1  3722 188 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  1596  70 DNA METHYLATION REDUCES THE YES-ASSOCIATED PROTEIN 1/WW DOMAIN CONTAINING TRANSCRIPTION REGULATOR 1 PATHWAY AND PREVENTS PATHOLOGIC REMODELING DURING BLADDER OBSTRUCTION BY LIMITING EXPRESSION OF BDNF. CHRONIC BLADDER OBSTRUCTION AND BLADDER SMOOTH MUSCLE CELL (SMC) STRETCH PROVIDE FIBROTIC AND MECHANICAL ENVIRONMENTS THAT CAN LEAD TO EPIGENETIC CHANGE. THEREFORE, WE EXAMINED THE ROLE OF DNA METHYLATION IN BLADDER PATHOLOGY AND TRANSCRIPTIONAL CONTROL. SPRAGUE-DAWLEY FEMALE RATS UNDERWENT PARTIAL BLADDER OBSTRUCTION BY LIGATION OF A SILK SUTURE AROUND THE PROXIMAL URETHRA NEXT TO A 0.9-MM STEEL ROD. SHAM OPERATION COMPRISED PASSING THE SUTURE AROUND THE URETHRA. AFTER 2 WEEKS, RATS WERE RANDOMIZED TO NORMAL SALINE OR DNA METHYLTRANSFERASE INHIBITOR, 5-AZA-2-DEOXYCYTIDINE (DAC) AT 1 MG/KG, THREE TIMES/WEEK INTRAPERITONEALLY. AFTER 6 WEEKS, BLADDERS WERE WEIGHED AND DIVIDED FOR HISTOLOGY AND RNA ANALYSIS BY HIGH-THROUGHPUT REAL-TIME QUANTITATIVE PCR ARRAYS. DAC TREATMENT DURING OBSTRUCTION IN VIVO PROFOUNDLY AUGMENTED BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION COMPARED WITH THE OBSTRUCTION WITH VEHICLE GROUP, WHICH WAS STATISTICALLY CORRELATED WITH PATHOPHYSIOLOGIC PARAMETERS. BDNF, CYSTEINE RICH ANGIOGENIC INDUCER 61 (CYR61), AND CONNECTIVE TISSUE GROWTH FACTOR (CTGF) EXPRESSION CLUSTERED TIGHTLY TOGETHER USING PEARSON'S CORRELATION ANALYSIS. THEIR PROMOTERS WERE ASSOCIATED WITH THE TEA DOMAIN FAMILY MEMBER 1 (TEAD1) AND YES-ASSOCIATED PROTEIN 1/WW DOMAIN CONTAINING TRANSCRIPTION REGULATOR 1 PATHWAYS. INTERESTINGLY, DAC TREATMENT INCREASED BDNF EXPRESSION IN BLADDER SMCS (P < 0.0002). STRETCH-INDUCED BDNF WAS INHIBITED BY THE YAP/WWTR1 INHIBITOR VERTEPORFIN. VERTEPORFIN IMPROVED THE SMC PHENOTYPE (PROLIFERATIVE MARKERS AND SMC MARKER EXPRESSION), IN PART BY REDUCING BDNF. EXPRESSION OF BDNF IS LIMITED BY DNA METHYLATION AND ASSOCIATED WITH PATHOPHYSIOLOGIC CHANGES DURING PARTIAL BLADDER OUTLET OBSTRUCTION AND SMC PHENOTYPIC CHANGE IN VITRO.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3  2779  77 EZH2 AND MATRIX CO-REGULATE PHENOTYPE AND KCNB2 EXPRESSION IN BLADDER SMOOTH MUSCLE CELLS. BACKGROUND: PARTIAL BLADDER OUTLET OBSTRUCTION (PBO) IS A WIDESPREAD CAUSE OF URINARY DYSFUNCTION AND PATIENT DISCOMFORT, RESULTING IN IMMENSE HEALTH CARE COSTS. PREVIOUSLY, WE FOUND THAT OBSTRUCTION IS ASSOCIATED WITH ALTERED REGULATION OF EPIGENETIC MACHINERY AND ALTERED FUNCTION. HERE WE EXAMINED IF PBO AND CHRONIC BLADDER OBSTRUCTIVE DISEASE (COBD) AFFECT EPIGENETIC MARKS IN A PROOF OF PRINCIPLE GENE AND EXPLORED MECHANISMS OF ITS EPIGENETIC REGULATION USING IN VITRO MODELS. METHODS: ARCHIVAL OBSTRUCTION TISSUES FROM COBD HAD BEEN CREATED IN 200-250 G FEMALE SPRAGUE-DAWLEY RATS BY SURGICAL LIGATION OF THE URETHRA FOR 6 WEEKS, FOLLOWED BY REMOVAL OF THE SUTURE AND FOLLOWING ANIMALS FOR 6 MORE WEEKS. OBSTRUCTION (PBO) IS THE 6-WEEK LIGATION ONLY. SHAM LIGATIONS COMPRISE PASSING THE SUTURE BEHIND THE URETHRA. HISTONE3 LYSINE27 TRIMETHYLATION (H3K27ME3) WAS STUDIED BY IMMUNOSTAINING AND CHROMATIN IMMUNOPRECIPITATION (CHIP)/PCR. THE INTERACTION OF MATRIX WITH KCNB2 REGULATION WAS STUDIED IN HUMAN BLADDER SMC PLATED ON DAMAGED MATRIX AND NATIVE COLLAGEN AND TREATED WITH VEHICLE OR UNC1999. CELLS WERE ANALYZED BY IMMUNOSTAINING FOR CELL PHENOTYPE, AND WESTERN BLOTTING FOR KCNB2, H3K27ME3 AND EZH2. EFFECTS OF CONDITIONED MEDIA FROM THESE CELLS WERE ALSO EXAMINED ON CELL PHENOTYPE. SIRNA AGAINST KCNB2 WAS EXAMINED FOR EFFECTS ON CELL PHENOTYPE AND GENE EXPRESSION BY RT-QPCR. RESULTS: H3K27ME3 INCREASED BY IMMUNOFLUORESCENCE DURING PBO, AND BY CHIP/PCR DURING COBD IN THE CPG ISLAND (CGI) AS WELL AS 350 BP UPSTREAM. OBSTRUCTION VS. SHAM ALSO SHOWED AN INCREASE IN H3K27ME3 DEPOSITION. IN SMC IN VITRO, EZH2 INHIBITION RESTORED KCNB2 EXPRESSION AND PARTIALLY RESTORED SMC PHENOTYPE. CONCLUSIONS: REGULATION OF KCNB2 AT THE PROMOTER DEMONSTRATED DYNAMIC CHANGES IN H3K27ME3 DURING COBD AND OBSTRUCTION. IN VITRO MODELS SUGGEST THAT MATRIX PLAYS A ROLE IN REGULATION OF EZH2, H3K27ME3 AND KCNB2, WHICH MAY PLAY A ROLE IN THE REGULATION OF SMOOTH MUSCLE PHENOTYPE IN VIVO.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4  5716  30 SIRT6 PROTECTS VASCULAR SMOOTH MUSCLE CELLS FROM OSTEOGENIC TRANSDIFFERENTIATION VIA RUNX2 IN CHRONIC KIDNEY DISEASE. VASCULAR CALCIFICATION (VC) IS REGARDED AS AN IMPORTANT PATHOLOGICAL CHANGE LACKING EFFECTIVE TREATMENT AND ASSOCIATED WITH HIGH MORTALITY. SIRTUIN 6 (SIRT6) IS A MEMBER OF THE SIRTUIN FAMILY, A CLASS III HISTONE DEACETYLASE AND A KEY EPIGENETIC REGULATOR. SIRT6 HAS A PROTECTIVE ROLE IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD). HOWEVER, THE EXACT ROLE AND MOLECULAR MECHANISM OF SIRT6 IN VC IN PATIENTS WITH CKD REMAIN UNCLEAR. HERE, WE DEMONSTRATED THAT SIRT6 WAS MARKEDLY DOWNREGULATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND IN THE RADIAL ARTERY TISSUE OF PATIENTS WITH CKD WITH VC. SIRT6-TRANSGENIC (SIRT6-TG) MICE SHOWED ALLEVIATED VC, WHILE VASCULAR SMOOTH MUSCLE CELL-SPECIFIC (VSMC-SPECIFIC) SIRT6 KNOCKED-DOWN MICE SHOWED SEVERE VC IN CKD. SIRT6 SUPPRESSED THE OSTEOGENIC TRANSDIFFERENTIATION OF VSMCS VIA REGULATION OF RUNT-RELATED TRANSCRIPTION FACTOR 2 (RUNX2). COIMMUNOPRECIPITATION (CO-IP) AND IMMUNOPRECIPITATION (IP) ASSAYS CONFIRMED THAT SIRT6 BOUND TO RUNX2. MOREOVER, RUNX2 WAS DEACETYLATED BY SIRT6 AND FURTHER PROMOTED NUCLEAR EXPORT VIA EXPORTIN 1 (XPO1), WHICH IN TURN CAUSED DEGRADATION OF RUNX2 THROUGH THE UBIQUITIN-PROTEASOME SYSTEM. THESE RESULTS DEMONSTRATED THAT SIRT6 PREVENTED VC BY SUPPRESSING THE OSTEOGENIC TRANSDIFFERENTIATION OF VSMCS, AND AS SUCH TARGETING SIRT6 MAY BE AN APPEALING THERAPEUTIC TARGET FOR VC IN CKD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5  1800  26 EFFECT OF HISTONE DEACETYLASE INHIBITOR ON ETHANOL WITHDRAWAL-INDUCED HYPERALGESIA IN RATS. BACKGROUND: INCREASED PAIN SENSITIVITY IS OBSERVED FOLLOWING ALCOHOL WITHDRAWAL, AND ATTEMPTS TO ALLEVIATE THIS HYPERALGESIA CAN CONTRIBUTE TO THE CYCLE OF ADDICTION. THE AIM OF THIS STUDY WAS TO DETERMINE IF ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA WAS OBSERVED IN A CHRONIC ETHANOL EXPOSURE MODEL AND IF THIS PAIN WAS AFFECTED BY HISTONE DEACETYLASE INHIBITORS, THUS REVEALING AN EPIGENETIC MECHANISM. METHODS: ADULT MALE SPRAGUE DAWLEY RATS RECEIVED LIEBER-DECARLI LIQUID CONTROL OR ETHANOL (9% V/V) DIET FOR 15 DAYS. MECHANICAL SENSITIVITY WAS MEASURED WITH VON FREY HAIR STIMULATION OF THE HINDPAW DURING ETHANOL ADMINISTRATION AND 24- AND 72-HOUR WITHDRAWAL. RESULTS: ETHANOL WITHDRAWAL PRODUCED SEVERE AND SUSTAINED MECHANICAL HYPERALGESIA, AN EFFECT NOT OBSERVED IN THE CONTROL OR ETHANOL-MAINTAINED GROUPS. FURTHERMORE, THIS HYPERALGESIA WAS ATTENUATED BY THE HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID TREATMENT. CONCLUSIONS: HEIGHTENED PAIN SENSITIVITY WAS OBSERVED FOLLOWING WITHDRAWAL FROM CHRONIC ETHANOL EXPOSURE, AND HISTONE DEACETYLASE INHIBITORS COULD BE NOVEL TREATMENTS FOR THIS ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6  4579  31 N(6)-METHYLADENOSINE METHYLASE METTL3 CONTRIBUTES TO NEUROPATHIC PAIN BY EPIGENETIC SILENCING OF MU OPIOID RECEPTOR. WE AIMED AT EXPLORING THE ROLE AND MECHANISM OF METTL3-MEDIATED M(6)A MODIFICATION IN NEUROPATHIC PAIN. MALE SPRAGUE-DAWLEY RATS WERE RANDOMLY DIVIDED INTO FOUR GROUPS: SHAM OPERATION GROUP (SHAM GROUP), CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE MODEL GROUP (NPP GROUP), INTRATHECAL INJECTION OF VIRUS DOWN-REGULATED METTL3 + CCI MODEL GROUP (M3 + NPP GROUP) AND INTRATHECAL INJECTION OF NEGATIVE CONTROL VIRUS + CCI MODEL GROUP (SCR + NPP GROUP). THE M3 + NPP GROUP AND THE SCR + NPP GROUP WERE INTRATHECALLY INJECTED WITH VIRUS NINETEEN DAYS BEFORE OPERATION. THE PAW WITHDRAWAL MECHANICAL THRESHOLDS AND PAW WITHDRAWAL LATENCY WERE RESPECTIVELY RECORDED ONE DAY BEFORE OPERATION, THREE DAYS, FIVE DAYS AND SEVEN DAYS AFTER OPERATION. THE RATS WERE SACRIFICED ON THE SEVENTH DAY AFTER OPERATION, AND THEIR SPINAL CORD TISSUES WERE TAKEN. THE FROZEN SECTIONS OF RATS WERE PERFORMED TO OBSERVE THE EXPRESSION OF GREEN FLUORESCENT PROTEIN OF THE VIRUS. THE METHYLATION LEVEL OF RNA, THE PROTEIN EXPRESSION OF M(6)A-RELATED ENZYME (METTL3) AND MU OPIOID RECEPTOR (MOR) IN SPINAL CORD TISSUES OF THE FOUR GROUPS WERE MEASURED. DOWNREGULATION OF METTL3 HAD NO EFFECT ON THE OVERALL METHYLATION LEVEL OF THE SPINAL CORD, BUT IT COULD REGULATE THE METHYLATION LEVEL OF THE OPRM1 GENE RNA ENCODING MOR, PARTIALLY RESTORE THE EXPRESSION OF MOR, AND RELIEVE PAIN IN RATS. IN THE PROCESS OF NPP, METTL3 MAY INHIBIT THE EXPRESSION OF MOR BY REGULATING THE METHYLATION LEVEL OF OPRM1 GENE RNA ENCODING MOR, AND ULTIMATELY PROMOTE THE OCCURRENCE AND DEVELOPMENT OF NPP.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  2326  35 EPIGENETIC REGULATION OF HOTAIR IN ADVANCED CHRONIC MYELOID LEUKEMIA. PURPOSE: CHRONIC MYELOID LEUKEMIA (CML) ACCOUNTS FOR ~10% OF LEUKEMIA CASES, AND ITS PROGRESSION INVOLVES EPIGENETIC GENE REGULATION. THIS STUDY INVESTIGATED EPIGENETIC REGULATION OF HOTAIR AND ITS TARGET MICRORNA, MIR-143, IN ADVANCED CML. PATIENTS AND METHODS: WE FIRST ISOLATED BONE MARROW MONONUCLEAR CELLS FROM 70 PATIENTS WITH DIFFERENT PHASES OF CML AND FROM HEALTHY DONORS AS NORMAL CONTROL; WE ALSO CULTURED K562 AND KCL22 CELLS, TREATED WITH DEMETHYLATION DRUG; MTT ASSAY, FLOW CYTOMETRY, QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR), METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), WESTERN BLOT, LUCIFERASE ASSAY, RNA PULL-DOWN ASSAY AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION (RIP) ASSAY WERE PERFORMED. RESULT: AS MEASURED BY QPCR, HOTAIR EXPRESSION IN K562 CELLS, KCL22 CELLS, AND SAMPLES FROM CASES OF ADVANCED-STAGE CML INCREASED WITH LEVELS OF SEVERAL DNA METHYLTRANSFERASES AND HISTONE DEACETYLATES, INCLUDING DNMT1, DNMT3A, HDAC1, EZH2, AND LSD1, AND MIR-143 LEVELS WERE DECREASED AND HOTAIR LEVELS WERE INCREASED. TREATMENT WITH 5-AZACYTIDINE, A DNA METHYLATION INHIBITOR, DECREASED DNMT1, DNMT3A, HDAC1, EZH2, LSD1 MRNA, PROTEIN LEVELS, AND HOTAIR MRNA LEVELS BUT INCREASED MIR-143 LEVELS. HOTAIR KNOCKDOWN AND MIR-143 OVEREXPRESSION BOTH INHIBITED PROLIFERATION AND PROMOTED APOPTOSIS IN KCL22 AND K562 CELLS THROUGH THE PI3K/AKT PATHWAY. RNA PULL-DOWN, MASS SPECTROMETRY, AND RIP ASSAYS SHOWED THAT HOTAIR INTERACTED WITH EZH2 AND LSD1. A DUAL-LUCIFERASE ASSAY DEMONSTRATED THAT HOTAIR INTERACTED WITH MIR-143. CONCLUSION: OUR FINDINGS DEMONSTRATE THE KEY EPIGENETIC INTERACTIONS OF HOTAIR RELATED TO CML PROGRESSION AND SUGGEST HOTAIR AS A POTENTIAL THERAPEUTIC TARGET FOR ADVANCED CML. FURTHERMORE, OUR RESULTS SUPPORT THE USE OF DEMETHYLATION DRUGS AS A CML TREATMENT STRATEGY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8  6456  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9  6612  29 ULTRA-LOW-DOSE NALOXONE ENHANCES THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN PTX-TREATED RATS: REGULATION ON GLOBAL HISTONE METHYLATION. OBJECTIVE: EPIGENETIC REPROGRAMMING MAY HAVE A POSSIBLE ROLE IN NEUROPATHIC PAIN DEVELOPMENT; THE PRESENT STUDY EXAMINED THE GLOBAL PATTERNS OF LYSINE HISTONE MODIFICATION. IN THIS SERIAL STUDY WE ANALYZED THE LEVELS OF HISTONE 3 LYSINE 4 MONOMETHYLATION, HISTONE 3 LYSINE 4 DIMETHYLATION, AND HISTONE 3 LYSINE 9 TRIMETHYLATION IN PERTUSSIS TOXIN (PTX)-INDUCED THERMAL HYPERALGESIC RAT SPINAL CORDS. METHODS: MALE WISTAR RATS IMPLANTED WITH AN INTRATHECAL CATHETER RECEIVED A SINGLE INTRATHECAL PTX (1 MUG IN 5 MUL SALINE) INJECTION. FOUR DAYS LATER, THEY WERE RANDOMLY ASSIGNED TO RECEIVE EITHER A SINGLE INJECTION OF SALINE, OR ULTRA-LOW-DOSE NALOXONE (15 NG IN 5 MUL SALINE), FOLLOWED BY MORPHINE (10 MUG IN 5 MUL SALINE) INJECTION 30 MINUTES LATER. RESULTS: THE RESULTS SHOWED THAT PTX INJECTION INDUCED THERMAL HYPERALGESIA AND SIGNIFICANT INCREASE OF GLOBAL HISTONE METHYLATION IN THE SPINAL CORDS. INTRATHECAL MORPHINE ALONE DID NOT AFFECT THE THERMAL HYPERALGESIA AND GLOBAL HISTONE METHYLATION. IN CONTRAST, INTRATHECAL ADMINISTRATION OF ULTRA-LOW-DOSE NALOXONE PLUS MORPHINE SIGNIFICANTLY ATTENUATED THE PTX-INDUCED THERMAL HYPERALGESIA AND DOWN-REGULATED THE GLOBAL HISTONE METHYLATION. CONCLUSION: THE RESULTS SUGGEST THAT ULTRA-LOW-DOSE NALOXONE MIGHT BE CLINICAL VALUABLE FOR NEUROPATHIC PAIN MANAGEMENT VIA REGULATING GLOBAL HISTONE MODIFICATION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10  3868  38 JMJD6 EXERTS FUNCTION IN NEUROPATHIC PAIN BY REGULATING NF?KAPPAB FOLLOWING PERIPHERAL NERVE INJURY IN RATS. TREATMENT OF NEUROPATHIC PAIN (NPP) CONTINUES TO BE A MAJOR CHALLENGE, AND THE UNDERLYING MECHANISMS REMAIN TO BE ELUCIDATED. PREVIOUS STUDIES HAVE DEMONSTRATED THAT HISTONE METHYLATION IS IMPORTANT IN SYNAPTIC PLASTICITY OF THE NERVOUS SYSTEM AND MAY AFFECT NUCLEAR FACTOR?KAPPAB (NF?KAPPAB) SIGNALING THROUGH EPIGENETIC MECHANISMS. THE PRESENT STUDY AIMED TO INVESTIGATE THE ROLE OF JUMONJI C DOMAIN 6 (JMJD6), A HISTONE DEMETHYLASE, IN A CHRONIC CONSTRICTION INJURY (CCI) MODEL OF NPP. ON THE THIRD DAY POST?CCI SURGERY, A JMJD6 OVEREXPRESSING LENTIVIRAL VECTOR (LV?JMJD6) WAS INTRATHECALLY INJECTED IN THE RATS. MECHANICAL WITHDRAWAL THRESHOLD AND THERMAL WITHDRAWAL LATENCY WERE ASSESSED PRIOR SURGERY AND ON DAYS 3, 7, 10 AND 14 POST?CCI. THE RESULTS SHOWED THAT INTRATHECAL INJECTION WITH THE LV?JMJD6 ATTENUATED CCI?INDUCED PAIN FACILITATION. THE EXPRESSION OF JMJD6 WAS LOWER FOLLOWING CCI SURGERY, AND ITS EXPRESSION WAS SIGNIFICANTLY INCREASED FOLLOWING INTRATHECAL INJECTION WITH LV?JMJD6, COMPARED WITH LEVELS IN NORMAL SALINE (NS)? AND NEGATIVE CONTROL LENTIVIRAL VECTOR (NC)?TREATED RATS. THE EXPRESSION OF SPINAL NF?KAPPAB PHOSPHORYLATED (P?)P65 SUBUNIT AND ITS DOWNSTREAM PAIN?ASSOCIATED EFFECTORS, INCLUDING INTERLEUKIN 1BETA (IL?1BETA), TUMOR NECROSIS FACTOR?ALPHA (TNF?ALPHA) AND VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), WERE INCREASED FOLLOWING CCI SURGERY. INTRATHECAL INJECTION WITH LV?JMJD6 SUPPRESSED ACTIVATION OF THE P?P65 SUBUNIT IN CCI RATS. IN ADDITION, EXPRESSION LEVELS OF ITS DOWNSTREAM EFFECTORS IL?1BETA, TNF?ALPHA AND VEGF WERE ATTENUATED BY INTRATHECAL TREATMENT WITH LV?JMJD6, COMPARED WITH THOSE IN THE NS? AND NC?TREATED CCI RATS. FURTHERMORE, THE JMJD6? AND P65?IMMUNOREACTIVE CELLS OVERLAPPED IN THE SPINAL DORSAL HORN, HOWEVER, CO?IMMUNOPRECIPITATION SHOWED THAT JMJD6 AND THE NF?KAPPAB P65 SUBUNIT DID NOT DIRECTLY INTERACT, INDICATING OTHER FUNCTIONAL CONNECTIONS MAY EXIST BETWEEN THESE FACTORS FOLLOWING CCI SURGERY. COLLECTIVELY, THESE FINDINGS INDICATED AN IMPORTANT MECHANISM UNDERLYING THE PATHOGENESIS OF NPP. JMJD6 MAY EXERT ITS THERAPEUTIC FUNCTION IN NPP BY REGULATING NF?KAPPAB FOLLOWING CCI.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11  1826  37 EFFECTS OF HISTONE DEACETYLASE INHIBITOR ON EXTRACELLULAR MATRIX PRODUCTION IN HUMAN NASAL POLYP ORGAN CULTURES. BACKGROUND: NASAL POLYPOSIS IS ASSOCIATED WITH A CHRONIC INFLAMMATORY CONDITION OF THE SINONASAL MUCOSA AND INVOLVES MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX (ECM) ACCUMULATION. EPIGENETIC MODULATION BY HISTONE DEACETYLASE (HDAC) INHIBITORS INCLUDING TRICHOSTATIN A (TSA) HAS BEEN REPORTED TO HAVE INHIBITORY EFFECTS ON MYOFIBROBLAST DIFFERENTIATION IN LUNG AND RENAL FIBROBLASTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE INHIBITORY EFFECT OF TSA ON MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION IN NASAL POLYP ORGAN CULTURES. METHODS: NASAL POLYP TISSUES FROM 18 PATIENTS WERE ACQUIRED DURING ENDOSCOPIC SINUS SURGERY. AFTER ORGAN CULTURE, NASAL POLYPS WERE STIMULATED WITH TGF-BETA1 AND THEN TREATED WITH TSA. ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), FIBRONECTIN, AND COLLAGEN TYPE I EXPRESSION LEVELS WERE EXAMINED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (PCR), REAL-TIME PCR, WESTERN BLOT, AND IMMUNOFLUORESCENT STAINING. HDAC2, HDAC4, AND ACETYLATED H4 EXPRESSION LEVELS WERE ASSAYED BY WESTERN BLOT. CYTOTOXICITY WAS ANALYZED BY THE TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE BIOTIN-DUTP NICK END LABELING ASSAY. RESULTS: THE EXPRESSION LEVELS OF ALPHA-SMA, FIBRONECTIN, AND COLLAGEN TYPE 1 WERE INCREASED IN NASAL POLYP AFTER TRANSFORMING GROWTH FACTOR (TGF) BETA1 TREATMENT. TSA-INHIBITED TGF-BETA1 INDUCED THESE GENE AND PROTEIN EXPRESSION LEVELS. FURTHERMORE, TSA SUPPRESSED PROTEIN EXPRESSION LEVELS OF HDAC2 AND HDAC4. HOWEVER, TSA INDUCED HYPERACETYLATION OF HISTONES H4. TREATMENT WITH TGF-BETA1 WITH OR WITHOUT TSA DID NOT HAVE CYTOTOXIC EFFECT. CONCLUSION: THESE FINDINGS PROVIDE NOVEL INSIGHTS INTO THE EPIGENETIC REGULATION IN MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION OF NASAL POLYP. TSA COULD BE A CANDIDATE OF A THERAPEUTIC AGENT FOR REVERSING THE TGF-BETA1-INDUCED ECM SYNTHESIS THAT LEADS TO NASAL POLYP DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12  2300  31 EPIGENETIC REGULATION OF BDNF EXPRESSION IN THE PRIMARY SENSORY NEURONS AFTER PERIPHERAL NERVE INJURY: IMPLICATIONS IN THE DEVELOPMENT OF NEUROPATHIC PAIN. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS KNOWN TO BE UP-REGULATED IN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY, AND TO CONTRIBUTE TO NEUROPATHIC PAIN. HERE, WE FOUND THAT THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA AT DAY 7 POST-INJURY WERE INHIBITED ONLY WHEN ANTI-BDNF ANTIBODY WAS INTRATHECALLY ADMINISTRATED AT DAY 2 POST-INJURY. CONSISTENT WITH BEHAVIORAL RESULTS, WESTERN BLOT ANALYSIS SHOWED THAT THE EXPRESSION LEVELS OF BDNF PROTEIN IN THE SPINAL DORSAL HORN WERE MARKEDLY INDUCED DURING EARLY STAGE POST-INJURY. MOREOVER, THE MAXIMAL INCREASE IN BDNF MRNA EXPRESSION IN THE DRG WAS OBSERVED AT DAY 1 POST-INJURY, AND SIGNIFICANTLY ELEVATED LEVELS WERE SUSTAINED FOR AT LEAST 14 DAYS. FOUR OF FIVE BDNF MRNA TRANSCRIPTS WERE UP-REGULATED AFTER NERVE INJURY, AND THE MOST INDUCIBLE TRANSCRIPT WAS EXON I. USING A CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY, WE FOUND THAT NERVE INJURY PROMOTES HISTONE H3 AND H4 ACETYLATION, TRANSCRIPTIONALLY ACTIVE MODIFICATIONS, AT BDNF PROMOTER I AT DAY 1 POST-INJURY, AND THE LEVELS OF HISTONE ACETYLATION REMAIN ELEVATED FOR AT LEAST 7 DAYS. TAKEN TOGETHER, OUR FINDINGS SUGGEST THAT AN INITIAL INCREASE IN BDNF EXON I EXPRESSION CONTROLLED BY EPIGENETIC MECHANISMS MIGHT HAVE A CRUCIAL ROLE IN THE DEVELOPMENT OF NEUROPATHIC PAIN.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13  1906  39 ENHANCER OF ZESTE HOMOLOG 2-CATALYSED H3K27 TRIMETHYLATION PLAYS A KEY ROLE IN ACUTE-ON-CHRONIC LIVER FAILURE VIA TNF-MEDIATED PATHWAY. ACUTE-ON-CHRONIC LIVER FAILURE IS MAINLY DUE TO HOST IMMUNITY SELF-DESTRUCTION. THE HISTONE H3 LYSINE 27 (H3K27) TRIMETHYLATING ENZYME, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) MEDIATES EPIGENETIC SILENCING OF GENE EXPRESSION AND REGULATES IMMUNITY, ALSO INVOLVES PATHOGENESIS OF SEVERAL LIVER DISEASES. THE CURRENT STUDY WAS TO DETERMINE THE ROLE OF METHYLTRANSFERASE EZH2 AND ITS CATALYSED H3K27 TRIMETHYLATION (H3K27ME3) IN LIVER FAILURE, AND TO FURTHER INVESTIGATE THE POTENTIAL TARGET FOR LIVER FAILURE TREATMENT. EZH2 AND ITS CATALYSED H3K27ME3 WERE DETERMINED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM LIVER FAILURE PATIENTS AND KUPFFER CELLS FROM EXPERIMENTAL MICE. FURTHERMORE, GSK126 (AN INHIBITOR FOR EZH2 TRIMETHYLATION FUNCTION) WAS APPLIED IN LIVER FAILURE MICE IN VIVO, AND LIPOPOLYSACCHARIDE-STIMULATED MONONUCLEAR CELLS IN VITRO. EZH2 AND H3K27ME3 WERE SIGNIFICANTLY UPREGULATED IN HUMAN PBMC FROM LIVER FAILURE PATIENTS OR MURINE KUPFFER CELLS FROM THE LIVER FAILURE ANIMALS, RESPECTIVELY. GSK126 AMELIORATED DISEASE SEVERITY IN LIVER FAILURE MICE, WHICH MAYBE ATTRIBUTE TO DOWN-REGULATE CIRCULATING AND HEPATIC PROINFLAMMATORY CYTOKINES, ESPECIALLY TNF VIA REDUCING H3K27ME3. IN-DEPTH CHROMATIN IMMUNOPRECIPITATION ANALYSIS UNRAVELLED THAT DECREASED ENRICHMENT OF H3K27ME3 ON TNF PROMOTOR, RESULTING IN TNF ELEVATION IN KUPFFER CELLS FROM LIVER FAILURE MICE. NUCLEAR FACTOR KAPPA B (NF-KAPPAB) AND PROTEIN KINASE B (AKT) SIGNALLING PATHWAYS WERE ACTIVATED UPON LIPOPOLYSACCHARIDE STIMULATION, BUT ATTENUATED BY USING GSK126, ACCOMPANIED WITH DECREASED TNF IN VITRO. IN CONCLUSION, EZH2 AND H3K27ME3 CONTRIBUTED TO THE PATHOGENESIS OF LIVER FAILURE VIA TRIGGERING TNF AND OTHER INDISPENSABLE PROINFLAMMATORY CYTOKINES. EZH2 WAS TO MODIFY H3K27ME3 ENRICHMENT, AS WELL AS, ACTIVATION OF THE DOWNSTREAM NF-KAPPAB AND AKT SIGNALLING PATHWAYS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  5479  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15   364  35 AMELIORATION OF UREMIC TOXIN INDOXYL SULFATE-INDUCED OSTEOBLASTIC CALCIFICATION BY SET DOMAIN CONTAINING LYSINE METHYLTRANSFERASE 7/9 PROTEIN. BACKGROUND: VASCULAR CALCIFICATION (VC) IS A VERY COMMON PHENOMENON IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD). IT HAS BEEN REPORTED THAT SOME HISTONE METHYLATION PLAY A ROLE IN VC AS AN EPIGENETIC REGULATOR. INDOXYL SULFATE (IS) IS A PROTEIN-BOUND UREMIC TOXIN THAT HAS BEEN PROVEN AS ONE OF THE MAJOR RISK FACTORS OF CARDIOVASCULAR DISEASE IN CKD. SET DOMAIN CONTAINING LYSINE METHYLTRANSFERASE 7/9 (SET7/9) IS ONE OF THE IMPORTANT HISTONE METHYLTRANSFERASES. OBJECTIVES: THIS STUDY AIMED TO DETERMINE THE EFFECT OF IS ON THE EXPRESSION OF SET7/9 AND THE ROLE OF SET7/9 IN IS-INDUCED OSTEOBLASTIC DIFFERENTIATION AND CALCIFICATION OF VASCULAR SMOOTH MUSCLE CELLS (VSMCS). METHODS: VSMCS WERE INCUBATED WITH VARIOUS CONCENTRATIONS OF IS FOR DIFFERENT DURATIONS TO ASSESS OSTEOBLASTIC DIFFERENTIATION AND EXPRESSION OF SET7/9. WESTERN BLOT ANALYSIS AND QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION WERE PERFORMED TO ASSESS THE PROTEIN AND MRNA LEVELS OF SET7/9 RESPECTIVELY. THE CALCIUM CONTENT WAS MEASURED TO EVALUATE CALCIFICATION. RESULTS: OSTEOBLASTIC DIFFERENTIATION AND CALCIFICATION OF VSMCS AND DOWNREGULATION OF THE EXPRESSION OF SET7/9 WERE OBSERVED AFTER IS TREATMENT. THE AUTOPHAGY WAS ACTIVATED AFTER TREATMENT WITH IS, WHEREAS THE INHIBITION OF THE AUTOPHAGY PARTIALLY ATTENUATED THE EFFECT OF IS ON BOTH THE STIMULATION OF THE EXPRESSION OF RUNT-RELATED TRANSCRIPTION FACTOR 2 AND CALCIUM DEPOSITION. CONCLUSIONS: OUR DATA DEMONSTRATED THAT SET7/9 DOWNREGULATION AND AUTOPHAGY ACTIVATION MAY BE THE KEY MECHANISM OF IS-INDUCED VC IN CKD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16  2452  34 EPIGENETIC SUPPRESSION OF POTASSIUM-CHLORIDE CO-TRANSPORTER 2 EXPRESSION IN INFLAMMATORY PAIN INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA). BACKGROUND: MULTIPLE MECHANISMS CONTRIBUTE TO THE STIMULUS-EVOKED PAIN HYPERSENSITIVITY THAT MAY BE EXPERIENCED AFTER PERIPHERAL INFLAMMATION. PERSISTENT PATHOLOGICAL STIMULI IN MANY PAIN CONDITIONS AFFECT THE EXPRESSION OF CERTAIN GENES THROUGH EPIGENETIC ALTERNATIONS. THE MAIN PURPOSE OF OUR STUDY WAS TO INVESTIGATE THE ROLE OF EPIGENETIC MODIFICATION ON POTASSIUM-CHLORIDE CO-TRANSPORTER 2 (KCC2) GENE EXPRESSION IN THE PERSISTENCE OF INFLAMMATORY PAIN. METHODS: PERSISTENT INFLAMMATORY PAIN WAS INDUCED THROUGH THE INJECTION OF COMPLETE FREUND'S ADJUVANT (CFA) IN THE LEFT HIND PAW OF RATS. ACETYL-HISTONE H3 AND H4 LEVEL WAS DETERMINED BY CHROMATIN IMMUNOPRECIPITATION IN THE SPINAL DORSAL HORN. PAIN BEHAVIOUR AND INHIBITORY SYNAPTIC FUNCTION OF SPINAL CORD WERE DETERMINED BEFORE AND AFTER CFA INJECTION. KCC2 EXPRESSION WAS DETERMINED BY REAL TIME RT-PCR AND WESTERN BLOT. INTRATHECAL KCC2 SIRNA (2 MUG PER 10 MUL PER RAT) OR HDAC INHIBITOR (10 MUG PER 10 MUL PER RAT) WAS INJECTED ONCE DAILY FOR 3 DAYS BEFORE CFA INJECTION. RESULTS: PERSISTENT INFLAMMATORY PAIN EPIGENETICALLY SUPPRESSED KCC2 EXPRESSION THROUGH HISTONE DEACETYLASE (HDAC)-MEDIATED HISTONE HYPOACETYLATION, RESULTING IN DECREASED INHIBITORY SIGNALLING EFFICACY. KCC2 KNOCK-DOWN CAUSED BY INTRATHECAL ADMINISTRATION OF KCC2 SIRNA IN NAIVE RATS REDUCED KCC2 EXPRESSION IN THE SPINAL CORD, LEADING TO SENSITIZED PAIN BEHAVIOURS AND IMPAIRED INHIBITORY SYNAPTIC TRANSMISSION IN THEIR SPINAL CORDS. MOREOVER, INTRATHECAL HDAC INHIBITOR INJECTION IN CFA RATS INCREASED KCC2 EXPRESSION, PARTIALLY RESTORING THE SPINAL INHIBITORY SYNAPTIC TRANSMISSION AND RELIEVING THE SENSITIZED PAIN BEHAVIOUR. CONCLUSION: THESE FINDINGS SUGGEST THAT THE TRANSCRIPTION OF SPINAL KCC2 IS REGULATED BY HISTONE ACETYLATION EPIGENETICALLY FOLLOWING CFA. SIGNIFICANCE: PERSISTENT PAIN SUPPRESSES KCC2 EXPRESSION THROUGH HDAC-MEDIATED HISTONE HYPOACETYLATION AND CONSEQUENTLY IMPAIRS THE INHIBITORY FUNCTION OF INHIBITORY INTERNEURONS. DRUGS SUCH AS HDAC INHIBITORS THAT SUPPRESS THE INFLUENCES OF PERSISTENT PAIN ON THE EXPRESSION OF KCC2 MAY SERVE AS A NOVEL ANALGESIC.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17  3809  40 INTRAPERITONEAL 5-AZACYTIDINE ALLEVIATES NERVE INJURY-INDUCED PAIN IN RATS BY MODULATING DNA METHYLATION. TO INVESTIGATE THE ROLE OF DNA METHYLATION IN MODULATING CHRONIC NEUROPATHIC PAIN (NPP), IDENTIFY POSSIBLE TARGET GENES OF DNA METHYLATION INVOLVED IN THIS PROCESS, AND PRELIMINARILY CONFIRM THE MEDICINAL VALUE OF THE DNA METHYLTRANSFERASES (DNMTS) INHIBITOR 5-AZACYTIDINE (5-AZA) IN NPP BY TARGETING GENE METHYLATION. TWO RAT NPP MODELS, CHRONIC CONSTRICTION INJURY (CCI) AND SPINAL NERVE LIGATION (SNL), WERE USED. THE DNA METHYLATION PROFILES IN THE LUMBAR SPINAL CORD WERE ASSAYED USING AN ARRAYSTAR RAT REFSEQ PROMOTER ARRAY. THE UNDERLYING GENES WITH DIFFERENTIAL METHYLATION WERE THEN IDENTIFIED AND SUBMITTED TO GENE ONTOLOGY AND PATHWAY ANALYSIS. METHYL-DNA IMMUNOPRECIPITATION QUANTITATIVE PCR (MEDIP-QPCR) AND QUANTITATIVE REVERSE TRANSCRIPTION-PCR (RT-QPCR) WERE USED TO CONFIRM GENE METHYLATION AND EXPRESSION. THE PROTECTIVE FUNCTION OF 5-AZA IN NPP AND GENE EXPRESSION WERE EVALUATED VIA BEHAVIORAL ASSAYS AND RT-QPCR, RESPECTIVELY. ANALYSIS OF THE DNA METHYLATION PATTERNS IN THE LUMBAR SPINAL CORD INDICATED THAT 1205 DIFFERENTIALLY METHYLATED FRAGMENTS IN CCI RATS WERE LOCATED WITHIN DNA PROMOTER REGIONS, INCLUDING 638 HYPERMETHYLATED FRAGMENTS AND 567 HYPOMETHYLATED FRAGMENTS. THE METHYLATION LEVELS OF GRM4, HTR4, ADRB2, KCNF1, GAD2, AND PPARG, WHICH ARE ASSOCIATED WITH LONG-TERM POTENTIATION (LTP) AND GLUTAMATERGIC SYNAPSE PATHWAYS, WERE INCREASED WITH A CORRESPONDING DECREASE IN THEIR MRNA EXPRESSION, IN THE SPINAL CORDS OF CCI RATS. MOREOVER, WE FOUND THAT THE INTRAPERITONEAL INJECTION OF 5-AZA (4 MG/KG) ATTENUATED CCI- OR SNL-INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA. FINALLY, THE MRNA EXPRESSION OF HYPERMETHYLATED GENES SUCH AS GRM4, HTR4, ADRB2, KCNF1, AND GAD2 WAS REVERSED AFTER 5-AZA TREATMENT. CCI INDUCED WIDESPREAD METHYLATION CHANGES IN THE DNA PROMOTER REGIONS IN THE LUMBAR SPINAL CORD. INTRAPERITONEAL 5-AZA ALLEVIATED HYPERALGESIA IN CCI AND SNL RATS, AN EFFECT ACCOMPANIED BY THE REVERSED EXPRESSION OF HYPERMETHYLATED GENES. THUS, DNA METHYLATION INHIBITION REPRESENTS A PROMISING EPIGENETIC STRATEGY FOR PROTECTION AGAINST CHRONIC NPP FOLLOWING NERVE INJURY. OUR STUDY LAYS A THEORETICAL FOUNDATION FOR 5-AZA TO BECOME A CLINICAL TARGETED DRUG.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18  2365  33 EPIGENETIC REGULATION OF SPINAL CXCR2 SIGNALING IN INCISIONAL HYPERSENSITIVITY IN MICE. BACKGROUND: THE REGULATION OF GENE EXPRESSION IN NOCICEPTIVE PATHWAYS CONTRIBUTES TO THE INDUCTION AND MAINTENANCE OF PAIN SENSITIZATION. HISTONE ACETYLATION IS A KEY EPIGENETIC MECHANISM CONTROLLING CHROMATIN STRUCTURE AND GENE EXPRESSION. CHEMOKINE CC MOTIF RECEPTOR 2 (CXCR2) IS A PROINFLAMMATORY RECEPTOR IMPLICATED IN NEUROPATHIC AND INFLAMMATORY PAIN AND IS KNOWN TO BE REGULATED BY HISTONE ACETYLATION IN SOME SETTINGS. THE AUTHORS SOUGHT TO INVESTIGATE THE ROLE OF HISTONE ACETYLATION ON SPINAL CXCR2 SIGNALING AFTER INCISION. METHODS: GROUPS OF 5-8 MICE UNDERWENT HIND PAW INCISION. SUBEROYLANILIDE HYDROXAMIC ACID AND ANACARDIC ACID WERE USED TO INHIBIT HISTONE DEACETYLASE AND HISTONE ACETYLTRANSFERASE, RESPECTIVELY. BEHAVIORAL MEASURES OF THERMAL AND MECHANICAL SENSITIZATION AS WELL AS HYPERALGESIC PRIMING WERE USED. BOTH MESSAGE RNA QUANTIFICATION AND CHROMATIN IMMUNOPRECIPITATION ANALYSIS WERE USED TO STUDY THE REGULATION OF CXCR2 AND LIGAND EXPRESSION. FINALLY, THE SELECTIVE CXCR2 ANTAGONIST SB225002 WAS ADMINISTERED INTRATHECALLY TO REVEAL THE FUNCTION OF SPINAL CXCR2 RECEPTORS AFTER HIND PAW INCISION. RESULTS: SUBEROYLANILIDE HYDROXAMIC ACID SIGNIFICANTLY EXACERBATED MECHANICAL SENSITIZATION AFTER INCISION. CONVERSELY, ANACARDIC ACID REDUCED INCISIONAL SENSITIZATION AND ALSO ATTENUATED INCISION-INDUCED HYPERALGESIC PRIMING. OVERALL, ACETYLATED HISTONE H3 AT LYSINE 9 WAS INCREASED IN SPINAL CORD TISSUES AFTER INCISION, AND ENHANCED ASSOCIATION OF ACETYLATED HISTONE H3 AT LYSINE 9 WITH THE PROMOTER REGIONS OF CXCR2 AND KERATINOCYTE-DERIVED CHEMOKINE (CXCL1) WAS OBSERVED AS WELL. BLOCKING CXCR2 REVERSED MECHANICAL HYPERSENSITIVITY AFTER HIND PAW INCISION. CONCLUSIONS: HISTONE MODIFICATION IS AN IMPORTANT EPIGENETIC MECHANISM REGULATING INCISION-INDUCED NOCICEPTIVE SENSITIZATION. THE SPINAL CXCR2 SIGNALING PATHWAY IS ONE EPIGENETICALLY REGULATED PATHWAY CONTROLLING EARLY AND LATENT SENSITIZATION AFTER INCISION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19  5764  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20  6108  36 THE ENRICHED ENVIRONMENT AMELIORATES CHRONIC UNPREDICTABLE MILD STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE IMPAIRMENT BY ACTIVATING THE SIRT1/MIR-134 SIGNALING PATHWAY IN HIPPOCAMPUS. BACKGROUND: CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IS AN IMPORTANT RISK FACTOR FOR DEPRESSION AND COGNITIVE DEFICITS IN HUMANS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON DEPRESSION AND COGNITION BY ENHANCING BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND SYNAPTIC PLASTICITY. HOWEVER, IT IS STILL NOT CLEARLY UNDERSTOOD WHETHER AN EPIGENETIC MECHANISM IS INVOLVED IN THE BDNF MODULATION AND SYNAPTIC PLASTICITY THAT OCCURS AFTER EE TREATMENT FOR THE DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS ELICITED BY CUMS. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE MECHANISM OF THE NEUROPROTECTIVE EFFECT OF EE. METHODS: ALL RATS WERE EXPOSED TO THE 5-WEEK CUMS PROCEDURE EXCEPT THE CONTROL GROUP. AFTER CUMS PROCEDURE, SOME RATS WERE STEREOTAXICALLY INJECTED WITH SIRT1 PHARMACOLOGIC INHIBITOR EX527 OR SIRT1 KNOCKING DOWN LENTIVIRUS (SH-SIRT1) IN THE HIPPOCAMPUS FOLLOWED BY EE TREATMENT FOR 3 WEEKS. OTHER RATS WERE DIRECTLY SUBJECTED TO EE TREATMENT WITHOUT STEREOTAXIC INJECTION. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION AFTER EE TREATMENT. THEN EPIGENETIC MOLECULES, SYNAPTIC PROTEINS, DENDRITIC SPINE DENSITY AND BRANCHES, AND SYNAPTIC MORPHOLOGY OF THE DORSAL HIPPOCAMPUS WERE DETERMINED. RESULTS: WE FOUND THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIORS INCLUDING DECREASED SUCROSE PREFERENCE RATIO, PROLONGED IMMOBILITY AND REDUCED LOCOMOTOR AND EXPLORATORY ACTIVITY; COGNITIVE DEFICITS INCLUDING SPATIAL LEARNING AND MEMORY IMPAIRMENT; REDUCED DENDRITIC SPINE DENSITY AND NUMBER OF BRANCHES; THINNED POSTSYNAPTIC DENSITY; DOWNREGULATED SIRT1/MICRORNA-134 PATHWAY, DECREASED BDNF AND SYNAPTIC PROTEINS INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95) EXPRESSION IN THE HIPPOCAMPUS. HOWEVER, THE CUMS-INDUCED DEPRESSIVE-LIKE BEHAVIORS, COGNITIVE DEFICITS, DENDRITIC SPINE DENSITY AND BRANCH NUMBER REDUCTION, POSTSYNAPTIC DENSITY THINNING, SIRT1/MICRORNA-134 PATHWAY DOWNREGULATION, BDNF AND SYNAPTIC PROTEINS REDUCTION, INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95), WERE REVERSED BY EE TREATMENT. HOWEVER, DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS WERE OBSERVED AGAIN IN RATS SUBJECTED TO STEREOTAXIC INJECTION WITH EX527 OR SH-SIRT1. FURTHERMORE, THIS STUDY ALSO FOUND THAT SIRT1/MICRORNA-134 REGULATES THE DOWNSTREAM MOLECULES BDNF, AND THE SYNAPTIC PROTEINS SYN AND PSD95 IN PRIMARY CULTURED HIPPOCAMPAL NEURONS. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE FOR THE NEUROPROTECTIVE ROLE OF EE ON DEPRESSION AND COGNITIVE DEFICITS BY ACTIVATING THE SIRT1/MICRORNA-134 PATHWAY, WHICH ACCOUNTS FOR THE REGULATION OF SYNAPTIC PROTEINS, INCLUDING BDNF, PSD95 AND SYN, DENDRITIC REMODELING AND ULTRASTRUCTURE CHANGES OF SYNAPSES IN THE HIPPOCAMPUS.	2019