1  3449 155 HYPERMETHYLATION OF THE NRF2 PROMOTER INDUCES FERROPTOSIS BY INHIBITING THE NRF2-GPX4 AXIS IN COPD. BACKGROUND: NUCLEAR FACTOR E2-RELATED FACTOR 2 (NRF2) IS INVOLVED IN OXIDATIVE STRESS AND LUNG INFLAMMATION AND REGULATES THE ETIOLOGY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). FERROPTOSIS IS CHARACTERIZED BY THE ACCUMULATION OF LIPID REACTIVE OXYGEN SPECIES (ROS) VIA FERROUS ION-DEPENDENT FENTON REACTIONS AND IS INVOLVED IN COPD. HOWEVER, THE ROLE OF NRF2 IN FERROPTOSIS AND ITS EPIGENETIC REGULATION IN THE PATHOGENESIS OF COPD REMAIN UNCLEAR. METHODS: FERROPTOSIS WAS DETECTED BY 4-HNE, MDA, C11BODIPY, DCFH-DA, PEALS' STAINING AND CCK-8 ASSAYS. QPCR AND WESTERN BLOTTING WERE PERFORMED TO EXAMINE THE NRF2 LEVELS IN PERIPHERAL LUNG TISSUES, PRIMARY EPITHELIAL CELLS COLLECTED FROM PATIENTS WITH COPD AND SUBJECTS WITH NORMAL PULMONARY FUNCTION (NEVER-SMOKER [CONTROL-NS]; SMOKER [CONTROL-S]), AND CIGARETTE SMOKE EXTRACT (CSE)-TREATED HUMAN BRONCHIAL EPITHELIAL (HBE) CELLS. ELISA WAS USED TO QUANTIFY IL-8 AND IL-1BETA LEVELS. METHYLATION OF THE NRF2 PROMOTER WAS ANALYZED BY BISULFITE SEQUENCING AND PYROSEQUENCING. RESULTS: FERROPTOSIS WAS INVOLVED IN COPD AND GLUTATHIONE PEROXIDASE 4 (GPX4) EXPRESSION WAS DOWNREGULATED IN THE COPD GROUP. REACTIVE OXYGEN SPECIES (ROS), LIPID PEROXIDES AND MDA WERE INCREASED, BUT GPX4 AND SOD WERE EXHAUSTED IN CSE-TREATED HBE CELLS. THE PRODUCTION OF IL-1BETA AND IL-8 WAS PROMOTED IN HBE CELLS IN RESPONSE TO CSE BUT COULD BE REVERSED BY THE FERROPTOSIS INHIBITOR FER-1. THE NRF2 LEVEL WAS SIGNIFICANTLY DECREASED IN THE COPD GROUP COMPARED WITH THE CONTROL-S AND CONTROL-NS GROUPS. INCREASED NRF2 EXPRESSION ENHANCED GPX4 AND SOD LEVELS AND INHIBITED FERROPTOSIS AND PROINFLAMMATORY CYTOKINES IN THE SUPERNATANT. INHIBITION OF GPX4 REVERSED THE EFFECT OF NRF2 OVEREXPRESSION AND PROMOTED FERROPTOSIS. TWO SPECIFIC CPG SITES WITHIN THE NRF2 PROMOTER WERE HYPERMETHYLATED IN THE COPD GROUP. SIMILARLY, CSE-TREATED HBE CELLS EXHIBITED HYPERMETHYLATION OF THE NRF2 GENE. CONCLUSION: NRF2 EXPRESSION WAS DOWNREGULATED IN THE LUNGS OF COPD PATIENTS DUE TO HYPERMETHYLATION OF THE NRF2 PROMOTER, INHIBITING NRF2/GPX4 AND FERROPTOSIS, WHICH IS RELATED TO THE INITIATION AND PROGRESSION OF COPD. TARGETING NRF2/GPX4 MAY INHIBIT FERROPTOSIS, WHICH COULD PROVIDE STRATEGIES TO DELAY OR TREAT COPD.	2021	
                                                                                                                                                                                                                                                                                                                                                           
2  5536  36 ROLE OF C-MIR-21, C-MIR-126, REDOX STATUS, AND INFLAMMATORY CONDITIONS AS POTENTIAL PREDICTORS OF VASCULAR DAMAGE IN T2DM PATIENTS. THE DEVELOPMENT OF TYPE 2 DIABETES MELLITUS (T2DM) VASCULAR COMPLICATIONS (VCS) IS ASSOCIATED WITH OXIDATIVE STRESS AND CHRONIC INFLAMMATION AND CAN RESULT IN ENDOTHELIAL DYSFUNCTIONS. CIRCULATING MICRORNAS PLAY AN IMPORTANT ROLE IN EPIGENETIC REGULATION OF THE ETIOLOGY OF T2DM. WE STUDIED 30 HEALTHY VOLUNTEERS, 26 T2DM PATIENTS WITH NO COMPLICATIONS, AND 26 T2DM PATIENTS WITH VCS, TO LOOK FOR NEW BIOMARKERS INDICATING A RISK OF DEVELOPING VCS IN T2DM PATIENTS. PERIPHERAL BLOOD SAMPLES WERE USED TO DETERMINE REDOX STATE, BY MEASURING THE ENDOGENOUS ANTIOXIDANT DEFENSE SYSTEM (SUPEROXIDE DISMUTASE, SOD; CATALASE, CAT; GLUTATHIONE REDUCTASE, GRD; GLUTATHIONE PEROXIDASE, GPX; AND GLUCOSE-6-PHOSPHATE DEHYDROGENASE, G6DP) AND MARKERS OF OXIDATIVE DAMAGE (ADVANCED OXIDATION PROTEIN PRODUCTS, AOPP; LIPID PEROXIDATION, LPO). ADDITIONALLY, INFLAMMATORY MARKER LEVELS (IL-1, IL-6, IL-18, AND TNF-ALPHA), C-MIR-21, AND C-MIR-126 EXPRESSION WERE ANALYZED. T2DM PATIENTS SHOWED THE HIGHEST OXIDATIVE DAMAGE WITH INCREASED GSSG/GSH RATIOS, LPO, AND AOPP LEVELS. IN BOTH DIABETIC GROUPS, WE FOUND THAT DIMINISHED SOD ACTIVITY WAS ACCOMPANIED BY INCREASED CAT AND DECREASED GRD AND G6PD ACTIVITIES. DIABETIC PATIENTS PRESENTED WITH INCREASED RELATIVE EXPRESSION OF C-MIR-21 AND DECREASED RELATIVE EXPRESSION OF C-MIR-126. OVERALL, C-MIR-21, SOD, CAT, AND IL-6 HAD HIGH PREDICTIVE VALUES FOR DIABETES DIAGNOSES. FINALLY, OUR DATA DEMONSTRATED THAT IL-6 EXHIBITED PREDICTIVE VALUE FOR VC DEVELOPMENT IN THE STUDIED POPULATION. MOREOVER, C-MIR-21 AND C-MIR-126, ALONG WITH GPX AND AOPP LEVELS, SHOULD BE CONSIDERED POSSIBLE MARKERS FOR VC DEVELOPMENT IN FUTURE STUDIES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3   616  33 BIOACTIVE COMPOUNDS IN OXIDATIVE STRESS-MEDIATED DISEASES: TARGETING THE NRF2/ARE SIGNALING PATHWAY AND EPIGENETIC REGULATION. OXIDATIVE STRESS IS A PATHOLOGICAL CONDITION OCCURRING DUE TO AN IMBALANCE BETWEEN THE OXIDANTS AND ANTIOXIDANT DEFENSE SYSTEMS IN THE BODY. NUCLEAR FACTOR E2-RELATED FACTOR 2 (NRF2), ENCODED BY THE GENE NFE2L2, IS THE MASTER REGULATOR OF PHASE II ANTIOXIDANT ENZYMES THAT PROTECT AGAINST OXIDATIVE STRESS AND INFLAMMATION. NRF2/ARE SIGNALING HAS BEEN CONSIDERED AS A PROMISING TARGET AGAINST OXIDATIVE STRESS-MEDIATED DISEASES LIKE DIABETES, FIBROSIS, NEUROTOXICITY, AND CANCER. THE CONSUMPTION OF DIETARY PHYTOCHEMICALS ACTS AS AN EFFECTIVE MODULATOR OF NRF2/ARE IN VARIOUS ACUTE AND CHRONIC DISEASES. IN THE PRESENT REVIEW, WE DISCUSSED THE ROLE OF NRF2 IN DIABETES, ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), CANCER, AND ATHEROSCLEROSIS. ADDITIONALLY, WE DISCUSSED THE PHYTOCHEMICALS LIKE CURCUMIN, QUERCETIN, RESVERATROL, EPIGALLOCATECHIN GALLATE, APIGENIN, SULFORAPHANE, AND URSOLIC ACID THAT HAVE EFFECTIVELY MODIFIED NRF2 SIGNALING AND PREVENTED VARIOUS DISEASES IN BOTH IN VITRO AND IN VIVO MODELS. BASED ON THE LITERATURE, IT IS CLEAR THAT DIETARY PHYTOCHEMICALS CAN PREVENT DISEASES BY (1) BLOCKING OXIDATIVE STRESS-INHIBITING INFLAMMATORY MEDIATORS THROUGH INHIBITING KEAP1 OR ACTIVATING NRF2 EXPRESSION AND ITS DOWNSTREAM TARGETS IN THE NUCLEUS, INCLUDING HO-1, SOD, AND CAT; (2) REGULATING NRF2 SIGNALING BY VARIOUS KINASES LIKE GSK3BETA, PI3/AKT, AND MAPK; AND (3) MODIFYING EPIGENETIC MODULATION, SUCH AS METHYLATION, AT THE NRF2 PROMOTER REGION; HOWEVER, FURTHER INVESTIGATION INTO OTHER UPSTREAM SIGNALING MOLECULES LIKE NRF2 AND THE EFFECT OF PHYTOCHEMICALS ON THEM STILL NEED TO BE INVESTIGATED IN THE NEAR FUTURE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4  5479  48 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  5227  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  3767  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7  6456  35 THYMOSIN BETA4 PREVENTS OXIDATIVE STRESS, INFLAMMATION, AND FIBROSIS IN ETHANOL- AND LPS-INDUCED LIVER INJURY IN MICE. THYMOSIN BETA 4 (TBETA4), AN ACTIN-SEQUESTERING PROTEIN, IS INVOLVED IN TISSUE DEVELOPMENT AND REGENERATION. IT PREVENTS INFLAMMATION AND FIBROSIS IN SEVERAL TISSUES. WE INVESTIGATED THE ROLE OF TBETA4 IN CHRONIC ETHANOL- AND ACUTE LIPOPOLYSACCHARIDE- (LPS-) INDUCED MOUSE LIVER INJURY. C57BL/6 MICE WERE FED 5% ETHANOL IN LIQUID DIET FOR 4 WEEKS PLUS BINGE ETHANOL (5 G/KG, GAVAGE) WITH OR WITHOUT LPS (2 MG/KG, INTRAPERITONEAL) FOR 6 HOURS. TBETA4 (1 MG/KG, INTRAPERITONEAL) WAS ADMINISTERED FOR 1 WEEK. WE DEMONSTRATED THAT TBETA4 PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN LIVER INJURY MARKERS AS WELL AS CHANGES IN LIVER PATHOLOGY. IT ALSO PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN OXIDATIVE STRESS BY DECREASING ROS AND LIPID PEROXIDATION AND INCREASING THE ANTIOXIDANTS, REDUCED GLUTATHIONE AND MANGANESE-DEPENDENT SUPEROXIDE DISMUTASE. IT ALSO PREVENTED THE ACTIVATION OF NUCLEAR FACTOR KAPPA B BY BLOCKING THE PHOSPHORYLATION OF THE INHIBITORY PROTEIN, IKAPPAB, THEREBY PREVENTED PROINFLAMMATORY CYTOKINE PRODUCTION. MOREOVER, TBETA4 PREVENTED FIBROGENESIS BY SUPPRESSING THE EPIGENETIC REPRESSOR, METHYL-CPG-BINDING PROTEIN 2, THAT COORDINATELY REVERSED THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND DOWNREGULATED FIBROGENIC GENES, PLATELET-DERIVED GROWTH FACTOR-BETA RECEPTOR, ALPHA-SMOOTH MUSCLE ACTIN, COLLAGEN 1, AND FIBRONECTIN, RESULTING IN REDUCED FIBROSIS. OUR DATA SUGGEST THAT TBETA4 HAS ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTIFIBROTIC POTENTIAL DURING ALCOHOLIC LIVER INJURY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8  3939  46 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  5860  38 SULFORAPHANE PREVENTS ANGIOTENSIN II-INDUCED CARDIOMYOPATHY BY ACTIVATION OF NRF2 THROUGH EPIGENETIC MODIFICATION. NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR (NRF2) IS AN IMPORTANT REGULATOR OF CELLULAR ANTIOXIDANT DEFENCE. WE PREVIOUSLY SHOWED THAT SFN PREVENTED ANG II-INDUCED CARDIAC DAMAGE VIA ACTIVATION OF NRF2. HOWEVER, THE UNDERLYING MECHANISM OF SFN'S PERSISTENT CARDIAC PROTECTION REMAINS UNCLEAR. THIS STUDY AIMED TO EXPLORE THE POTENTIAL OF SFN IN ACTIVATING CARDIAC NRF2 THROUGH EPIGENETIC MECHANISMS. WILD-TYPE MICE WERE INJECTED SUBCUTANEOUSLY WITH ANG II, WITH OR WITHOUT SFN. ADMINISTRATION OF CHRONIC ANG II-INDUCED CARDIAC INFLAMMATORY FACTOR EXPRESSION, OXIDATIVE DAMAGE, FIBROSIS AND CARDIAC REMODELLING AND DYSFUNCTION, ALL OF WHICH WERE EFFECTIVELY IMPROVED BY SFN TREATMENT, COUPLED WITH AN UP-REGULATION OF NRF2 AND DOWNSTREAM GENES. BISULFITE GENOME SEQUENCING AND CHROMATIN IMMUNOPRECIPITATION (CHIP) WERE PERFORMED TO DETECT THE METHYLATION LEVEL OF THE FIRST 15 CPGS AND HISTONE H3 ACETYLATION (AC-H3) STATUS IN THE NRF2 PROMOTER REGION, RESPECTIVELY. THE RESULTS SHOWED THAT SFN REDUCED ANG II-INDUCED CPG HYPERMETHYLATION AND PROMOTED AC-H3 ACCUMULATION IN THE NRF2 PROMOTER REGION, ACCOMPANIED BY THE INHIBITION OF GLOBAL DNMT AND HDAC ACTIVITY, AND A DECREASED PROTEIN EXPRESSION OF KEY DNMT AND HDAC ENZYMES. TAKEN TOGETHER, SFN EXERTS ITS CARDIOPROTECTIVE EFFECT THROUGH EPIGENETIC MODIFICATION OF NRF2, WHICH MAY PARTIALLY CONTRIBUTE TO LONG-TERM ACTIVATION OF CARDIAC NRF2.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10  4303  33 MICRORNA-223 INHIBITS TISSUE FACTOR EXPRESSION IN VASCULAR ENDOTHELIAL CELLS. OBJECTIVE: ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY PROCESS, IN WHICH VASCULAR ENDOTHELIAL CELLS (ECS) BECOME DYSFUNCTIONAL OWING TO THE EFFECTS OF CHEMICAL SUBSTANCES, SUCH AS INFLAMMATORY FACTOR AND GROWTH FACTORS. TISSUE FACTOR (TF) EXPRESSION IS INDUCED BY THE ABOVE CHEMICAL SUBSTANCES IN ACTIVATED ECS. TF INITIATES THROMBOSIS ON DISRUPTED ATHEROSCLEROTIC PLAQUES WHICH PLAYS AN ESSENTIAL ROLE DURING THE ONSET OF ACUTE CORONARY SYNDROMES (ACS). INCREASING EVIDENCES SUGGEST THE IMPORTANT ROLE OF MICRORNAS AS EPIGENETIC REGULATORS OF ATHEROSCLEROTIC DISEASE. THE AIM OF OUR STUDY IS TO IDENTIFY IF MICRORNA-223 (MIR-223) TARGETS TF IN ECS. METHODS AND RESULTS: BIOINFORMATIC ANALYSIS SHOWED THAT TF IS A TARGET CANDIDATE OF MIR-223. WESTERN BLOTTING ANALYSIS REVEALED THAT TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) INCREASED TF EXPRESSION IN AORTA OF C57BL/6J MICE AND CULTURED ECS (EA.HY926 CELLS AND HUVEC) AFTER 4 H TREATMENT. IN TNF-ALPHA TREATED ECS, TF MRNA WAS ALSO INCREASED MEASURED BY REAL-TIME PCR. REAL-TIME PCR RESULTS SHOWED THAT MIR-223 LEVELS WERE DOWNREGULATED IN TNF-ALPHA-TREATED AORTA OF C57BL/6J MICE AND CULTURED ECS. TRANSFECTION OF ECS WITH MIR-223 MIMIC OR MIR-223 INHIBITOR MODIFIED TF EXPRESSION BOTH IN MRNA AND PROTEIN LEVELS. LUCIFERASE ASSAYS CONFIRMED THAT MIR-223 SUPPRESSED TF EXPRESSION BY BINDING TO THE SEQUENCE OF TF 3'-UNTRANSLATED REGIONS (3'UTR). TF PROCOAGULANT ACTIVITY WAS INHIBITED BY OVEREXPRESSING MIR-223 WITH OR WITHOUT TNF-ALPHA STIMULATION. CONCLUSIONS: MIR-223-MEDIATED SUPPRESSION OF TF EXPRESSION PROVIDES A NOVEL MOLECULAR MECHANISM FOR THE REGULATION OF COAGULATION CASCADE, AND SUGGESTS A CLUE AGAINST THROMBOGENESIS DURING THE PROCESS OF ATHEROSCLEROTIC PLAQUE RUPTURE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  1848  44 EFFECTS OF VENLAFAXINE ON THE EXPRESSION LEVEL AND METHYLATION STATUS OF GENES INVOLVED IN OXIDATIVE STRESS IN RATS EXPOSED TO A CHRONIC MILD STRESS. RECENT HUMAN AND ANIMAL STUDIES INDICATE THAT OXIDATIVE AND NITROSATIVE STRESS MAY PLAY A ROLE IN THE AETIOLOGY AND PATHOGENESIS OF DEPRESSION. THIS STUDY INVESTIGATES THE EFFECT OF CHRONIC ADMINISTRATION OF THE SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITOR, VENLAFAXINE, ON THE EXPRESSION AND METHYLATION STATUS OF SOD1, SOD2, GPX1, GPX4, CAT, NOS1 AND NOS2 IN THE BRAIN AND BLOOD OF RATS EXPOSED TO A CHRONIC MILD STRESS (CMS) MODEL OF DEPRESSION. SEPARATE GROUPS OF ANIMALS WERE EXPOSED TO CMS FOR 2 OR 7 WEEKS; THE SECOND GROUP RECEIVED SALINE OR VENLAFAXINE (10 MG/KG/D, IP) FOR 5 WEEKS. AFTER COMPLETION OF BOTH STRESS CONDITIONS AND DRUG ADMINISTRATION, THE MRNA AND PROTEIN EXPRESSION OF SELECTED GENES AND THE METHYLATION STATUS OF THEIR PROMOTERS WERE MEASURED IN PERIPHERAL MONONUCLEAR BLOOD CELLS (PBMCS) AND IN BRAIN STRUCTURES (HIPPOCAMPUS, AMYGDALA, HYPOTHALAMUS, MIDBRAIN, CORTEX, BASAL GANGLIA) WITH THE USE OF TAQMAN GENE EXPRESSION ASSAY, WESTERN BLOT AND METHYLATION-SENSITIVE HIGH-RESOLUTION MELTING TECHNIQUES. CMS CAUSED A DECREASE IN SUCROSE CONSUMPTION, AND THIS EFFECT WAS NORMALIZED BY FLUOXETINE. IN PBMCS, SOD1, SOD2 AND NOS2 MRNA EXPRESSION CHANGED ONLY AFTER VENLAFAXINE ADMINISTRATION. IN BRAIN, CAT, GPX1, GPX4 AND NOS1 GENE EXPRESSION CHANGED FOLLOWING CMS OR VENLAFAXINE EXPOSURE, MOST PROMINENTLY IN THE HIPPOCAMPUS, MIDBRAIN AND BASAL GANGLIA. CMS INCREASED THE METHYLATION OF THE GPX1 PROMOTER IN PBMCS, THE SECOND GPX4 PROMOTER IN MIDBRAIN AND BASAL GANGLIA, AND SOD1 AND SOD2 IN HIPPOCAMPUS. THE CMS ANIMALS TREATED WITH VENLAFAXINE DISPLAYED A SIGNIFICANTLY HIGHER CAT LEVEL IN MIDBRAIN AND CEREBRAL CORTEX. CMS CAUSED AN ELEVATION OF GPX4 IN THE HIPPOCAMPUS, WHICH WAS LOWERED IN CEREBRAL CORTEX BY VENLAFAXINE. THE RESULTS INDICATE THAT CMS AND VENLAFAXINE ADMINISTRATION AFFECT THE METHYLATION OF PROMOTERS OF GENES INVOLVED IN OXIDATIVE AND NITROSATIVE STRESS. THEY ALSO INDICATE THAT PERIPHERAL AND CENTRAL TISSUE DIFFER IN THEIR RESPONSE TO STRESS OR ANTIDEPRESSANT TREATMENTS. IT IS POSSIBLE THAT THAT APART FROM DNA METHYLATION, A CRUCIAL ROLE OF EXPRESSION LEVEL OF GENES MAY BE PLAYED BY OTHER FORMS OF EPIGENETIC REGULATION, SUCH AS HISTONE MODIFICATION OR MICRORNA INTERFERENCE. THESE FINDINGS PROVIDE STRONG EVIDENCE FOR THESIS THAT ANALYSIS OF THE LEVEL OF MRNA AND PROTEIN EXPRESSION AS WELL AS THE STATUS OF PROMOTER METHYLATION CAN HELP IN UNDERSTANDING THE PATHOMECHANISMS OF MENTAL DISEASES, INCLUDING DEPRESSION, AND THE MECHANISMS OF ACTION OF DRUGS EFFECTIVE IN THEIR THERAPY.	2020	

12  3456  38 HYPOMETHYLATION OF IL1RN AND NFKB1 GENES IS LINKED TO THE DYSBALANCE IN IL1BETA/IL-1RA AXIS IN FEMALE PATIENTS WITH TYPE 2 DIABETES MELLITUS. INFLAMMATION HAS RECEIVED CONSIDERABLE ATTENTION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS (T2DM). SUPPORTING THIS CONCEPT, ENHANCED EXPRESSION OF INTERLEUKIN (IL)-1BETA AND INCREASED INFILTRATION OF MACROPHAGES ARE OBSERVED IN PANCREATIC ISLETS OF PATIENTS WITH T2DM. ALTHOUGH IL-1 RECEPTOR ANTAGONIST (IL-1RA) PLAYS A MAJOR ROLE IN CONTROLLING OF IL-1BETA-MEDIATED INFLAMMATION, ITS COUNTERACTION EFFECTS AND EPIGENETIC ALTERATIONS IN T2DM ARE LESS STUDIED. THUS, WE AIMED TO ANALYZE THE DNA METHYLATION STATUS IN IL1RN, RELA (P65) AND NFKB1 (P50) GENES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM TREATED T2DM PATIENTS (N = 35) AND AGE-/SEX- MATCHED HEALTHY CONTROLS (N = 31). PRODUCTION OF IL-1BETA AND IL-1RA WAS ANALYZED IN PLASMA AND SUPERNATANTS FROM LPS-INDUCED PBMCS. IMMUNOMODULATORY EFFECTS OF IL-1BETA AND IL-1RA WERE STUDIED ON THP-1 CELLS. AVERAGE DNA METHYLATION LEVEL OF IL1RN AND NFKB1 GENE PROMOTERS WAS SIGNIFICANTLY DECREASED IN T2DM PATIENTS IN COMPARISON WITH HEALTHY CONTROLS (P< 0.05), WHICH WAS ASSOCIATED WITH THE INCREASED IL-1RA (P< 0.001) AND IL-1BETA (P = 0.039) PLASMA LEVELS IN T2DM PATIENTS. NEGATIVE ASSOCIATION BETWEEN AVERAGE METHYLATION OF IL1RN GENE AND IL-1RA PLASMA LEVELS WERE OBSERVED IN FEMALE T2DM PATIENTS. METHYLATION OF NFKB1 GENE WAS NEGATIVELY CORRELATED WITH IL-1RA LEVELS IN THE PATIENTS AND POSITIVELY WITH IL-1BETA LEVELS IN FEMALE PATIENTS. LPS-STIMULATED PBMCS FROM FEMALE PATIENTS FAILED TO RAISE IL-1BETA PRODUCTION, WHILE THE CELLS FROM HEALTHY FEMALES INCREASED IL-1BETA PRODUCTION IN COMPARISON WITH UNSTIMULATED CELLS (P< 0.001). TAKEN TOGETHER, THE FINDINGS SUGGEST THAT HYPOMETHYLATION OF IL1RN AND NFKB1 GENE PROMOTERS MAY PROMOTE THE INCREASED IL-1BETA/IL-1RA PRODUCTION AND REGULATE CHRONIC INFLAMMATION IN T2DM. FURTHER STUDIES ARE NECESSARY TO ELUCIDATE THE CAUSAL DIRECTION OF THESE ASSOCIATIONS AND POTENTIAL ROLE OF IL-1RA IN ANTI-INFLAMMATORY PROCESSES IN TREATED PATIENTS WITH T2DM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13  4836  38 ONCOGENIC FUNCTIONS OF THE TRANSCRIPTION FACTOR NRF2. NUCLEAR FACTOR E2-RELATED FACTOR 2 (NRF2) IS A TRANSCRIPTION FACTOR THAT CONTROLS THE EXPRESSION OF A LARGE POOL OF ANTIOXIDANT AND CYTOPROTECTIVE GENES REGULATING THE CELLULAR RESPONSE TO OXIDATIVE AND ELECTROPHILIC STRESS. NRF2 IS NEGATIVELY REGULATED BY KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (KEAP1) AND, UPON STIMULATION BY AN OXIDATIVE OR ELECTROPHILIC INSULT, IS RAPIDLY ACTIVATED BY PROTEIN STABILIZATION. OWING TO ITS CYTOPROTECTIVE FUNCTIONS, NRF2 HAS BEEN TRADITIONALLY STUDIED IN THE FIELD OF CHEMOPREVENTION; HOWEVER, THERE IS ACCUMULATED EVIDENCE THAT KEAP1/NRF2 MUTATIONS OR UNBALANCED REGULATION THAT LEADS TO OVEREXPRESSION OR HYPERACTIVATION OF NRF2 MAY PARTICIPATE IN TUMORIGENESIS AND BE INVOLVED IN CHEMORESISTANCE OF A WIDE NUMBER OF SOLID CANCERS AND LEUKEMIAS. IN ADDITION TO PROTECTING CELLS FROM REACTIVE OXYGEN SPECIES, NRF2 SEEMS TO PLAY A DIRECT ROLE IN CELL GROWTH CONTROL AND IS RELATED TO APOPTOSIS-REGULATING PATHWAYS. MOREOVER, NRF2 ACTIVITY IS CONNECTED WITH ONCOGENIC KINASE PATHWAYS, STRUCTURAL PROTEINS, HORMONAL REGULATION, OTHER TRANSCRIPTION FACTORS, AND EPIGENETIC ENZYMES INVOLVED IN THE PATHOGENESIS OF VARIOUS TYPES OF TUMORS. THE AIM OF THIS REVIEW IS TO COMPILE AND SUMMARIZE EXISTING KNOWLEDGE OF THE ONCOGENIC FUNCTIONS OF NRF2 TO PROVIDE A SOLID BASIS FOR ITS POTENTIAL USE AS A MOLECULAR MARKER AND PHARMACOLOGICAL TARGET IN CANCER.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  5868  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  4899  50 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  5764  37 SORAFENIB ATTENUATES FIBROTIC HEPATIC INJURY THROUGH MEDIATING LYSINE CROTONYLATION. BACKGROUND: LIVER FIBROSIS IS AN INDEPENDENT CONTRIBUTOR OF CHRONIC LIVER DISEASES, AND REGRESSING LIVER FIBROSIS IS CONSIDERED A POTENTIAL THERAPEUTIC TARGET FOR CHRONIC LIVER DISEASES. WE AIMED TO EXPLORE THE EFFECTS AND MECHANISM OF SORAFENIB IN LIVER FIBROSIS. METHODS: MALE SPRAGUE DAWLEY (SD) RATS WERE SUBJECTED TO SUBCUTANEOUS INJECTION OF CARBON TETRACHLORIDE (CCL(4)) FOR 8 WEEKS TO INDUCE LIVER FIBROSIS AND THEN TREATED WITH SORAFENIB. THE DEGREE OF LIVER FIBROSIS WAS ANALYZED BY HEMATOXYLIN-EOSIN (H&E) STAINING, MASSON STAINING, AND PICROSIRIUS RED (PSR) STAINING. SERUM BIOCHEMICAL INDEXES WERE DETECTED BY FULLY AUTOMATIC BIOCHEMICAL ANALYZER OR ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA). QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR) WAS PERFORMED TO DETECT THE EXPRESSION OF PRO-FIBROTIC GENES. IMMUNOHISTOCHEMICAL STAINING AND WESTERN BLOTTING WERE CARRIED OUT TO EVALUATE THE LEVELS OF LYSINE CROTONYLATION. RESULTS: LIVER INDEX WAS REDUCED WITH ORAL SORAFENIB IN CCL(4)-INDUCED RATS. SERUM LIVER FUNCTION (ALANINE AMINOTRANSFERASE (ALT), ASPARTATE AMINOTRANSFERASE (AST), AND TOTAL BILIRUBIN (TBIL)) AND FIBROSIS INDICATORS (TYPE III PROCOLLAGEN (PC-III), HYALURONIC ACID (HA), AND LAMININ (LN)) WERE ATTENUATED WITH SORAFENIB TREATMENT. SORAFENIB IMPROVED THE HEPATIC STRUCTURE AND FIBROTIC PROGRESSION. THE EXPRESSION OF FIBROSIS-RELATED GENES WAS REMARKELY REDUCED WITH SORAFENIB TREATMENT. MEANWHILE, SORAFENIB INHIBITED ALPHA-SMA AND COLLAGEN I CUMULATION INDUCED BY CCL(4) INJECTION. BESIDES, PROTEIN LYSINE CROTONYLATION ESPECIALLY THE CROTONYLATED H2BK12 (H2BK12CR) AND CROTONYLATED H3K18 (H3K18CR) WERE REVERSED BY SORAFENIB, WHICH WERE DECREASED IN RESPONSE TO CCL(4) TREATMENT. SPEARMAN CORRELATION ANALYSIS SHOWN LYSINE CROTONYLATION EXPRESSION WAS NEGATIVELY CORRELATED WITH SERUM FIBROTIC INDICATORS. CONVERSELY, CROTONYLATION-REGULATED ENZYMES, WHICH NEGATIVELY REGULATE PROTEIN CROTONYLATION, WERE INCREASED IN RESPONSE TO CCL(4) TREATMENT, WHILE SORAFENIB REDUCED THEIR EXPRESSION. CONCLUSION: SORAFENIB EXERTS SIGNIFICANT ANTI-FIBROTIC EFFECTS THROUGH MEDIATING CROTONYLATION-REGULATED ENZYMES AND PROTEIN CROTONYLATION IN FIBROTIC RATS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                            
17  3447  55 HYPERMETHYLATION OF MITOCHONDRIAL TRANSCRIPTION FACTOR A INDUCED BY CIGARETTE SMOKE IS ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. PURPOSE OF THE STUDY: CIGARETTE SMOKING IS A LEADING ENVIRONMENTAL CONTRIBUTOR TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BUT ITS EPIGENETIC REGULATION OF MTTFA GENE REMAINS ELUSIVE. THIS STUDY AIMS TO EXPLORE THE RELATIONSHIP OF DNA METHYLATION OF MTTFA AND CIGARETTE SMOKING IN COPD. MATERIALS AND METHODS: WE ANALYZED DNA METHYLATION ON MTTFA PROMOTERS IN CLINICAL SAMPLES FROM COPD PATIENTS AND SUBJECTS WITH NORMAL PULMONARY FUNCTION. EXPRESSION OF MTTFA MRNA IN THE CLINICAL SAMPLES AND MTTFA MRNA AND PROTEIN IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS(HUVECS) TREATED WITH CIGARETTE SMOKE EXTRACT (CSE) WAS EVALUATED. MTTFA MRNA AND PROTEIN LEVELS WERE MEASURED TO DETERMINE EFFECTS OF DEMETHYLATION AGENTS ON CSE-TREATED HUVECS. RESULTS: THE DNA METHYLATION LEVEL OF THE MTTFA PROMOTER WAS SIGNIFICANTLY INCREASED IN COPD GROUP. EXPRESSION OF MTTFA MRNA WAS DOWNREGULATED IN THE LUNGS AS A CONSEQUENCE OF HYPERMETHYLATION OF MTTFA PROMOTER. EXPRESSION OF MTTFA MRNA AND PROTEIN WAS DOWNREGULATED IN CSE-TREATED HUVECS AS A CONSEQUENCE OF HYPERMETHYLATION OF THE MTTFA PROMOTER. MTTFA EXPRESSION IN CSE-TREATED HUVECS WAS RESTORED BY THE METHYLATION INHIBITOR, 5-AZA-2'-DEOXYCYTIDINE(AZA). CONCLUSIONS: CIGARETTE SMOKE-INDUCED HYPERMETHYLATION OF THE MTTFA PROMOTER IS RELATED TO THE INITIATION AND PROGRESSION OF COPD. OUR FINDING MAY PROVIDE A NEW STRATEGY FOR THE INTERVENTION OF COPD BY DEVELOPING DEMETHYLATION AGENTS TARGETING MTTFA HYPERMETHYLATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
18  2784  34 EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. PULPITIS IS A COMPLICATED CHRONIC INFLAMMATORY PROCESS WHICH CAN BE IN A DYNAMIC BALANCE BETWEEN DAMAGE AND REPAIR. THE EXTRACELLULAR MATRIX PLAYS AN IMPORTANT REGULATORY ROLE IN WOUND HEALING AND TISSUE REPAIR. THE AIM OF THIS STUDY WAS TO EXPLORE THE ROLE OF THE EPIGENETIC MARK, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) ON THE DEGRADATION OF EXTRACELLULAR MATRIX DURING PULPITIS. QUANTITATIVE POLYMERASE CHAIN REACTION WAS USED TO ASSESS THE EXPRESSION OF MATRIX METALLOPROTEINASES (MMPS) AND TYPE I COLLAGEN IN HUMAN DENTAL PULP CELLS (HDPCS) UPON EZH2 AND EI1 (EZH2 INHIBITOR) STIMULATION. THE MECHANISM OF EZH2 AFFECTING EXTRACELLULAR MATRIX WAS EXPLORED THROUGH QUANTITATIVE POLYMERASE CHAIN REACTION AND WESTERN BLOT. A RAT MODEL OF DENTAL PULP INFLAMMATION WAS ESTABLISHED, AND THE EXPRESSION OF TYPE I COLLAGEN IN DENTAL PULP UNDER EZH2 STIMULATION WAS DETECTED BY IMMUNOHISTOCHEMICAL STAINING. EZH2 UPREGULATED THE EXPRESSION OF MMP-1, MMP-3, MMP-8, AND MMP-10 AND DECREASED THE PRODUCTION OF TYPE I COLLAGEN IN HDPCS, WHILE EI1 HAD THE OPPOSITE EFFECT. EZH2 ACTIVATED THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN HDPCS, THE INHIBITION OF WHICH REVERSED THE INDUCTION OF MMPS AND THE SUPPRESSION OF TYPE I COLLAGEN. EZH2 CAN DOWNREGULATE THE TYPE I COLLAGEN LEVELS IN AN EXPERIMENTAL MODEL OF DENTAL PULPITIS IN RATS. EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. EZH2 CAN DECREASE THE TYPE I COLLAGEN LEVELS IN VIVO AND IN VITRO.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19  5760  51 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20  5052  32 PHARMACOLOGICAL TARGETING OF HEME OXYGENASE-1 IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGING-ASSOCIATED DISEASE THAT CLINICALLY MANIFESTS AS JOINT PAIN, MOBILITY LIMITATIONS, AND COMPROMISED QUALITY OF LIFE. TODAY, OA TREATMENT IS LIMITED TO PAIN MANAGEMENT AND JOINT ARTHROPLASTY AT THE LATER STAGES OF DISEASE PROGRESSION. OA PATHOGENESIS IS PREDOMINANTLY MEDIATED BY OXIDATIVE DAMAGE TO JOINT CARTILAGE EXTRACELLULAR MATRIX AND LOCAL CELLS SUCH AS CHONDROCYTES, OSTEOCLASTS, OSTEOBLASTS, AND SYNOVIAL FIBROBLASTS. UNDER NORMAL CONDITIONS, CELLS PREVENT THE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) UNDER OXIDATIVELY STRESSFUL CONDITIONS THROUGH THEIR ADAPTIVE CYTOPROTECTIVE MECHANISMS. HEME OXYGENASE-1 (HO-1) IS AN IRON-DEPENDENT CYTOPROTECTIVE ENZYME THAT FUNCTIONS AS THE INDUCIBLE FORM OF HO. HO-1 AND ITS METABOLITES CARBON MONOXIDE AND BILIVERDIN CONTRIBUTE TOWARDS THE MAINTENANCE OF REDOX HOMEOSTASIS. HO-1 EXPRESSION IS PRIMARILY REGULATED AT THE TRANSCRIPTIONAL LEVEL THROUGH TRANSCRIPTIONAL FACTOR NUCLEAR FACTOR ERYTHROID 2 (NF-E2)-RELATED FACTOR 2 (NRF2), SPECIFICITY PROTEIN 1 (SP1), TRANSCRIPTIONAL REPRESSOR BTB-AND-CNC HOMOLOGY 1 (BACH1), AND EPIGENETIC REGULATION. SEVERAL STUDIES REPORT THAT HO-1 EXPRESSION CAN BE REGULATED USING VARIOUS ANTIOXIDATIVE FACTORS AND CHEMICAL COMPOUNDS, SUGGESTING THERAPEUTIC IMPLICATIONS IN OA PATHOGENESIS AS WELL AS IN THE WIDER CONTEXT OF JOINT DISEASE. HERE, WE REVIEW THE PROTECTIVE ROLE OF HO-1 IN OA WITH A FOCUS ON THE REGULATORY MECHANISMS THAT MEDIATE HO-1 ACTIVITY.	2021