRATION, AND AGE OF THE FEMALES. THE RESULTS REVEALED THAT CHRONIC GO INTOXICATION HAD ADVERSE EFFECTS ON THE VG EXPRESSION PATTERN. THE 1ST GENERATION OF INSECTS SHOWING LOW VG EXPRESSION WAS MOST AFFECTED. THE 2ND GENERATION OF A. DOMESTICUS PRESENTED A HIGH VG EXPRESSION. THE LAST INVESTIGATED GENERATION SEEMED TO COPE WITH STRESS CAUSED BY GO, AND THE VG EXPRESSION WAS BALANCED. WE SUGGEST THAT THE EPIGENETIC MECHANISMS MAY PLAY A ROLE IN THE INFORMATION TRANSFER TO THE NEXT GENERATIONS ON HOW TO REACT TO THE RISK FACTOR AND KEEP REPRODUCTION AT A HIGH RATE. WE SUSPECT THAT CHRONIC GO INTOXICATION CAN DISTURB THE REGULAR FORMATION OF THE VG QUATERNARY STRUCTURE, RESULTING IN CONSEQUENCES FOR DEVELOPING AN EMBRYO.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7  2838  31 FORMALDEHYDE CARCINOGENICITY RESEARCH: 30 YEARS AND COUNTING FOR MODE OF ACTION, EPIDEMIOLOGY, AND CANCER RISK ASSESSMENT. FORMALDEHYDE IS A WIDELY USED HIGH PRODUCTION CHEMICAL THAT IS ALSO RELEASED AS A BYPRODUCT OF COMBUSTION, OFF-GASSING OF VARIOUS BUILDING PRODUCTS, AND AS A FIXATIVE FOR PATHOLOGISTS AND EMBALMERS. WHAT IS NOT OFTEN REALIZED IS THAT FORMALDEHYDE IS ALSO PRODUCED AS A NORMAL PHYSIOLOGIC CHEMICAL IN ALL LIVING CELLS. IN 1980, CHRONIC INHALATION OF HIGH CONCENTRATIONS OF FORMALDEHYDE WAS SHOWN TO BE CARCINOGENIC, INDUCING A HIGH INCIDENCE OF NASAL SQUAMOUS CELL CARCINOMAS IN RATS. SOME EPIDEMIOLOGIC STUDIES HAVE ALSO FOUND INCREASED NUMBERS OF NASOPHARYNGEAL CARCINOMA AND LEUKEMIA IN HUMANS EXPOSED TO FORMALDEHYDE THAT RESULTED IN FORMALDEHYDE BEING CONSIDERED A KNOWN HUMAN CARCINOGEN. THIS ARTICLE REVIEWS THE DATA FOR RODENT AND HUMAN CARCINOGENICITY, EARLY MODE OF ACTION STUDIES, MORE RECENT MOLECULAR STUDIES OF BOTH ENDOGENOUS AND EXOGENOUS DNA ADDUCTS, AND EPIGENETIC STUDIES. IT GOES ON TO DEMONSTRATE THE POWER OF THESE RESEARCH STUDIES TO PROVIDE CRITICAL DATA TO IMPROVE OUR ABILITY TO DEVELOP SCIENCE-BASED CANCER RISK ASSESSMENTS, INSTEAD OF DEFAULT APPROACHES. THE COMPLEXITY OF CONSTANT PHYSIOLOGIC EXPOSURE TO A KNOWN CARCINOGEN REQUIRES THAT NEW WAYS OF THINKING BE INCORPORATED INTO DETERMINATIONS OF CANCER RISK ASSESSMENT FOR FORMALDEHYDE, OTHER ENDOGENOUS CARCINOGENS, AND THE ROLE OF BACKGROUND ENDOGENOUS DNA DAMAGE AND MUTAGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  3939  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9  1853  32 ELEVATED METHIONINE FLUX DRIVES PYROPTOSIS EVASION IN PERSISTER CANCER CELLS. INDUCTION OF CELL DEATH REPRESENTS A PRIMARY GOAL OF MOST ANTICANCER TREATMENTS. DESPITE THE EFFICACY OF SUCH APPROACHES, A SMALL POPULATION OF "PERSISTERS" DEVELOP EVASION STRATEGIES TO THERAPY-INDUCED CELL DEATH. WHILE PREVIOUS STUDIES HAVE IDENTIFIED MECHANISMS OF RESISTANCE TO APOPTOSIS, THE MECHANISMS BY WHICH PERSISTERS DAMPEN OTHER FORMS OF CELL DEATH, SUCH AS PYROPTOSIS, REMAIN TO BE ELUCIDATED. PYROPTOSIS IS A FORM OF INFLAMMATORY CELL DEATH THAT INVOLVES FORMATION OF MEMBRANE PORES, ION GRADIENT IMBALANCE, WATER INFLOW, AND MEMBRANE RUPTURE. HEREIN, WE INVESTIGATE MECHANISMS BY WHICH CANCER PERSISTERS RESIST PYROPTOSIS, SURVIVE, THEN PROLIFERATE IN THE PRESENCE OF TYROSINE KINASE INHIBITORS (TKI). LUNG, PROSTATE, AND ESOPHAGEAL CANCER PERSISTER CELLS REMAINING AFTER TREATMENTS EXHIBITED SEVERAL HALLMARKS INDICATIVE OF PYROPTOSIS RESISTANCE. THE INFLAMMATORY ATTRIBUTES OF PERSISTERS INCLUDED CHRONIC ACTIVATION OF INFLAMMASOME, STING, AND TYPE I INTERFERONS. COMPREHENSIVE METABOLOMIC CHARACTERIZATION UNCOVERED THAT TKI-INDUCED PYROPTOTIC PERSISTERS DISPLAY HIGH METHIONINE CONSUMPTION AND EXCESSIVE TAURINE PRODUCTION. ELEVATED METHIONINE FLUX OR EXOGENOUS TAURINE PRESERVED PLASMA MEMBRANE INTEGRITY VIA OSMOLYTE-MEDIATED EFFECTS. INCREASED DEPENDENCY ON METHIONINE FLUX DECREASED THE LEVEL OF ONE CARBON METABOLISM INTERMEDIATE S-(5'-ADENOSYL)-L-HOMOCYSTEINE, A DETERMINANT OF CELL METHYLATION CAPACITY. THE CONSEQUENT INCREASE IN METHYLATION POTENTIAL INDUCED DNA HYPERMETHYLATION OF GENES REGULATING METAL ION BALANCE AND INTRINSIC IMMUNE RESPONSE. THIS ENABLED THWARTING TKI RESISTANCE BY USING THE HYPOMETHYLATING AGENT DECITABINE. IN SUMMARY, THE EVOLUTION OF RESISTANCE TO PYROPTOSIS CAN OCCUR VIA A STEPWISE PROCESS OF PHYSICAL ACCLIMATION AND EPIGENETIC CHANGES WITHOUT EXISTING OR RECURRENT MUTATIONS. SIGNIFICANCE: METHIONINE ENABLES CANCER CELLS TO PERSIST BY EVADING PYROPTOTIC OSMOTIC LYSIS, WHICH LEADS TO GENOME-WIDE HYPERMETHYLATION THAT ALLOWS PERSISTERS TO GAIN PROLIFERATIVE ADVANTAGES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10  3767  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11  5227  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12  1730  18 DYSREGULATION OF STEM CELL SIGNALING NETWORK DUE TO GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION IN GASTRIC CANCER. GENETIC FACTORS, HELICOBACTER PYLORI INFECTION, SALT OVER-UPTAKE, DECREASED VEGETABLE/FRUIT CONSUMPTION, SMOKING, AND METABOLIC SYNDROME ARE RISK FACTORS OF HUMAN GASTRIC CANCER. GERMLINE MUTATIONS OF CDH1 GENE, AND SNPS OF PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 AND RUNX3 GENES ARE ASSOCIATED WITH GASTRIC CANCER. HELICOBACTER PYLORI ACTIVATES CAGA-SHP2-ERK AND PEPTIDOGLYCAN-NOD1-NFKAPPAB SIGNALING CASCADES IN GASTRIC EPITHELIAL CELLS USING TYPE IV SECRETION SYSTEM, AND ALSO TRAF6-MAP3K7-NFKAPPAB AND TRAF6-MAP3K7-AP-1 SIGNALING CASCADES IN EPITHELIAL AND IMMUNE CELLS THROUGH LIPOPOLYSACCHARIDE RECOGNITION BY TLR2 OR TLR4. IL-1BETA, IL-6, IL-8, TNFALPHA AND IFNGAMMA ARE ELEVATED IN GASTRIC MUCOSA WITH HELICOBACTER PYLORI INFECTION. IL-6 AND TNFALPHA INDUCE UPREGULATION OF WNT5A AND WNT10B, RESPECTIVELY. WNT SIGNALS ARE TRANSDUCED TO BETA-CATENIN-TCF/LEF, RHOA, JNK, PKC, NFAT, AND NLK SIGNALING CASCADES. WNT-BETA-CATENIN-TCF/LEF SIGNALING INDUCES UPREGULATION OF MYC, CCND1, WISP1, FGF20, JAG1 AND DKK1 GENES. NOTCH SIGNALS ARE TRANSDUCED TO CSL-NICD-MAML AND NFKAPPAB SIGNALING CASCADES. FGF SIGNALS ARE TRANSDUCED TO ERK, PI3K-AKT, PKC, AND NFAT SIGNALING CASCADES. HELICOBACTER PYLORI INFECTION INDUCES SHH UPREGULATION IN PARIETAL CELL LINEAGE, WHILE BMP SIGNALS INDUCE IHH UPREGULATION IN PIT CELL LINEAGE. HEDGEHOG SIGNALS INDUCE UPREGULATION OF GLI1, PTCH1, CCND2, FOXL1, JAG2 AND SFRP1 GENES. JAG1 AND JAG2 ACTIVATE NOTCH SIGNALING, WHILE DKK1 AND SFRP1 INHIBIT WNT SIGNALING. STEM CELL SIGNALING NETWORK, CONSISTING OF WNT, NOTCH, FGF, HEDGEHOG AND BMP SIGNALING PATHWAYS, IS ACTIVATED DURING CHRONIC HELICOBACTER PYLORI INFECTION. EPIGENETIC SILENCING OF SFRP1 GENE OCCURS IN THE EARLIER STAGE OF CARCINOGENESIS IN THE STOMACH, WHILE AMPLIFICATION AND OVEREXPRESSION OF FGFR2 GENE IN THE LATER STAGE. DYSREGULATION OF THE STEM CELL SIGNALING NETWORK DUE TO THE ACCUMULATION OF GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION GIVES RISE TO GASTRIC CANCER. SNP TYPING AND CUSTOM-MADE MICROARRAY ANALYSES ON GENES ENCODING STEM CELL SIGNALING MOLECULES COULD BE UTILIZED FOR THE PERSONALIZED MEDICINE.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  5760  37 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  3701  28 INFLAMMATORY RESPONSE TO REGULATED CELL DEATH IN GOUT AND ITS FUNCTIONAL IMPLICATIONS. GOUT, A CHRONIC INFLAMMATORY ARTHRITIS DISEASE, IS CHARACTERIZED BY HYPERURICEMIA AND CAUSED BY INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND METABOLIC FACTORS. ACUTE GOUT SYMPTOMS ARE TRIGGERED BY THE INFLAMMATORY RESPONSE TO MONOSODIUM URATE CRYSTALS, WHICH IS MEDIATED BY THE INNATE IMMUNE SYSTEM AND IMMUNE CELLS (E.G., MACROPHAGES AND NEUTROPHILS), THE NACHT, LRR, AND PYD DOMAINS-CONTAINING PROTEIN 3 (NLRP3) INFLAMMASOME ACTIVATION, AND PRO-INFLAMMATORY CYTOKINE (E.G., IL-1BETA) RELEASE. RECENT STUDIES HAVE INDICATED THAT THE MULTIPLE PROGRAMMED CELL DEATH PATHWAYS INVOLVED IN THE INFLAMMATORY RESPONSE INCLUDE PYROPTOSIS, NETOSIS, NECROPTOSIS, AND APOPTOSIS, WHICH INITIATE INFLAMMATORY REACTIONS. IN THIS REVIEW, WE EXPLORE THE CORRELATION AND INTERACTIONS AMONG THESE FACTORS AND THEIR ROLES IN THE PATHOGENESIS OF GOUT TO PROVIDE FUTURE RESEARCH DIRECTIONS AND POSSIBILITIES FOR IDENTIFYING POTENTIAL NOVEL THERAPEUTIC TARGETS AND ENHANCING OUR UNDERSTANDING OF GOUT PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15   307  28 ALBUMINURIA DOWNREGULATION OF THE ANTI-AGING FACTOR KLOTHO: THE MISSING LINK POTENTIALLY EXPLAINING THE ASSOCIATION OF PATHOLOGICAL ALBUMINURIA WITH PREMATURE DEATH. TEN PERCENT OF THE ADULT POPULATION HAS CHRONIC KIDNEY DISEASE (CKD), WHICH IS DIAGNOSED WHEN THE GLOMERULAR FILTRATION RATE (GFR) IS BELOW 60 ML/MIN PER 1.73 M(2) OR WHEN ALBUMINURIA IS ABOVE 30 MG/DAY. THE NUMERICAL THRESHOLDS WERE CHOSEN BECAUSE THEY ARE ASSOCIATED WITH AN INCREASED RISK OF CKD PROGRESSION OR PREMATURE DEATH WITHIN A WIDER SCENARIO OF ACCELERATED AGING. INDEED, CKD IS ONE OF THE FASTEST GROWING CAUSES OF DEATH WORLDWIDE. A DECREASED GFR IS ASSOCIATED WITH THE ACCUMULATION OF URAEMIC TOXINS THAT MAY PROMOTE TISSUE AND ORGAN DAMAGE. HOWEVER, CKD MAY BE DIAGNOSED WHEN THE GFR IS COMPLETELY NORMAL, AS LONG AS THERE IS PATHOLOGICAL ALBUMINURIA. A KEY UNANSWERED QUESTION TO STEM THE RISE OF CKD-ASSOCIATED DEATHS IS WHETHER THE ASSOCIATION BETWEEN ISOLATED ALBUMINURIA (WHEN THE GFR IS NORMAL) AND PREMATURE DEATH IS CAUSAL. THE RECENT DEMONSTRATION THAT ALBUMINURIA PER SE DIRECTLY SUPPRESSES THE PRODUCTION OF THE ANTI-AGING FACTOR KLOTHO BY KIDNEY TUBULAR CELLS MAY BE ONE OF THE FIRST STEPS TO ADDRESS THE CAUSALITY OF THE ALBUMINURIA-PREMATURE DEATH-ACCELERATED AGING ASSOCIATION. THIS HYPOTHESIS SHOULD BE TESTED IN INTERVENTIONAL STUDIES THAT SHOULD DRAW FROM TRANSLATIONAL SCIENCE ADVANCES. THUS, THE OBSERVATION THAT ALBUMINURIA DECREASES KLOTHO PRODUCTION THROUGH EPIGENETIC MECHANISMS IMPLIES THAT KLOTHO DOWNREGULATION MAY PERSIST AFTER THE CORRECTION OF ALBUMINURIA, AND INNOVATIVE THERAPEUTIC APPROACHES ARE NEEDED TO RESTORE KLOTHO PRODUCTION. ON THE BASIS OF RECENT LITERATURE, THESE MAY INCLUDE MANIPULATION OF NF-KAPPAB REGULATORS SUCH AS B CELL LYMPHOMA 3 PROTEIN (BCL-3), AND EPIGENETIC REGULATORS SUCH AS HISTONE DEACETYLASES, OR THE REPURPOSING OF DRUGS SUCH AS PENTOXIFYLLINE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  1632  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17  3722  32 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	
                                                                                                                                                                                                                                         
18  5010  35 PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA DAMAGE AND CYTOGENETIC EFFECTS. IN THE PRESENT STUDY, THE POSSIBLE ROLE OF THE POLYUNSATURATED FATTY ACIDS LINOLEIC AND ARACHIDONIC ACID IN THE CHEMICAL INDUCTION OF CARCINOGENESIS HAS BEEN INVESTIGATED. ANALYSIS OF 7,8-DIHYDRO-8-OXO-2'-DEOXYGUANOSINE (8-OXODG) LEVELS IN 2'-DEOXYGUANOSINE (DG) AND ISOLATED DNA HAS DEMONSTRATED THAT LINOLEIC AND ARACHIDONIC ACID ARE CAPABLE OF INDUCING THIS SPECIFIC GENOTOXIC DAMAGE. THIS EFFECT APPEARS TO BE RELATED TO THE DEGREE OF FATTY ACID UNSATURATION, SINCE IT WAS NOT INDUCED BY MONOUNSATURATED OLEIC ACID. ENZYMATIC PEROXIDATION OF LINOLEIC AND ARACHIDONIC ACID RESULTED IN A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE. STUDIES ON THE INTERFERENCE OF RADICAL SCAVENGERS WITH THE INDUCTION OF 8-OXODG IN COMBINATION WITH ELECTRON SPIN RESONANCE SPECTROSCOPY DEMONSTRATED THAT THE SUPEROXIDE ANION WAS GENERATED DURING PEROXIDATION OF THESE FATTY ACIDS AND THAT SINGLET OXYGEN IS MOST LIKELY INVOLVED IN THE FORMATION OF OXIDATIVE DNA DAMAGE. THE LEVEL OF OXIDATIVE DAMAGE IN DG AND SINGLE-STRANDED DNA WAS HIGHER AS COMPARED TO THAT IN NATIVE DNA AFTER EQUIMOLAR TREATMENT. EXPOSURE OF HUMAN LYMPHOCYTES TO LINOLEIC OR ARACHIDONIC ACID DID NOT RESULT IN A SIGNIFICANT INCREASE IN LEVELS OF 8-OXODG. THIS MAY INDICATE THAT THE RATE OF INTRACELLULAR PEROXIDATION IS RELATIVELY LOW AND/OR THAT NUCLEAR DNA IN INTACT CELLS IS EFFECTIVELY PROTECTED AGAINST GENETIC DAMAGE INDUCED BY REACTIVE OXYGEN SPECIES. IT IS THEREFORE CONCLUDED THAT RELATIVELY SHORT PERIODS OF LINOLEIC OR ARACHIDONIC ACID ADMINISTRATION ARE NOT LIKELY TO IMPOSE A DIRECT GENOTOXIC RISK. IT CAN, HOWEVER, NOT BE EXCLUDED THAT CHRONIC EXPOSURE TO POLYUNSATURATED FATTY ACIDS INDUCES OXIDATIVE DNA DAMAGE OR IS RELATED TO CANCER RISK BY EPIGENETIC MECHANISMS, AS IS ALSO INDICATED BY THE OBSERVED CYTOTOXIC EFFECTS OF LINOLEIC AND ARACHIDONIC ACID.	1994	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19  4899  26 OXIDATIVE STRESS MEDIATES THE APOPTOSIS AND EPIGENETIC MODIFICATION OF THE BCL-2 PROMOTER VIA DNMT1 IN A CIGARETTE SMOKE-INDUCED EMPHYSEMA MODEL. BACKGROUND: EMPHYSEMA IS A CRUCIAL PATHOLOGICAL CHARACTERISTIC OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). OXIDATIVE STRESS, APOPTOSIS AND EPIGENETIC MECHANISMS CONTRIBUTE TO THE PATHOGENESIS OF EMPHYSEMA. HOWEVER, AN ATTEMPT TO ACCURATELY IDENTIFY WHETHER THESE MECHANISMS INTERACT WITH EACH OTHER AND HOW THEY ARE TRIGGERED HAS NEVER BEEN CONDUCTED. METHOD: THE TOTAL REACTIVE OXYGEN SPECIES (ROS) LEVEL, PULMONARY APOPTOSIS AND B-CELL LYMPHOMA/LEUKEMIA-2 (BCL-2) EXPRESSION, AN APOPTOSIS REGULATOR, WERE DETECTED IN SAMPLES FROM COPD PATIENTS. BISULFITE SEQUENCING PCR (BSP) WAS CONDUCTED TO OBSERVE THE ALTERATIONS IN THE METHYLATION OF THE BCL-2 PROMOTER IN SPECIMENS. THE DYSREGULATION OF DNA METHYLTRANSFERASE ENZYME 1 (DNMT1), A VITAL DNA METHYLTRANSFERASE ENZYME, IN THE LUNGS OF PATIENTS WAS CONFIRMED THROUGH WESTERN BLOTTING. TO FIND OUT INTERACTIONS BETWEEN OXIDATIVE STRESS AND DNA METHYLATION IN EMPHYSEMA, MOUSE MODELS WERE BUILT WITH ANTIOXIDANT TREATMENT AND DNMT1 SILENCING, AND WERE EXAMINED WITH THE PULMONARY APOPTOSIS, BCL-2 AND DNMT1 LEVELS, AND EPIGENETIC ALTERATIONS OF BCL-2. RESULTS: HIGHER ROS LEVELS AND PULMONARY APOPTOSIS WERE OBSERVED IN COPD PATIENTS THAN IN HEALTHY CONTROLS. DOWNREGULATED BCL-2 EXPRESSION WITH INCREASED PROMOTER METHYLATION AND DNMT1 PROTEIN EXPRESSION WAS FOUND IN COPD PATIENTS. ANTIOXIDANT TREATMENT REDUCED THE LEVEL OF ROS, DNMT1 PROTEIN AND EMPHYSEMATOUS PROGRESSION IN THE SMOKING MODELS. FOLLOWING DNMT1 BLOCKADE, SMOKING MODELS SHOWED IMPROVED LUNG FUNCTION, PULMONARY APOPTOSIS, EMPHYSEMATOUS PROGRESSION, AND INCREASED BCL-2 PROTEIN LEVEL WITH LESS PROMOTER METHYLATION THAN EMPHYSEMA MICE. CONCLUSION: CIGARETTE-INDUCED OXIDATIVE STRESS MEDIATES PULMONARY APOPTOSIS AND HYPERMETHYLATION OF THE BCL-2 PROMOTER IN EMPHYSEMA MODELS THROUGH DNMT1.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  6485  36 TOXICOLOGICAL MECHANISM OF INDIVIDUAL SUSCEPTIBILITY TO FORMALDEHYDE-INDUCED RESPIRATORY EFFECTS. UNDERSTANDING THE MECHANISMS OF INDIVIDUAL SUSCEPTIBILITY TO EXPOSURE TO ENVIRONMENTAL POLLUTANTS HAS BEEN A CHALLENGE IN HEALTH RISK ASSESSMENT. HERE, AN INTEGRATED APPROACH COMBINING A CRISPR SCREEN IN HUMAN CELLS AND EPIDEMIOLOGICAL ANALYSIS WAS DEVELOPED TO IDENTIFY THE INDIVIDUAL SUSCEPTIBILITY TO THE ADVERSE HEALTH EFFECTS OF AIR POLLUTANTS BY TAKING FORMALDEHYDE (FA) AND THE ASSOCIATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AS A CASE STUDY. AMONG THE PRIMARY HITS OF CRISPR SCREENING OF FA IN HUMAN A549 CELLS, HTR4 WAS THE ONLY GENE GENETICALLY ASSOCIATED WITH COPD SUSCEPTIBILITY IN GLOBAL POPULATIONS. HOWEVER, THE ASSOCIATION BETWEEN HTR4 AND FA-INDUCED RESPIRATORY TOXICITY IS UNKNOWN IN THE LITERATURE. ADVERSE OUTCOME PATHWAY (AOP) NETWORK ANALYSIS OF CRISPR SCREEN HITS PROVIDED A POTENTIAL MECHANISTIC LINK BETWEEN ACTIVATION OF HTR4 (MOLECULAR INITIATING EVENT) AND FA-INDUCED LUNG INJURY (ADVERSE OUTCOME). SYSTEMATIC TOXICOLOGY TESTS (IN VITRO AND ANIMAL EXPERIMENTS) WERE CONDUCTED TO REVEAL THE HTR4-INVOLVED BIOLOGICAL MECHANISMS UNDERLYING THE SUSCEPTIBILITY TO ADVERSE HEALTH EFFECTS OF FA. FUNCTIONALITY AND ENHANCED EXPRESSION OF HTR4 WERE REQUIRED FOR SUSCEPTIBILITY TO FA-INDUCED LUNG INJURY, AND FA-INDUCED EPIGENETIC CHANGES COULD RESULT IN ENHANCED EXPRESSION OF HTR4. SPECIFIC EPIGENETIC AND GENETIC CHARACTERISTICS OF HTR4 WERE ASSOCIATED WITH THE PROGRESSION AND PREVALENCE OF COPD, RESPECTIVELY, AND THESE GENETIC RISK FACTORS FOR COPD COULD BE POTENTIAL BIOMARKERS OF INDIVIDUAL SUSCEPTIBILITY TO ADVERSE RESPIRATORY EFFECTS OF FA. THESE BIOMARKERS COULD BE OF GREAT SIGNIFICANCE FOR DEFINING SUBPOPULATIONS SUSCEPTIBLE TO EXPOSURE TO FA AND REDUCING UNCERTAINTY IN THE NEXT-GENERATION HEALTH RISK ASSESSMENT OF AIR POLLUTANTS. OUR STUDY DELINEATED A NOVEL TOXICOLOGICAL PATHWAY MEDIATED BY HTR4 IN FA-INDUCED LUNG INJURY, WHICH COULD PROVIDE A MECHANISTIC UNDERSTANDING OF THE POTENTIAL BIOMARKERS OF INDIVIDUAL SUSCEPTIBILITY TO ADVERSE RESPIRATORY EFFECTS OF FA.	2022