1 1038 141 CLINACANTHUS NUTANS EXTRACTS MODULATE EPIGENETIC LINK TO CYTOSOLIC PHOSPHOLIPASE A2 EXPRESSION IN SH-SY5Y CELLS AND PRIMARY CORTICAL NEURONS. CLINACANTHUS NUTANS LINDAU (C. NUTANS), COMMONLY KNOWN AS SABAH SNAKE GRASS IN SOUTHEAST ASIA, IS WIDELY USED IN FOLK MEDICINE DUE TO ITS ANALGESIC, ANTIVIRAL, AND ANTI-INFLAMMATORY PROPERTIES. OUR RECENT STUDY PROVIDED EVIDENCE FOR THE REGULATION OF CYTOSOLIC PHOSPHOLIPASE A2 (CPLA2) MRNA EXPRESSION BY EPIGENETIC FACTORS (TAN ET AL. IN MOL NEUROBIOL. DOI: 10.1007/S12035-015-9314-Z , 2015). THIS ENZYME CATALYZES THE RELEASE OF ARACHIDONIC ACID FROM GLYCEROPHOSPHOLIPIDS, AND FORMATION OF PRO-INFLAMMATORY EICOSANOIDS OR TOXIC LIPID PEROXIDATION PRODUCTS SUCH AS 4-HYDROXYNONENAL. IN THIS STUDY, WE EXAMINED THE EFFECTS OF C. NUTANS ETHANOL LEAF EXTRACTS ON EPIGENETIC REGULATION OF CPLA2 MRNA EXPRESSION IN SH-SY5Y HUMAN NEUROBLASTOMA CELLS AND MOUSE PRIMARY CORTICAL NEURONS. C. NUTANS MODULATED INDUCTION OF CPLA2 EXPRESSION IN SH-SY5Y CELLS BY HISTONE DEACETYLASE (HDAC) INHIBITORS, MS-275, MC-1568, AND TSA. C. NUTANS EXTRACTS ALSO INHIBITED HISTONE ACETYLASE (HAT) ACTIVITY. LEVELS OF CPLA2 MRNA EXPRESSION WERE INCREASED IN PRIMARY CORTICAL NEURONS SUBJECTED TO 0.5-H OXYGEN-GLUCOSE DEPRIVATION INJURY (OGD). THIS INCREASE WAS SIGNIFICANTLY INHIBITED BY C. NUTANS TREATMENT. TREATMENT OF PRIMARY NEURONS WITH THE HDAC INHIBITOR MS-275 AUGMENTED OGD-INDUCED CPLA2 MRNA EXPRESSION, AND THIS INCREASE WAS MODULATED BY C. NUTANS EXTRACTS. OGD-STIMULATED INCREASE IN CPLA2 MRNA EXPRESSION WAS ALSO REDUCED BY A TIP60 HAT INHIBITOR, NU9056. IN VIEW OF A KEY ROLE OF CPLA2 IN THE PRODUCTION OF PRO-INFLAMMATORY EICOSANOIDS AND FREE RADICAL DAMAGE, AND THE FACT THAT EPIGENETIC EFFECTS ON GENES ARE OFTEN LONG-LASTING, RESULTS SUGGEST A ROLE FOR C. NUTANS AND PHYTOCHEMICALS TO INHIBIT THE PRODUCTION OF ARACHIDONIC ACID-DERIVED PRO-INFLAMMATORY EICOSANOIDS AND CHRONIC INFLAMMATION, THROUGH EPIGENETIC REGULATION OF CPLA2 EXPRESSION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                      
2 2311  56 EPIGENETIC REGULATION OF CYTOSOLIC PHOSPHOLIPASE A2 IN SH-SY5Y HUMAN NEUROBLASTOMA CELLS. GROUP IVA CYTOSOLIC PHOSPHOLIPASE A2 (CPLA2 OR PLA2G4A) IS A KEY ENZYME THAT CONTRIBUTES TO INFLAMMATION VIA THE GENERATION OF ARACHIDONIC ACID AND EICOSANOIDS. WHILE MUCH IS KNOWN ABOUT REGULATION OF CPLA2 BY POSTTRANSLATIONAL MODIFICATION SUCH AS PHOSPHORYLATION, LITTLE IS KNOWN ABOUT ITS EPIGENETIC REGULATION. IN THIS STUDY, TREATMENT WITH HISTONE DEACETYLASE (HDAC) INHIBITORS, TRICHOSTATIN A (TSA), VALPROIC ACID, TUBACIN AND THE CLASS I HDAC INHIBITOR, MS-275, WERE FOUND TO INCREASE CPLA2ALPHA MESSENGER RNA (MRNA) EXPRESSION IN SH-SY5Y HUMAN NEUROBLASTOMA CELLS. CO-TREATMENT OF THE HISTONE ACETYLTRANSFERASE (HAT) INHIBITOR, ANACARDIC ACID, MODULATED UPREGULATION OF CPLA2ALPHA INDUCED BY TSA. SPECIFIC INVOLVEMENT OF CLASS I HDACS AND HAT IN CPLA2ALPHA REGULATION WAS FURTHER SHOWN, AND A TIP60-SPECIFIC HAT INHIBITOR, NU9056, MODULATED THE UPREGULATION OF CPLA2ALPHA INDUCED BY MS-275. IN ADDITION, CO-TREATMENT OF WITH HISTONE METHYLTRANSFERASE (HMT) INHIBITOR, 5'-DEOXY-5'-METHYLTHIOADENOSINE (MTA) SUPPRESSED TSA-INDUCED CPLA2ALPHA UPREGULATION. THE ABOVE CHANGES IN CPLA2 MRNA EXPRESSION WERE REFLECTED AT THE PROTEIN LEVEL BY WESTERN BLOTS AND IMMUNOCYTOCHEMISTRY. CHROMATIN IMMUNOPRECIPITATION (CHIP) SHOWED TSA INCREASED BINDING OF TRIMETHYLATED H3K4 TO THE PROXIMAL PROMOTER REGION OF THE CPLA2ALPHA GENE. CELL INJURY AFTER TSA TREATMENT AS INDICATED BY LACTATE DEHYDROGENASE (LDH) RELEASE WAS MODULATED BY ANACARDIC ACID, AND A ROLE OF CPLA2 IN MEDIATING TSA-INDUCED INJURY SHOWN, AFTER CO-INCUBATION WITH THE CPLA2 SELECTIVE INHIBITOR, ARACHIDONOYL TRIFLUOROMETHYL KETONE (AACOCF3). TOGETHER, RESULTS INDICATE EPIGENETIC REGULATION OF CPLA2 AND THE POTENTIAL OF SUCH REGULATION FOR TREATMENT OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
3 1777  41 EDIBLE BLUE-GREEN ALGAE REDUCE THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES BY INHIBITING NF-KAPPAB PATHWAY IN MACROPHAGES AND SPLENOCYTES. BACKGROUND: CHRONIC INFLAMMATION CONTRIBUTES TO THE DEVELOPMENT OF PATHOLOGICAL DISORDERS INCLUDING INSULIN RESISTANCE AND ATHEROSCLEROSIS. IDENTIFICATION OF ANTI-INFLAMMATORY NATURAL PRODUCTS CAN PREVENT THE INFLAMMATORY DISEASES. METHODS: ANTI-INFLAMMATORY EFFECTS OF BLUE-GREEN ALGAE (BGA), I.E., NOSTOC COMMUNE VAR. SPHAEROIDES KUTZING (NO) AND SPIRULINA PLATENSIS (SP), WERE COMPARED IN RAW 264.7 AND MOUSE BONE MARROW-DERIVED MACROPHAGES (BMM) AS WELL AS SPLENOCYTES FROM APOLIPOPROTEIN E KNOCKOUT (APOE(-/-)) MICE FED BGA. RESULTS: WHEN MACROPHAGES PRETREATED WITH 100MUG/ML NO LIPID EXTRACT (NOE) OR SP LIPID EXTRACT (SPE) WERE ACTIVATED BY LIPOPOLYSACCHARIDE (LPS), EXPRESSION AND SECRETION OF PRO-INFLAMMATORY CYTOKINES, SUCH AS TUMOR NECROSIS FACTOR ALPHA (TNFALPHA), INTERLEUKIN 1BETA (IL-1BETA), AND IL-6, WERE SIGNIFICANTLY REPRESSED. NOE AND SPE ALSO SIGNIFICANTLY REPRESSED THE EXPRESSION OF TNFALPHA AND IL-1BETA IN BMM. LPS-INDUCED SECRETION OF IL-6 WAS LOWER IN SPLENOCYTES FROM APOE(-/-) FED AN ATHEROGENIC DIET CONTAINING 5% NO OR SP FOR 12WEEKS. IN RAW 264.7 MACROPHAGES, NOE AND SPE MARKEDLY DECREASED NUCLEAR TRANSLOCATION OF NF-KAPPAB. THE DEGREE OF REPRESSION OF PRO-INFLAMMATORY GENE EXPRESSION BY ALGAL EXTRACTS WAS MUCH STRONGER THAN THAT OF SN50, AN INHIBITOR OF NF-KAPPAB NUCLEAR TRANSLOCATION. TRICHOSTATIN A, A PAN HISTONE DEACETYLASE INHIBITOR, INCREASED BASAL EXPRESSION OF IL-1BETA AND ATTENUATED THE REPRESSION OF THE GENE EXPRESSION BY SPE. SPE SIGNIFICANTLY DOWN-REGULATED MRNA ABUNDANCE OF 11 HDAC ISOFORMS, CONSEQUENTLY INCREASING ACETYLATED HISTONE 3 LEVELS. CONCLUSION: NOE AND SPE REPRESS PRO-INFLAMMATORY CYTOKINE EXPRESSION AND SECRETION IN MACROPHAGES AND SPLENOCYTES VIA INHIBITION OF NF-KAPPAB PATHWAY. HISTONE ACETYLATION STATE IS LIKELY INVOLVED IN THE INHIBITION. GENERAL SIGNIFICANCE: THIS STUDY UNDERSCORES NATURAL PRODUCTS CAN EXERT ANTI-INFLAMMATORY EFFECTS BY EPIGENETIC MODIFICATIONS SUCH AS HISTONE ACETYLATION.	2013	
                                                                                                                                                                                                                                                  
4  685  33 BRAIN-DERIVED NEUROTROPHIC FACTOR INVOLVED EPIGENETIC REPRESSION OF UGT2B7 IN COLORECTAL CARCINOMA: A MECHANISM TO ALTER MORPHINE GLUCURONIDATION IN TUMOR. URIDINE DIPHOSPHATE-GLUCURONOSYLTRANSFERASE (UGT) 2B7, AS ONE OF SIGNIFICANT DRUG ENZYMES, IS RESPONSIBLE ON THE GLUCURONIDATION OF ABUNDANT ENDOBIOTICS OR XENOBIOTICS. WE HERE REPORT THAT IT IS MARKEDLY REPRESSED IN THE TUMOR TISSUES OF COLORECTAL CARCINOMA (CRC) PATIENTS. ACCORDINGLY, MORPHINE IN CRC CELLS WILL STIMULATE THE EXPRESSION OF ITS MAIN METABOLIC ENZYME, UGT2B7 DURING TOLERANCE GENERATION BY ACTIVATING THE POSITIVE SIGNALS IN HISTONE 3, ESPECIALLY FOR TRIMETHYLATED LYSINE 27 (H3K4ME3) AND ACETYLATED LYSINE 4 (H3K27AC). FURTHER STUDY REVEALS THAT BRAIN-DERIVED NEUTROPHILIC FACTOR (BDNF), A SECRETORY NEUROTROPHIN, ENRICHED IN CRC CAN INTERACT AND INHIBIT UGT2B7 BY PRIMARILY BLOCKING THE POSITIVE SIGNALS OF H3K4ME3 AS WELL AS ACTIVATING H3K27AC ON THE PROMOTER REGION OF UGT2B7. MEANWHILE, BDNF REPRESSION ATTRIBUTES TO THE SENSITIZATIONS OF MAIN CORE FACTORS IN POLY-COMB REPRESSIVE COMPLEX (PRC) 1 RATHER THAN PRC2 AS THE REASON OF THE DEPRESSION OF SUZ12 IN THE LATER COMPLEX. BESIDES THAT, THE PRODUCTIONS OF TWO MAIN MORPHINE GLUCURONIDES ARE BOTH INCREASED IN THE BDNF DEFICIENT OR TSA AND BIX-01294 TREATED MORPHINE TOLERANCE-LIKE HCT-116 CELLS. ON THE SAME CONDITION, ACTIVE METABOLITE, MORPHINE-6-GLUCURONIDE (M6G) WAS ACCUMULATED MORE THAN INACTIVE M3G. OUR FINDINGS IMPLY THAT ENZYMATIC ACTIVITY ENHANCEMENT AND SUBSTRATE REGIOSELECTIVE CATALYSIS ALTERATION OF UGT2B7 MAY RELEASE MORPHINE TOLERANCE UNDER THE CURE OF TUMOR-INDUCED PAIN.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5 4696  29 NF-KAPPAB REPRESSES RETINOIC ACID RECEPTOR-MEDIATED GPRC5A TRANSACTIVATION IN LUNG EPITHELIAL CELLS TO PROMOTE NEOPLASIA. CHRONIC INFLAMMATION IS ASSOCIATED WITH LUNG TUMORIGENESIS, IN WHICH NF-KAPPAB-MEDIATED EPIGENETIC REGULATION PLAYS A CRITICAL ROLE. LUNG TUMOR SUPPRESSOR G PROTEIN-COUPLED RECEPTOR, FAMILY C, MEMBER 5A (GPRC5A), IS REPRESSED IN MOST NON-SMALL CELL LUNG CANCER (NSCLC); HOWEVER, THE MECHANISMS REMAIN UNCLEAR. HERE, WE SHOW THAT NF-KAPPAB ACTS AS A TRANSCRIPTIONAL REPRESSOR IN SUPPRESSION OF GPRC5A. NF-KAPPAB INDUCED GPRC5A REPRESSION BOTH IN VITRO AND IN VIVO. INTRIGUINGLY, TRANSACTIVATION OF NF-KAPPAB DOWNSTREAM TARGETS WAS NOT REQUIRED, BUT THE TRANSACTIVATION DOMAIN OF RELA/P65 WAS REQUIRED FOR GPRC5A REPRESSION. NF-KAPPAB DID NOT BIND TO ANY POTENTIAL CIS-ELEMENT IN THE GPRC5A PROMOTER. INSTEAD, P65 WAS COMPLEXED WITH RETINOIC ACID RECEPTOR ALPHA/BETA (RARALPHA/BETA) AND RECRUITED TO THE RA RESPONSE ELEMENT SITE AT THE GPRC5A PROMOTER, RESULTING IN DISRUPTED RNA POLYMERASE II COMPLEXING AND SUPPRESSED TRANSCRIPTION. NOTABLY, PHOSPHORYLATION ON SERINE 276 OF P65 WAS REQUIRED FOR INTERACTION WITH RARALPHA/BETA AND REPRESSION OF GPRC5A. MOREOVER, NF-KAPPAB-MEDIATED EPIGENETIC REPRESSION WAS THROUGH SUPPRESSION OF ACETYLATED HISTONE H3K9 (H3K9AC), BUT NOT DNA METHYLATION OF THE CPG ISLANDS, AT THE GPRC5A PROMOTER. CONSISTENTLY, A HISTONE DEACETYLASE INHIBITOR, BUT NOT DNA METHYLATION INHIBITOR, RESTORED GPRC5A EXPRESSION IN NSCLC CELLS. THUS, NF-KAPPAB INDUCES TRANSCRIPTIONAL REPRESSION OF GPRC5A VIA A COMPLEX WITH RARALPHA/BETA AND MEDIATES EPIGENETIC REPRESSION VIA SUPPRESSION OF H3K9AC.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6 1298  29 DECREASED NUCLEAR RECEPTOR ACTIVITY AND EPIGENETIC MODULATION ASSOCIATES WITH DOWN-REGULATION OF HEPATIC DRUG-METABOLIZING ENZYMES IN CHRONIC KIDNEY DISEASE. PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) REQUIRE MANY MEDICATIONS. CYP2C AND CYP3A DRUG-METABOLIZING ENZYMES PLAY A CRITICAL ROLE IN DETERMINING THE PHARMACOKINETICS OF THE MAJORITY OF PRESCRIBED MEDICATIONS. THESE ENZYMES ARE TRANSCRIPTIONALLY REGULATED BY THE NUCLEAR RECEPTORS PREGNANE X RECEPTOR (PXR) AND HEPATIC NUCLEAR FACTOR 4ALPHA (HNF-4ALPHA). EXPRESSION OF CYP2C AND CYP3A IS DECREASED IN CKD; HOWEVER, THE MECHANISMS BY WHICH THIS OCCURS IS UNKNOWN. WE INDUCED CKD IN RATS BY 5/6 NEPHRECTOMY AND USED CHROMATIN IMMUNOPRECIPITATION (CHIP) TO DETERMINE NUCLEAR RECEPTOR- AND EPIGENETIC ALTERATION-MEDIATED DIFFERENCES IN THE PROMOTER REGION OF THE CYP2C AND CYP3A GENES. RNA POLYMERASE II AND HNF-4ALPHA BINDING WAS DECREASED 76 AND 57% IN THE CYP2C11 PROMOTOR AND 71 AND 77% IN THE CYP3A2 PROMOTER, RESPECTIVELY (P<0.05). CHIP ALSO REVEALED A 57% DECREASE IN PXR BINDING TO THE CYP3A2 PROMOTER IN CKD RATS (P<0.05). THE DECREASE IN PXR AND HNF-4ALPHA BINDING WAS ACCOMPANIED BY DIMINISHED HISTONE 4 ACETYLATION IN THE CYP3A2 PROMOTER (48%) AND HISTONE 3 ACETYLATION IN THE CYP2C11 (77%) AND CYP3A2 (77%) PROMOTER LOCI FOR NUCLEAR RECEPTOR ACTIVATION (P<0.05). THIS STUDY SUGGESTS THAT DECREASED NUCLEAR RECEPTOR BINDING AND HISTONE ACETYLATION MAY CONTRIBUTE TO THE MECHANISM OF DRUG-METABOLIZING ENZYME DOWN-REGULATION AND ALTERED PHARMACOKINETICS IN CKD.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7 2345  38 EPIGENETIC REGULATION OF MATRIX METALLOPROTEINASE-1 AND -3 EXPRESSION IN MYCOBACTERIUM TUBERCULOSIS INFECTION. IN PULMONARY TUBERCULOSIS (TB), THE INFLAMMATORY IMMUNE RESPONSE AGAINST MYCOBACTERIUM TUBERCULOSIS (MTB) IS ASSOCIATED WITH TISSUE DESTRUCTION AND CAVITATION, WHICH DRIVES DISEASE TRANSMISSION, CHRONIC LUNG DISEASE, AND MORTALITY. MATRIX METALLOPROTEINASE (MMP)-1 IS A HOST ENZYME CRITICAL FOR THE DEVELOPMENT OF CAVITATION. MMP EXPRESSION HAS BEEN SHOWN TO BE EPIGENETICALLY REGULATED IN OTHER INFLAMMATORY DISEASES, BUT THE IMPORTANCE OF SUCH MECHANISMS IN MTB-ASSOCIATED INDUCTION OF MMP-1 IS UNKNOWN. WE INVESTIGATED THE ROLE OF CHANGES IN HISTONE ACETYLATION IN MTB-INDUCED MMP EXPRESSION USING INHIBITORS OF HISTONE DEACETYLASES (HDACS) AND HISTONE ACETYLTRANSFERASES (HAT), HDAC SIRNA, PROMOTER-REPORTER CONSTRUCTS, AND CHROMATIN IMMUNOPRECIPITATION ASSAYS. MTB INFECTION DECREASED CLASS I HDAC GENE EXPRESSION BY OVER 50% IN PRIMARY HUMAN MONOCYTE-DERIVED MACROPHAGES BUT NOT IN NORMAL HUMAN BRONCHIAL EPITHELIAL CELLS (NHBES). NON-SELECTIVE INHIBITION OF HDAC ACTIVITY DECREASED MMP-1/-3 EXPRESSION BY MTB-STIMULATED MACROPHAGES AND NHBES, WHILE CLASS I HDAC INHIBITION INCREASED MMP-1 SECRETION BY MTB-STIMULATED NHBES. MMP-3 EXPRESSION, BUT NOT MMP-1, WAS DOWNREGULATED BY SIRNA SILENCING OF HDAC1. INHIBITION OF HAT ACTIVITY ALSO SIGNIFICANTLY DECREASED MMP-1/-3 SECRETION BY MTB-INFECTED MACROPHAGES. THE MMP-1 PROMOTER REGION BETWEEN -2,001 AND -2,942 BASE PAIRS FROM THE TRANSCRIPTIONAL START SITE WAS KEY IN CONTROL OF MTB-DRIVEN MMP-1 GENE EXPRESSION. HISTONE H3 AND H4 ACETYLATION AND RNA POL II BINDING IN THE MMP-1 PROMOTER REGION WERE INCREASED IN STIMULATED NHBES. IN SUMMARY, EPIGENETIC MODIFICATION OF HISTONE ACETYLATION VIA HDAC AND HAT ACTIVITY HAS A KEY REGULATORY ROLE IN MTB-DEPENDENT GENE EXPRESSION AND SECRETION OF MMP-1 AND -3, ENZYMES WHICH DRIVE HUMAN IMMUNOPATHOLOGY. MANIPULATION OF EPIGENETIC REGULATORY MECHANISMS MAY HAVE POTENTIAL AS A HOST-DIRECTED THERAPY TO IMPROVE OUTCOMES IN THE ERA OF RISING TB DRUG RESISTANCE.	2017	
                                                                                                                                                                                                                                                                                        
8  368  36 AMYLOID BETA-MEDIATED EPIGENETIC ALTERATION OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 3 CONTROLS CELL SURVIVAL IN ALZHEIMER'S DISEASE. SWEDISH DOUBLE MUTATION (KM670/671NL) OF AMYLOID PRECURSOR PROTEIN (APP) IS REPORTED TO INCREASE TOXIC AMYLOID BETA (ABETA) PRODUCTION VIA ABERRANT CLEAVAGE AT THE BETA-SECRETASE SITE AND THEREBY CAUSE EARLY-ONSET ALZHEIMER'S DISEASE (AD). HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS LEADING TO AD PATHOGENESIS REMAINS LARGELY UNKNOWN. PREVIOUSLY, OUR TRANSCRIPTOME SEQUENCE ANALYSES REVEALED GLOBAL EXPRESSIONAL MODIFICATIONS OF OVER 600 GENES IN APP-SWEDISH MUTANT-EXPRESSING H4 (H4-SW) CELLS COMPARED TO WILD TYPE H4 CELLS. INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 3 (IGFBP3) IS ONE GENE THAT SHOWED SIGNIFICANTLY DECREASED MRNA EXPRESSION IN H4-SW CELLS. IN THIS STUDY, WE INVESTIGATED THE FUNCTIONAL ROLE OF IGFBP3 IN AD PATHOGENESIS AND ELUCIDATED THE MECHANISMS REGULATING ITS EXPRESSION. WE OBSERVED DECREASED IGFBP3 EXPRESSION IN THE H4-SW CELL LINE AS WELL AS THE HIPPOCAMPUS OF AD MODEL TRANSGENIC MICE. TREATMENT WITH EXOGENOUS IGFBP3 PROTEIN INHIBITED ABETA1-42- INDUCED CELL DEATH AND CASPASE-3 ACTIVITY, WHEREAS SIRNA-MEDIATED SUPPRESSION OF IGFBP3 EXPRESSION INDUCED CELL DEATH AND CASPASE-3 CLEAVAGE. IN PRIMARY HIPPOCAMPAL NEURONS, ADMINISTRATION OF IGFBP3 PROTEIN BLOCKED APOPTOTIC CELL DEATH DUE TO ABETA1-42 TOXICITY. THESE DATA IMPLICATE A PROTECTIVE ROLE FOR IGFBP3 AGAINST ABETA1-42-MEDIATED APOPTOSIS. NEXT, WE INVESTIGATED THE REGULATORY MECHANISMS OF IGFBP3 EXPRESSION IN AD PATHOGENESIS. WE OBSERVED ABNORMAL IGFBP3 HYPERMETHYLATION WITHIN THE PROMOTER CPG ISLAND IN H4-SW CELLS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR 5-AZA-2'-DEOXYCYTIDINE RESTORED IGFBP3 EXPRESSION AT BOTH THE MRNA AND PROTEIN LEVELS. CHRONIC EXPOSURE TO ABETA1-42 INDUCED IGFBP3 HYPERMETHYLATION AT CPGS, PARTICULARLY AT LOCI -164 AND -173, AND SUBSEQUENTLY SUPPRESSED IGFBP3 EXPRESSION. THEREFORE, WE DEMONSTRATE THAT EXPRESSION OF ANTI-APOPTOTIC IGFBP3 IS REGULATED BY EPIGENETIC DNA METHYLATION, SUGGESTING A MECHANISM THAT CONTRIBUTES TO AD PATHOGENESIS.	2014	
                                                                                                                                                                                                                                                
9 4919  33 PANNEXIN-1 UP-REGULATION IN THE DORSAL ROOT GANGLION CONTRIBUTES TO NEUROPATHIC PAIN DEVELOPMENT. PANNEXIN-1 (PANX1) IS A LARGE-PORE MEMBRANE CHANNEL INVOLVED IN THE RELEASE OF ATP AND OTHER SIGNALING MEDIATORS. LITTLE IS KNOWN ABOUT THE EXPRESSION AND FUNCTIONAL ROLE OF PANX1 IN THE DORSAL ROOT GANGLION (DRG) IN THE DEVELOPMENT OF CHRONIC NEUROPATHIC PAIN. IN THIS STUDY, WE DETERMINED THE EPIGENETIC MECHANISM INVOLVED IN INCREASED PANX1 EXPRESSION IN THE DRG AFTER NERVE INJURY. SPINAL NERVE LIGATION IN RATS SIGNIFICANTLY INCREASED THE MRNA AND PROTEIN LEVELS OF PANX1 IN THE DRG BUT NOT IN THE SPINAL CORD. IMMUNOCYTOCHEMICAL LABELING SHOWED THAT PANX1 WAS PRIMARILY EXPRESSED IN A SUBSET OF MEDIUM AND LARGE DRG NEURONS IN CONTROL RATS AND THAT NERVE INJURY MARKEDLY INCREASED THE NUMBER OF PANX1-IMMUNOREACTIVE DRG NEURONS. NERVE INJURY SIGNIFICANTLY INCREASED THE ENRICHMENT OF TWO ACTIVATING HISTONE MARKS (H3K4ME2 AND H3K9AC) AND DECREASED THE OCCUPANCY OF TWO REPRESSIVE HISTONE MARKS (H3K9ME2 AND H3K27ME3) AROUND THE PROMOTER REGION OF PANX1 IN THE DRG. HOWEVER, NERVE INJURY HAD NO EFFECT ON THE DNA METHYLATION LEVEL AROUND THE PANX1 PROMOTER IN THE DRG. FURTHERMORE, INTRATHECAL INJECTION OF THE PANX1 BLOCKERS OR PANX1-SPECIFIC SIRNA SIGNIFICANTLY REDUCED PAIN HYPERSENSITIVITY INDUCED BY NERVE INJURY. IN ADDITION, SIRNA KNOCKDOWN OF PANX1 EXPRESSION IN A DRG CELL LINE SIGNIFICANTLY REDUCED CASPASE-1 RELEASE INDUCED BY NEURONAL DEPOLARIZATION. OUR FINDINGS SUGGEST THAT NERVE INJURY INCREASES PANX1 EXPRESSION LEVELS IN THE DRG THROUGH ALTERED HISTONE MODIFICATIONS. PANX1 UP-REGULATION CONTRIBUTES TO THE DEVELOPMENT OF NEUROPATHIC PAIN AND STIMULATION OF INFLAMMASOME SIGNALING.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10 5601  24 RORALPHA IS CRUCIAL FOR ATTENUATED INFLAMMATORY RESPONSE TO MAINTAIN INTESTINAL HOMEOSTASIS. RETINOIC ACID-RELATED ORPHAN RECEPTOR ALPHA (RORALPHA) FUNCTIONS AS A TRANSCRIPTION FACTOR FOR VARIOUS BIOLOGICAL PROCESSES, INCLUDING CIRCADIAN RHYTHM, CANCER, AND METABOLISM. HERE, WE GENERATE INTESTINAL EPITHELIAL CELL (IEC)-SPECIFIC RORALPHA-DEFICIENT (RORALPHA(DELTAIEC)) MICE AND FIND THAT RORALPHA IS CRUCIAL FOR MAINTAINING INTESTINAL HOMEOSTASIS BY ATTENUATING NUCLEAR FACTOR KAPPAB (NF-KAPPAB) TRANSCRIPTIONAL ACTIVITY. RORALPHA(DELTAIEC) MICE EXHIBIT EXCESSIVE INTESTINAL INFLAMMATION AND HIGHLY ACTIVATED INFLAMMATORY RESPONSES IN THE DEXTRAN SULFATE SODIUM (DSS) MOUSE COLITIS MODEL. TRANSCRIPTOME ANALYSIS REVEALS THAT DELETION OF RORALPHA LEADS TO UP-REGULATION OF NF-KAPPAB TARGET GENES IN IECS. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALS CORECRUITMENT OF RORALPHA AND HISTONE DEACETYLASE 3 (HDAC3) ON NF-KAPPAB TARGET PROMOTERS AND SUBSEQUENT DISMISSAL OF CREB BINDING PROTEIN (CBP) AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) FOR TRANSCRIPTIONAL REPRESSION. TOGETHER, WE DEMONSTRATE THAT RORALPHA/HDAC3-MEDIATED ATTENUATION OF NF-KAPPAB SIGNALING CONTROLS THE BALANCE OF INFLAMMATORY RESPONSES, AND THERAPEUTIC STRATEGIES TARGETING THIS EPIGENETIC REGULATION COULD BE BENEFICIAL TO THE TREATMENT OF CHRONIC INFLAMMATORY DISEASES, INCLUDING INFLAMMATORY BOWEL DISEASE (IBD).	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11 1016  36 CIITA EXPRESSION IS REGULATED BY HISTONE DEACETYLASE ENZYMES AND HAS A ROLE IN ALPHA-SYNUCLEIN PRE-FORMED FIBRIL-INDUCED ANTIGEN PRESENTATION IN MURINE MICROGLIAL CELL LINE. AIM: PARKINSON'S DISEASE (PD) IS A CHRONIC NEURODEGENERATIVE DISORDER RELATED WITH SEVERAL GENETIC AND EPIGENETIC FACTORS. IN THE CONTEXT OF EPIGENETIC FACTORS, HISTONE ACETYLATION IS ONE OF THE MOST ASSOCIATED MECHANISMS WITH PARKINSON'S DISEASE PROGRESSION. THIS STUDY INVESTIGATES THE EFFECTS OF THE INCREASED HISTONE ACETYLATION ON ANTIGEN PRESENTATION IN MICROGLIAL CELLS WHICH WERE INDUCED BY PRE-FORMED FIBRILS OF ALPHA-SYNUCLEIN (PFF ALPHA-SYNUCLEIN). METHODS: PARKINSON'S DISEASE MODEL WAS CREATED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION TO THE BV-2 MICROGLIAL CELLS. BV-2 CELLS WERE CO-TREATED WITH CUDC-907 AND TMP-195 TO INCREASE HISTONE ACETYLATION IN THE PRESENCE OF ALPHA-SYNUCLEIN. ANTIGEN REPRESENTATION WAS EVALUATED BY DETERMINING EXPRESSION LEVELS OF MAJOR HISTOCOMPATIBILITY COMPLEX-II (MHC-II) AND CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX (CIITA). RESULTS: OUR RESULTS SHOWED THAT PFF ALPHA-SYNUCLEIN SIGNIFICANTLY INCREASED MHC-II EXPRESSION, AND THAT EFFECT WAS MOST SEVERE AT 6 H OF ADMINISTRATION OF ALPHA-SYNUCLEIN. INCREASING HISTONE ACETYLATION VIA CUDC-907 AND TMP-195 ENHANCED MHC-II LEVELS EXPRESSION, WHICH WAS MORE SEVERE IN CUDC-907. ADDITIONALLY, CIITA EXPRESSION LEVELS WERE SIGNIFICANTLY INCREASED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION AND INTENSIFIED WITH THE CO-TREATMENT OF CUDC-907 AND TMP-195. FURTHERMORE, PFF ALPHA-SYNUCLEIN CAUSED A TIME-DEPENDENT INCREASE IN THE IFN-GAMMA (IFN-?) AND INTERLEUKIN-16(IL-16) LEVELS, AND THAT INCREASE WAS POTENTIATED WITH CUDC-907 AND TMP-195. CONCLUSION: CHANGES IN MHC-II AND CIITA EXPRESSION INDICATE THAT HISTONE ACETYLATION INCREASES THE ANTIGEN PRESENTATION PROPERTIES OF MICROGLIAL CELLS AFTER PFF ALPHA-SYNUCLEIN OR HISTONE DEACETYLASE INHIBITOR (HDACI) ADMINISTRATION. OUR RESULTS SHOW THAT MICROGLIAL ANTIGEN PRESENTATION MIGHT HAVE AN ESSENTIAL ROLE IN THE PATHOLOGY OF PARKINSON'S DISEASE, AND ALPHA-SYNUCLEIN LIKELY TO PLAY A PRIMARY ROLE IN THIS MECHANISM.	2022	
                                                                                                                                                                                                                                 
12 6664  28 UPREGULATION OF LNCRNA71132 IN THE SPINAL CORD REGULATES HYPERSENSITIVITY IN A RAT MODEL OF BONE CANCER PAIN. BONE CANCER PAIN (BCP) IS A PERVASIVE CLINICAL SYMPTOM WHICH IMPAIRS THE QUALITY LIFE. LONG NONCODING RNAS (LNCRNAS) ARE ENRICHED IN THE CENTRAL NERVOUS SYSTEM AND PLAY INDISPENSABLE ROLES IN NUMEROUS BIOLOGICAL PROCESSES, WHILE ITS REGULATORY FUNCTION IN NOCICEPTIVE INFORMATION PROCESSING REMAINS ELUSIVE. HERE, WE REPORTED THAT FUNCTIONAL MODULATORY ROLE OF ENSRNOT00000071132 (LNCRNA71132) IN THE BCP PROCESS AND SPONGING WITH MIR-143 AND ITS DOWNSTREAM GPR85-DEPENDENT SIGNALING CASCADE. SPINAL LNCRNA71132 WAS REMARKABLY INCREASED IN THE RAT MODEL OF BONE CANCER PAIN. THE KNOCKDOWN OF SPINAL LNCRNA71132 REVERTED BCP BEHAVIORS AND SPINAL C-FOS NEURONAL SENSITIZATION. OVEREXPRESSION OF SPINAL LNCRNA71132 IN NAIVE RAT GENERATED PAIN BEHAVIORS, WHICH WERE ACCOMPANIED BY INCREASED SPINAL C-FOS NEURONAL SENSITIZATION. FURTHERMORE, IT WAS FOUND THAT LNCRNA71132 PARTICIPATES IN THE MODULATION OF BCP BY INVERSELY REGULATING THE PROCESSING OF MIR-143-5P. IN ADDITION, AN INCREASE IN EXPRESSION OF SPINAL LNCRNA71132 RESULTED IN THE DECREASE IN EXPRESSION OF MIR-143 UNDER THE BCP STATE. FINALLY, IT WAS FOUND THAT MIR-143-5P REGULATES PAIN BEHAVIORS BY TARGETING GPR85. OVEREXPRESSION OF MIR-143-5P IN THE SPINAL CORD REVERTED THE NOCICEPTIVE BEHAVIORS TRIGGERED BY BCP, ACCOMPANIED BY A DECREASE IN EXPRESSION OF SPINAL GPR85 PROTEIN, BUT NO INFLUENCE ON EXPRESSION OF GPR85 MRNA. THE FINDINGS OF THIS STUDY INDICATE THAT LNCRNA71132 WORKS AS A MIRNA SPONGE IN MIR-143-5P-MEDIATED POSTTRANSCRIPTIONAL MODULATION OF GPR85 EXPRESSION IN BCP. THEREFORE, EPIGENETIC INTERVENTIONS AGAINST LNCRNA71132 MAY POTENTIALLY WORK AS NOVEL TREATMENT AVENUES IN TREATING NOCICEPTIVE HYPERSENSITIVITY TRIGGERED BY BONE CANCER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13 5625  26 SELECTIVE CLASS I HISTONE DEACETYLASE INHIBITORS SUPPRESS PERSISTENT SPONTANEOUS NOCICEPTION AND THERMAL HYPERSENSITIVITY IN A RAT MODEL OF BEE VENOM-INDUCED INFLAMMATORY PAIN. TO CONFIRM WHETHER CLASS I HISTONE DEACETYLASE INHIBITORS (HDACIS) ARE EFFECTIVE IN RELIEF OF PERIPHERAL INFLAMMATORY PAIN, THE EFFECTS OF TWO SELECTIVE INHIBITORS, MS-275 AND MGCD0103, WERE STUDIED IN RATS INFLAMED BY SUBCUTANEOUS (S.C.) INJECTION OF BEE VENOM (BV). THE BV TEST IS CHARACTERIZED BY DISPLAYING BOTH PERSISTENT SPONTANEOUS NOCICEPTION (PSN) AND PRIMARY HYPERSENSITIVITY. INTRATHECAL (I.T.) PRE-TREATMENT OF EITHER MS-275 OR MGCD0103 WITH A SINGLE DOSE OF 60 NMOL/20 MUL RESULTED IN PROFOUND SUPPRESSION OF BOTH PSN AND PRIMARY THERMAL HYPERSENSITIVITY BUT WITHOUT SIGNIFICANT INFLUENCE UPON THE PRIMARY MECHANICAL HYPERSENSITIVITY AND MIRROR-IMAGE THERMAL HYPERSENSITIVITY. MOREOVER, THE UP-REGULATION OF BOTH HDAC1 AND HDAC2 INDUCED BY S.C. BV INJECTION WAS COMPLETELY SUPPRESSED BY I.T. PRE-TREATMENT OF MS-275. THE PRESENT RESULTS PROVIDE WITH ANOTHER NEW LINE OF EVIDENCE SHOWING INVOLVEMENT OF EPIGENETIC REGULATION OF CHROMATIN STRUCTURE BY HDAC1/2-MEDIATED HISTONE HYPOACETYLATION IN THE BV-INDUCED PSN AND THERMAL HYPERSENSITIVITY AND DEMONSTRATE THE BENEFICIAL EFFECTS OF CLASS I HDACIS IN PREVENTION OF PERIPHERAL INFLAMMATORY PAIN FROM OCCURRING.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14 3161  26 GRAINYHEAD-LIKE 2 (GRHL2) INHIBITS KERATINOCYTE DIFFERENTIATION THROUGH EPIGENETIC MECHANISM. WE RECENTLY IDENTIFIED GRAINYHEAD-LIKE 2 (GRHL2), A MAMMALIAN HOMOLOG OF GRAINYHEAD IN DROSOPHILA, TO BE A NOVEL TRANSCRIPTION FACTOR THAT REGULATES HTERT GENE EXPRESSION AND ENHANCES PROLIFERATION OF NORMAL HUMAN EPIDERMAL KERATINOCYTES (NHEK). IN THE CURRENT STUDY, WE SHOW THAT GRHL2 IMPAIRS KERATINOCYTE DIFFERENTIATION THROUGH TRANSCRIPTIONAL INHIBITION OF THE GENES CLUSTERED AT THE EPIDERMAL DIFFERENTIATION COMPLEX (EDC), LOCATED AT CHROMOSOME 1Q21. GENE EXPRESSION PROFILING AND SUBSEQUENT IN VITRO ASSAYS REVEALED CONSISTENT DOWNREGULATION OF EDC GENES, FOR EXAMPLE, IVL, KRT1, FLG, LCES, AND SPRRS, IN NHEK EXPRESSING EXOGENOUS GRHL2. IN VIVO BINDING ASSAY BY CHROMATIN IMMUNOPRECIPITATION REVEALED GRHL2 ASSOCIATION AT THE PROMOTER REGIONS OF ITS TARGET GENES, MANY OF WHICH BELONG TO EDC. EXOGENOUS GRHL2 EXPRESSION ALSO INHIBITED RECRUITMENT OF HISTONE DEMETHYLASE JMJD3 TO THE EDC GENE PROMOTERS AND ENHANCED THE LEVEL OF HISTONE 3 LYS 27 TRIMETHYLATION ENRICHMENT AT THESE PROMOTERS. SURVEY OF GRHL2 EXPRESSION IN HUMAN SKIN TISSUES DEMONSTRATED ENHANCED PROTEIN AND MRNA LEVELS IN CHRONIC SKIN LESIONS WITH IMPAIRED KERATINOCYTE DIFFERENTIATION, FOR EXAMPLE, ATOPIC DERMATITIS AND PSORIASIS, COMPARED WITH NORMAL EPIDERMIS. THESE DATA INDICATE THAT GRHL2 IMPAIRS EPIDERMAL DIFFERENTIATION BY INHIBITING EDC GENE EXPRESSION THROUGH EPIGENETIC MECHANISMS AND SUPPORT ITS ROLE IN THE HYPERPROLIFERATIVE SKIN DISEASES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15 3237  38 HEPATIC COX-2 EXPRESSION PROTECTS MICE FROM AN ALCOHOL-HIGH FAT DIET-INDUCED METABOLIC DISORDER BY INVOLVING PROTEIN ACETYLATION RELATED ENERGY METABOLISM. PURPOSE: A DIET HIGH IN FAT AND ETHANOL OFTEN RESULTS IN CHRONIC METABOLIC DISORDER, HEPATIC STEATOSIS, AND LIVER INFLAMMATION. CONSTITUTIVE HEPATIC CYCLOOXYGENASE-2 (COX-2) EXPRESSION COULD PROTECT FROM HIGH FAT-INDUCED METABOLISM DISTURBANCE IN A MURINE MODEL. IN THIS STUDY, WE EXPLORED THE INFLUENCE OF HCOX-2 TRANSGENIC [TG] TO HIGH FAT WITH ETHANOL-INDUCED METABOLIC DISORDER AND LIVER INJURY USING A MOUSE ANIMAL MODEL. METHODS: 12-WEEK-OLD MALE HEPATIC HCOX-2 TRANSGENIC (TG) OR WILD TYPE MICE (WT) WERE FED EITHER A HIGH FAT AND ETHANOL LIQUID DIET (HF+ETH) OR A REGULAR CONTROL DIET (RCD) FOR 5 WEEKS (FOUR GROUPS: RCD/WT, RCD/TG; HF+ETH/TG, HF+ETH/WT). WE ASSESSED METABOLIC BIOMARKERS, CYTOKINE PROFILES, HISTOMORPHOLOGY, AND GENE EXPRESSION TO STUDY THE IMPACT OF PERSISTENT HEPATIC COX-2 EXPRESSION ON DIET-INDUCED LIVER INJURY. RESULTS: IN THE HF+ETH DIET, CONSTITUTIVELY HEPATIC HUMAN COX-2 EXPRESSION PROTECTS MICE FROM BODY WEIGHT GAIN AND WHITE ADIPOSE TISSUE ACCUMULATION, ACCOMPANIED BY IMPROVED IPGTT RESPONSE, SERUM TRIGLYCERIDE/CHOLESTEROL LEVELS, AND LOWER LEVELS OF SERUM AND LIVER INFLAMMATORY CYTOKINES. HISTOLOGICALLY, HCOX-2 MICE SHOWED DECREASED HEPATIC LIPID DROPLETS ACCUMULATION, DECREASED HEPATOCYTE BALLOONING, AND IMPROVED STEATOSIS SCORES. HEPATIC HCOX-2 OVEREXPRESSION ENHANCED AKT INSULIN SIGNALING AND INCREASED FATTY ACID SYNTHESIS IN BOTH RCD AND HF+ETH DIET GROUPS. THE ANTI-LIPOGENIC EFFECT OF HCOX-2 TG IN THE HF+ETH DIET ANIMALS WAS MEDIATED BY INCREASING LIPID DISPOSAL THROUGH ENHANCED BETA-OXIDATION VIA ELEVATIONS IN THE EXPRESSION OF PPARALPHA AND PPARGAMMA, AND INCREASED HEPATIC AUTOPHAGY AS ASSESSED BY THE RATIO OF AUTOPHAGY MARKERS LC3 II/I IN HEPATIC TISSUE. VARIOUS PROTEIN ACETYLATION PATHWAY COMPONENTS, INCLUDING HAT, HDAC1, SIRT1, AND SNAIL1, WERE MODULATED IN HCOX-2 TG MICE IN EITHER RCD OR HF+ETH DIET. CONCLUSIONS: HEPATIC HUMAN COX-2 EXPRESSION PROTECTED MICE FROM THE METABOLIC DISORDER AND LIVER INJURY INDUCED BY A HIGH FAT AND ETHANOL DIET BY ENHANCING HEPATIC LIPID EXPENDITURE. EPIGENETIC REPROGRAMMING OF DIVERSE METABOLIC GENES MIGHT BE INVOLVED IN THE ANTI-LIPOGENIC EFFECT OF COX-2.	2021	
                                   
16 2450  31 EPIGENETIC SUPPRESSION OF LIVER X RECEPTOR BETA IN ANTERIOR CINGULATE CORTEX BY HDAC5 DRIVES CFA-INDUCED CHRONIC INFLAMMATORY PAIN. BACKGROUND: LIVER X RECEPTORS (LXRS), INCLUDING LXRALPHA AND LXRBETA, ARE KEY REGULATORS OF TRANSCRIPTIONAL PROGRAMS FOR BOTH CHOLESTEROL HOMEOSTASIS AND INFLAMMATION IN THE BRAIN. HERE, THE MODES OF ACTION OF LXRS AND THE EPIGENETIC MECHANISMS REGULATING LXRBETA EXPRESSION IN ANTERIOR CINGULATE CORTEX (ACC) OF CHRONIC INFLAMMATORY PAIN (CIP) ARE INVESTIGATED. METHODS: THE DEFICIT OF LXR ISOFORM AND ANALGESIC EFFECT OF LXR ACTIVATION BY GW3965 WERE EVALUATED USING THE MOUSE MODEL OF CIP INDUCED BY HINDPAW INJECTION OF COMPLETE FREUND'S ADJUVANT (CFA). THE MECHANISMS INVOLVED IN GW-MEDIATED ANALGESIC EFFECTS WERE ANALYZED WITH IMMUNOHISTOCHEMICAL METHODS, ELISA, CO-IMMUNOPRECIPITATION (CO-IP), WESTERN BLOT, AND ELECTROPHYSIOLOGICAL RECORDING. THE EPIGENETIC REGULATION OF LXRBETA EXPRESSION WAS INVESTIGATED BY CHROMATIN IMMUNOPRECIPITATION, QUANTITATIVE REAL-TIME PCR, AND SEQUENCING. RESULTS: WE REVEALED THAT CFA INSULT LED TO LXRBETA REDUCTION IN ACC, WHICH WAS ASSOCIATED WITH UPREGULATED EXPRESSION OF HISTONE DEACETYLASE 5 (HDAC5), AND KNOCKDOWN OF LXRBETA BY SHRNA LED TO THERMAL HYPERALGESIA. CO-IP SHOWED THAT LXRBETA INTERACTED WITH NF-KAPPAB P65 PHYSICALLY. LXRBETA ACTIVATION BY GW3965 EXERTED ANALGESIC EFFECTS BY INHIBITING THE NUCLEAR TRANSLOCATION OF NF-KAPPAB, REDUCING THE PHOSPHORYLATION OF MITOGEN-ACTIVATED PROTEIN KINASES (MAPKS) IN ACC, AND DECREASING THE PROMOTED INPUT-OUTPUT AND ENHANCED MEPSC FREQUENCY IN ACC NEURONS AFTER CFA EXPOSURE. IN VITRO EXPERIMENTS CONFIRMED THAT HDAC5 TRIGGERED HISTONE DEACETYLATION ON THE PROMOTER REGION OF LXRBETA, RESULTING IN DOWNREGULATION OF LXRBETA TRANSCRIPTION. CONCLUSION: THESE FINDINGS HIGHLIGHT AN EPIGENETIC MECHANISM UNDERLYING LXRBETA DEFICITS LINKED TO CIP, AND LXRBETA ACTIVATION MAY REPRESENT A POTENTIAL NOVEL TARGET FOR THE TREATMENT OF CIP WITH AN ALTERATION IN INFLAMMATION RESPONSES AND SYNAPTIC TRANSMISSION IN ACC.	2019	
                                                                                                                                                                                                                                                                                                                        
17 3128  38 GIPC-REGULATED IGFBP-3 PROMOTES HSC MIGRATION IN VITRO AND PORTAL HYPERTENSION IN VIVO THROUGH A BETA1-INTEGRIN PATHWAY. BACKGROUND & AIMS: TRANSFORMING GROWTH FACTOR (TGF-BETA)-INDUCED ACTIVATION OF QUIESCENT HEPATIC STELLATE CELLS (HSCS) AND THEIR TRANSFORMATION TO MYOFIBROBLASTS IS A KEY EVENT IN LIVER FIBROSIS AND PORTAL HYPERTENSION. GIPC (ALSO REFERRED TO AS SYNECTIN) IS A DOWNSTREAM SIGNAL ACTIVATION MOLECULE OF TGF-BETA AND OTHER RECEPTORS. IN THIS STUDY, WE SOUGHT TO IDENTIFY NOVEL GENES TARGETED BY TGF-BETA AND GIPC AND ELUCIDATE IF AND HOW THEY MAY CONTRIBUTE TO LIVER FIBROSIS. METHODS: WE PERFORMED SEQUENTIAL MESSENGER RNA SEQUENCING ANALYSIS ON TGF-BETA-STIMULATED HSCS AND THEN ON TGF-BETA-STIMULATED HSCS IN THE PRESENCE AND ABSENCE OF GIPC ALSO REFERRED TO AS SYNECTIN (GIPC) KNOCKDOWN. INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN-3 (IGFBP-3) TRANSPORT PROTEIN EMERGED AS A TOP ACTIVATION TARGET OF BOTH TGF-BETA AND GIPC. QUANTITATIVE POLYMERASE CHAIN REACTION, ENZYME-LINKED IMMUNOSORBENT ASSAY, TARGETED CHROMATIN IMMUNOPRECIPITATION, AND WESTERN BLOT ANALYSIS WERE DONE FOR FURTHER CONFIRMATION. RESULTS: IGFBP-3, AN INSULIN GROWTH FACTOR TRANSPORT PROTEIN, EMERGED AS A TOP ACTIVATION TARGET OF BOTH TGF-BETA AND GIPC, WHICH WAS CONFIRMED BY QUANTITATIVE POLYMERASE CHAIN REACTION, ENZYME-LINKED IMMUNOSORBENT ASSAY, AND WESTERN BLOT ANALYSIS. TARGETED CHROMATIN IMMUNOPRECIPITATION SHOWED THAT GIPC INCREASES THE HISTONE 3 LYSINE 27 (H3K27) ACETYLATION ACTIVATING MARK AND CONCURRENTLY DECREASES THE H3K27 INHIBITORY TRIMETHYLATION (H3K27M3) MARK, PROVIDING AN EPIGENETIC CORRELATE TO THE GENE REGULATION CHANGES. IN VIVO, GLOBAL KNOCKOUT OF IGFBP-3 MICE RESULTED IN ATTENUATION OF HSC ACTIVATION MARKERS AND ATTENUATION OF PORTAL PRESSURE IN RESPONSE TO CHRONIC LIVER INJURY MODELS. ANALYSIS OF SERUM LEVELS FROM CIRRHOTIC PATIENTS ALSO SHOWED AN IGFBP-3 INCREASE OF MORE THAN 2-FOLD COMPARED WITH HEALTHY CONTROLS. FINALLY, IN VITRO MECHANISM STUDIES SHOWED THAT IGFBP-3 PROMOTES HSC MIGRATION THROUGH INTEGRIN-DEPENDENT PHOSPHORYLATION OF PROTEIN KINASE B. CONCLUSIONS: TGF-BETA UP-REGULATES IGFBP-3 THROUGH GIPC, LEADING TO INCREASED HSC MIGRATION IN VITRO AND PROMOTES PORTAL HYPERTENSION IN VIVO. THESE STUDIES SUPPORT THE ROLE OF IGFBP-3 AS A POTENTIAL PATHOPHYSIOLOGIC TARGET OR BIOMARKER IN CHRONIC LIVER DISEASE.	2020	

18 2032  32 EPIGENETIC CHANGES IN P21 EXPRESSION IN RENAL CELLS AFTER EXPOSURE TO BROMATE. THIS STUDY TESTED THE HYPOTHESIS THAT BROMATE (KBRO3)-INDUCED RENAL CELL DEATH IS MEDIATED BY EPIGENETIC MECHANISMS. GLOBAL DNA METHYLATION, AS ASSESSED BY 5-METHYLCYTOSINE STAINING, WAS NOT CHANGED IN NORMAL RAT KIDNEY CELLS TREATED WITH ACUTE CYTOTOXIC DOSES OF KBRO3 (100 AND 200 PPM), AS COMPARED WITH CONTROLS. HOWEVER, KBRO3 TREATMENT DID INCREASE P38, P53 AND HISTONE 2AX (H2AX) PHOSPHORYLATION, AND P21 EXPRESSION. TREATMENT OF CELLS WITH INHIBITORS OF DNA METHYLTRANSFERASE (5-AZACYTIDINE OR 5-AZA) AND HISTONE DEACETYLASE (TRICHOSTATIN A OR TSA) IN ADDITION TO KBRO3 INCREASED CYTOTOXICITY, AS COMPARED WITH CELLS EXPOSED TO KBRO3 ALONE. 5-AZA AND TSA CO-TREATMENT DID NOT ALTER P38 OR P53 PHOSPHORYLATION, BUT SLIGHTLY DECREASED H2AX PHOSPHORYLATION AND SIGNIFICANTLY DECREASED P21 EXPRESSION. WE ALSO ASSESSED EPIGENETIC CHANGES IN CELLS TREATED UNDER SUB-CHRONIC CONDITIONS WITH ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF KBRO3. UNDER THESE CONDITIONS (0-10PPM KBRO3 FOR UP TO 18 DAYS), WE DETECTED NO INCREASES IN CELL DEATH OR DNA DAMAGE. IN CONTRAST, SLIGHT ALTERATIONS WERE DETECTED IN THE PHOSPHORYLATION OF H2AX, P38, AND P53. SUB-CHRONIC LOW-DOSE KBRO3 TREATMENT ALSO INDUCED A BIPHASIC RESPONSE IN P21 EXPRESSION, WITH LOWER CONCENTRATIONS INCREASING EXPRESSION, BUT HIGHER CONCENTRATIONS DECREASING EXPRESSION. METHYLATION-SPECIFIC PCR DEMONSTRATED THAT SUB-CHRONIC KBRO3 TREATMENT ALTERED THE METHYLATION OF CYTOSINE BASES IN THE P21 GENE, AS COMPARED WITH CONTROLS, CORRELATING TO ALTERATIONS IN P21 PROTEIN EXPRESSION. COLLECTIVELY, THESE DATA SHOW THE NOVEL FINDING THAT KBRO3-INDUCED RENAL CELL DEATH IS ALTERED BY INHIBITORS OF EPIGENETIC MODIFYING ENZYMES AND THAT KBRO3 ITSELF INDUCES EPIGENETIC CHANGES IN THE P21 GENE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19 3126  38 GINSENOSIDE REDUCES COGNITIVE IMPAIRMENT DURING CHRONIC CEREBRAL HYPOPERFUSION THROUGH BRAIN-DERIVED NEUROTROPHIC FACTOR REGULATED BY EPIGENETIC MODULATION. INCREASED EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN ASSOCIATED WITH MEMORY-ENHANCING AND NEUROPROTECTIVE PROPERTIES OF SOME DRUGS UNDER CHRONIC CEREBRAL HYPOPERFUSION (CCH) CONDITION. GINSENOSIDE RD (GSRD), ONE OF THE MAIN ACTIVE INGREDIENTS IN PANAX GINSENG, IS WIDELY USED FOR BRAIN PROTECTION. HOWEVER, IT IS POORLY UNDERSTOOD WHETHER EPIGENETIC MECHANISMS IMPLIED IN THE BDNF MODULATION AFTER GSRD TREATMENT FOR CCH REMAIN ELUSIVE. HERE, WE INVESTIGATED THE NEUROPROTECTIVE EFFECTS OF GSRD AND THE INVOLVED MECHANISMS. WE DEMONSTRATED THAT GSRD ADMINISTRATION AMELIORATED CCH-INDUCED IMPAIRMENT OF LEARNING AND MEMORY BEHAVIORS, EVIDENCED BY DECREASED ESCAPE LATENCY AND INCREASED NUMBER OF CROSSING THE PLATFORM IN MORRIS WATER MAZE TEST. THIS IMPROVEMENT WAS ASSOCIATED WITH PROMOTED NEURON SURVIVAL AND INCREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND PREFRONTAL CORTEX OF CCH MICE. GSRD IMPROVED NEURON SURVIVAL AND DECREASED NEURON APOPTOSIS AND THE LEVEL OF CASPASE-3 UNDER OXYGEN-GLUCOSE DEPRIVATION/REOXYGENATION (OGD/R) BY UPREGULATION OF BDNF AS WELL AS IN VITRO. THE LEVELS OF ACETYLATED HISTONE H3 (AC-H3) AND HISTONE DEACETYLASE (HISTONE DEACETYLASE 2 (HDAC2)) WERE ALTERED UNDER OGD/R IN A TIME-DEPENDENT MANNER, AND GSRD REESTABLISHED THE BALANCE BETWEEN AC-H3 AND HDAC2 WHICH RESULTED IN UPREGULATION OF BDNF AND INCREASED NEURON SURVIVAL. MS-275, AN INHIBITOR OF CLASS I HDACS, ABOLISHED THE LEVELS OF AC-H3 AT THE BDNF PROMOTERS AND ENHANCED UPREGULATION OF BDNF AFTER GSRD ADMINISTRATION, SUGGESTING A SYNERGISTIC EFFECT BETWEEN GSRD AND MS-275. ALL THE DATA SUGGESTED THAT GSRD PROVIDED NEUROPROTECTION BY EPIGENETIC MODULATION WHICH ACCOUNTED FOR THE REGULATION OF BDNF IN CCH MICE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
20  460  30 ARACHIDONIC ACID 15-LIPOXYGENASE: EFFECTS OF ITS EXPRESSION, METABOLITES, AND GENETIC AND EPIGENETIC VARIATIONS ON AIRWAY INFLAMMATION. ARACHIDONIC ACID 15-LIPOXYGENASE (ALOX15) IS AN ENZYME THAT CAN OXIDIZE POLYUNSATURATED FATTY ACIDS. ALOX15 IS STRONGLY EXPRESSED IN AIRWAY EPITHELIAL CELLS, WHERE IT CATALYZES THE CONVERSION OF ARACHIDONIC ACID TO 15-HYDROXYEICOSATETRAENOIC ACID (15-HETE) INVOLVED IN VARIOUS AIRWAY INFLAMMATORY DISEASES. INTERLEUKIN (IL)-4 AND IL-13 INDUCE ALOX15 EXPRESSION BY ACTIVATING JAK2 AND TYK2 KINASES AS WELL AS SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION (STATS) 1/3/5/6. ALOX15 UP-REGULATION AND SUBSEQUENT ASSOCIATION WITH PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN 1 (PEBP1) ACTIVATE THE MITOGEN-ACTIVATED EXTRACELLULAR SIGNAL-REGULATED KINASE (MEK)-EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) PATHWAY, THUS INDUCING EOSINOPHIL-MEDIATED AIRWAY INFLAMMATION. IN ADDITION, ALOX15 PLAYS A SIGNIFICANT ROLE IN PROMOTING THE MIGRATION OF IMMUNE CELLS, SUCH AS IMMATURE DENDRITIC CELLS, ACTIVATED T CELLS, AND MAST CELLS, AND AIRWAY REMODELING, INCLUDING GOBLET CELL DIFFERENTIATION. GENOME-WIDE ASSOCIATION STUDIES HAVE REVEALED MULTIPLE ALOX15 VARIANTS AND THEIR SIGNIFICANT CORRELATION WITH THE RISK OF DEVELOPING AIRWAY DISEASES. THE EPIGENETIC MODIFICATIONS OF THE ALOX15 GENE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS, HAVE BEEN SHOWN TO CLOSELY RELATE WITH AIRWAY INFLAMMATION. THIS REVIEW SUMMARIZES THE ROLE OF ALOX15 IN DIFFERENT PHENOTYPES OF ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CHRONIC RHINOSINUSITIS, ASPIRIN-EXACERBATED RESPIRATORY DISEASE, AND NASAL POLYPS, SUGGESTING NEW TREATMENT STRATEGIES FOR THESE AIRWAY INFLAMMATORY DISEASES WITH COMPLEX ETIOLOGY AND POOR TREATMENT RESPONSE.	2021