1 4105 69 MECHANISM AND THERAPEUTIC TARGETS OF C-JUN-N-TERMINAL KINASES ACTIVATION IN NONALCOHOLIC FATTY LIVER DISEASE. NON-ALCOHOLIC FATTY LIVER (NAFL) IS THE MOST COMMON CHRONIC LIVER DISEASE. ACTIVATION OF MITOGEN-ACTIVATED KINASES (MAPK) CASCADE, WHICH LEADS TO C-JUN N-TERMINAL KINASE (JNK) ACTIVATION OCCURS IN THE LIVER IN RESPONSE TO THE NUTRITIONAL AND METABOLIC STRESS. THE ABERRANT ACTIVATION OF MAPKS, ESPECIALLY C-JUN-N-TERMINAL KINASES (JNKS), LEADS TO UNWANTED GENETIC AND EPI-GENETIC MODIFICATIONS IN ADDITION TO THE METABOLIC STRESS ADAPTATION IN HEPATOCYTES. A MECHANISM OF SUSTAINED P-JNK ACTIVATION WAS IDENTIFIED IN ACUTE AND CHRONIC LIVER DISEASES, SUGGESTING AN IMPORTANT ROLE OF ABERRANT JNK ACTIVATION IN NASH. THEREFORE, MODULATION OF JNK ACTIVATION, RATHER THAN TARGETING JNK PROTEIN LEVELS, IS A PLAUSIBLE THERAPEUTIC APPLICATION FOR THE TREATMENT OF CHRONIC LIVER DISEASE. 2022 2 2450 20 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 3 1013 25 CIGARETTE SMOKE-INDUCED INFLAMMATION: NLRP10-MEDIATED MECHANISMS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A PROGRESSIVE, LIFE-THREATENING DISEASE THAT CAUSES IRREVERSIBLE LUNG DAMAGE. CIGARETTE SMOKING IS THE CHIEF ETIOLOGIC FACTOR FOR THE COMMENCEMENT OF THIS CONDITION. DESPITE CONSTANT EFFORTS TO DEVELOP THERAPEUTIC INTERVENTIONS AND TO ASCERTAIN THE MOLECULAR MECHANISM LEADING TO THE PATHOPHYSIOLOGY OF THIS DISEASE, MUCH REMAINS UNKNOWN. HOWEVER, PATTERN RECOGNITION RECEPTORS (PRRS), I.E., TOLL-LIKE-RECEPTORS (TLRS) AND NOD-LIKE RECEPTORS (NLRS) ARE BELIEVED TO PLAY IMPORTANT ROLES IN COPD AND COULD SERVE AS EFFECTIVE THERAPEUTIC TARGETS. ALTHOUGH THE ROLE OF TLRS IN COPD HAS BEEN WELL STUDIED, THE IMPORTANCE OF NLRS HAS NOT YET BEEN EXPLORED IN DETAIL. THE NLR FAMILY MEMBER NLRP10 (AKA NOD8, PAN5, PYNOD) IS THE ONLY MEMBER OF THIS FAMILY OF PROTEINS THAT LACKS THE LEUCINE RICH REPEAT (LRR) DOMAIN RESPONSIBLE FOR DETECTION OF PATHOGEN AND DANGER-ASSOCIATED MOLECULAR PATTERNS (PAMPS/DAMPS). THEREFORE, INSTEAD OF FUNCTIONING AS A PRR, NLRP10 MAY HAVE A BROADER REGULATORY ROLE. TO ELUCIDATE THE ROLE OF NLRP10 IN SECONDHAND SMOKE (SHS)-INDUCED INFLAMMATION, WE EXPOSED C57BL/6 (WT) AND NLRP10-DEFICIENT MICE (NLRP10(-/-)) ON THE C57BL/6 BACKGROUND TO FILTERED AIR- OR SHS- FOR 6 WEEKS (ACUTE EXPOSURE) AND ASSESSED THE RESULTING MOLECULAR EVENTS. LEUKOCYTE RECRUITMENT IN SHS-EXPOSED NLRP10(-/-) MICE WAS FOUND TO BE SIGNIFICANTLY LOWER COMPARED TO SHS-EXPOSED WT MICE. IN ADDITION, WE OBSERVED AN IMPORTANT ROLE FOR NLRP10 IN SHS-MEDIATED CASPASE-1 ACTIVATION, CYTOKINE/CHEMOKINE PRODUCTION (IL-1BETA, IL-18, MCP-1 AND IL-17A), AND INDUCTION OF NF-KAPPAB AND MAPKS IN THE LUNGS OF C57BL/6 MICE. THE REDUCED INFLUX OF CD4(+)IL-17A(+) AND CD8(+)IL-17A(+) CELLS INTO THE LUNGS OF SHS-EXPOSED NLRP10(-/-) MICE AND IMPAIRED DIFFERENTIATION OF NLRP10(-/-) TH0 CELLS INTO TH17 CELLS (EX VIVO) PROVIDE INSIGHT INTO THE MECHANISTIC DETAILS UNDERLYING NLRP10-DEPENDENT IL-17 PRODUCTION. WE FURTHER SUBSTANTIATED OUR IN VIVO FINDINGS BY CHALLENGING HUMAN ALVEOLAR TYPE II EPITHELIAL CELLS (A549) TRANSFECTED WITH SCRAMBLED- OR NLRP10-SIRNA WITH CIGARETTE SMOKE EXTRACT (CSE). WE OBSERVED AN IMPORTANT ROLE OF NLRP10 IN CYTOKINE AND CHEMOKINE PRODUCTION AS WELL AS EXPRESSION OF NF-KAPPAB AND MAPKS IN CSE-EXPOSED A549 CELLS. FURTHERMORE, REPLENISHMENT OF A549 CELL CULTURE WITH RECOMBINANT IL-17A (RIL-17A) DURING NLRP10 KNOCKDOWN RESCUED CSE-INDUCED INFLAMMATORY RESPONSES. TO IDENTIFY UPSTREAM MEDIATORS OF NLRP10 REGULATION WE INVESTIGATED EPIGENETIC MARKERS WITHIN THE NLRP10 PROMOTER FOLLOWING CIGARETTE SMOKE EXPOSURE AND OBSERVED SIGNIFICANT CHANGES IN ACTIVE AS WELL AS REPRESSIVE GENE MARKERS ON HISTONE 3 AND HISTONE 4 USING BOTH IN VIVO AND IN VITRO STUDY MODELS. FURTHER, ALTERATIONS IN THE RESPECTIVE HISTONE ACETYL- AND METHYLTRANSFERASES (PCAF, SET1, ESET, SUV20H1) CORRELATED WELL WITH THE OBSERVED HISTONE MODIFICATIONS. OVERALL, OUR FINDINGS SUGGEST A NOVEL ROLE OF EPIGENETICALLY REGULATED NLRP10 IN TH17/IL-17 SIGNALING DURING CS EXPOSURE. 2018 4 1667 19 DOWNREGULATION OF PCAF BY MIR-181A/B PROVIDES FEEDBACK REGULATION TO TNF-ALPHA-INDUCED TRANSCRIPTION OF PROINFLAMMATORY GENES IN LIVER EPITHELIAL CELLS. ABERRANT CELLULAR RESPONSES TO PROINFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA, ARE PATHOGENIC FEATURES IN MOST CHRONIC INFLAMMATORY DISEASES. A VARIETY OF EXTRACELLULAR AND INTRACELLULAR FEEDBACK PATHWAYS HAS EVOLVED TO PREVENT AN INAPPROPRIATE CELLULAR REACTION TO THESE PROINFLAMMATORY CYTOKINES. IN THIS STUDY, WE REPORT THAT TNF-ALPHA TREATMENT OF HUMAN AND MOUSE CHOLANGIOCYTES AND HEPATOCYTES DOWNREGULATED EXPRESSION OF P300/CBP-ASSOCIATED FACTOR (PCAF), A COACTIVATOR AND AN ACETYLTRANSFERASE THAT PROMOTES HISTONE ACETYLATION AND GENE TRANSCRIPTION. OF THESE UPREGULATED MICRORNAS IN TNF-ALPHA-TREATED CELLS, MIR-181A/B (MIR-181A AND MIR-181B) SUPPRESSED TRANSLATION OF PCAF MRNA. FUNCTIONAL MANIPULATION OF MIR-181A/B CAUSED RECIPROCAL ALTERATIONS IN PCAF PROTEIN EXPRESSION IN CULTURED CHOLANGIOCYTES AND HEPATOCYTES. INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS BLOCKED TNF-ALPHA-INDUCED SUPPRESSION OF PCAF EXPRESSION. PROMOTER RECRUITMENT OF PCAF WAS SHOWN TO BE ASSOCIATED WITH TNF-ALPHA-INDUCED TRANSCRIPTION OF INFLAMMATORY GENES. INTRIGUINGLY, PRETREATMENT OF CELLS WITH TNF-ALPHA INHIBITED TRANSCRIPTION OF INFLAMMATORY GENES IN RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. OVEREXPRESSION OF PCAF OR INHIBITION OF MIR-181A/B FUNCTION WITH ANTI-MIRS ATTENUATED THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON EPITHELIAL INFLAMMATORY RESPONSE TO SUBSEQUENT TNF-ALPHA STIMULATION. DOWNREGULATION OF PCAF AND THE INHIBITORY EFFECTS OF TNF-ALPHA PRETREATMENT ON LIVER EPITHELIAL INFLAMMATORY RESPONSE WERE FURTHER CONFIRMED IN A MOUSE MODEL OF TNF-ALPHA I.P. INJECTION. THESE DATA SUGGEST THAT PCAF IS A TARGET FOR MIR-181A/B, AND DOWNREGULATION OF PCAF BY TNF-ALPHA PROVIDES NEGATIVE FEEDBACK REGULATION TO INFLAMMATORY REACTIONS IN LIVER EPITHELIAL CELLS, A PROCESS THAT MAY BE RELEVANT TO THE EPIGENETIC FINE-TUNING OF EPITHELIAL INFLAMMATORY PROCESSES IN GENERAL. 2012 5 5227 16 PRMT6 MEDIATES INFLAMMATION VIA ACTIVATION OF THE NF-KAPPAB/P65 PATHWAY ON A CIGARETTE SMOKE EXTRACT-INDUCED MURINE EMPHYSEMA MODEL. INTRODUCTION: SMOKE-DRIVEN LUNG INFLAMMATION IS CONSIDERED TO BE THE MAJOR PATHOPHYSIOLOGY MECHANISM OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA. PROTEIN ARGININE METHYLTRANSFERASE 6 (PRMT6) IS A KEY EPIGENETIC ENZYME, WHICH IS RELATED TO PROTECTING THE TRI-METHYLATION OF H3K4 (H3K4ME3). WE HYPOTHESIZED THAT PTMT6 PROTECTS LUNG INFLAMMATION THROUGH THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY. METHODS: MICE WERE INJECTED WITH CIGARETTE SMOKE EXTRACT (CSE) OR PBS TO ESTABLISH A MICE MODEL, INTRATRACHEALLY INSTILLED WITH OVEREXPRESSED PRMT6 OR NEGATIVE CONTROL VECTOR. MORPHOMETRY OF LUNG SLIDES AND LUNG FUNCTION WERE MEASURED. WE DETERMINED THE PROTEIN EXPRESSION OF PRMT6 AND ITS RELATED HISTONE TARGETS, THE ACTIVATION OF NF-KAPPAB PATHWAY, THE LEVEL OF TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) AND INTERLEUKIN-1BETA (IL-1BETA). RESULTS: AFTER PRMT6 OVEREXPRESSION, THE MORPHOMETRY INDEXES AND LUNG FUNCTION WERE IMPROVED. ALSO, THE EXPRESSION OF H3K4ME3 WAS DECREASED. OVEREXPRESSED PRMT6 COULD SUPPRESS CSE-INDUCED NF-KAPPAB ACTIVATION AND PRO-INFLAMMATION GENES EXPRESSION. CONCLUSIONS: THE OVEREXPRESSED PRMT6 COULD SERVE AS AN INFLAMMATION INHIBITOR, POTENTIALLY THROUGH BLOCKING THE NF-KAPPAB/P65 PATHWAY IN THE MURINE EMPHYSEMA MODEL. 2020 6 5479 13 RESVERATROL ATTENUATES CIGARETTE SMOKE EXTRACT INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY ACCELERATED LUNG AGING. SMOKING IS THE CRITICAL RISK FACTOR FOR COPD. CELLULAR SENESCENCE OF AIRWAY EPITHELIAL CELLS IS THE CYTOLOGICAL BASIS OF ACCELERATED LUNG AGING IN COPD, AND THE REGULATION OF MICRORNAS (MIRNAS) IS THE CENTRAL EPIGENETIC MECHANISM OF CELLULAR SENESCENCE. RESVERATROL (RES) IS A POLYPHENOL WITH ANTI-AGING PROPERTIES. THIS STUDY INVESTIGATED WHETHER RES ATTENUATES CIGARETTE SMOKE EXTRACT (CSE)-INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS (BEAS-2B) THROUGH THE MIR-34A/SIRT1/NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) PATHWAY. BEAS-2B CELLS WERE TREATED WITH RES, CSE AND TRANSFECTED WITH MIR-34A-5P MIMICS. CELLULAR SENESCENCE WAS EVALUATED BY SENESCENCE -RELATED BETA-GALACTOSIDASE (SA-BETA-GAL) STAINING AND EXPRESSION OF SENESCENCE-RELATED GENES (P16, P21, AND P53). THE EXPRESSIONS OF MIR-34A-5P, SIRT1, AND NF-KAPPAB P65 WERE EXAMINED USING QUANTITATIVE REAL TIME POLYMERASE CHAIN REACTION AND WESTERN BLOTTING. THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) WERE ASSESSED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. THE BINDING BETWEEN MIR-34A-5P AND SIRT1 WAS CONFIRMED BY DUAL-LUCIFERASE REPORTER ASSAY. THE RESULTS SHOWED THAT CSE DOSE-DEPENDENTLY DECREASED CELL VIABILITY AND ELEVATED CELLULAR SENESCENCE, CHARACTERIZED BY INCREASED SA-BETA-GAL STAINING AND SENESCENCE-RELATED GENE EXPRESSIONS (P16, P21, AND P53). FURTHER, CSE DOSE-DEPENDENTLY INCREASED THE EXPRESSION OF MIR-34A-5P AND SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN BEAS-2B CELLS. PRETREATMENT WITH RES INHIBITED CSE-INDUCED CELLULAR SENESCENCE AND SECRETION OF SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN A DOSE-DEPENDENT MANNER. MOREOVER, RES REVERSED THE CSE-INDUCED DOWN-REGULATION OF SIRT1 AND UP-REGULATION OF MIR-34A-5P AND NF-KAPPAB P65. SIRT1 IS A TARGET OF MIR-34A-5P. OVEREXPRESSION OF MIR-34A-5P VIA TRANSFECTION WITH MIR-34A-5P MIMIC IN BEAS-2B CELLS ATTENUATED THE INHIBITORY EFFECT OF RES ON CELLULAR SENESCENCE, ACCOMPANIED BY REVERSING THE EXPRESSION OF SIRT1 AND NF-KAPPAB P65. IN CONCLUSION, RES ATTENUATED CSE-INDUCED CELLULAR SENESCENCE IN BEAS-2B CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY, WHICH MAY PROVIDE A NEW APPROACH FOR COPD TREATMENT. 2022 7 692 19 BRD4 PROMOTES HEPATIC STELLATE CELLS ACTIVATION AND HEPATIC FIBROSIS VIA MEDIATING P300/H3K27AC/PLK1 AXIS. HEPATIC FIBROSIS (HF) IS A REVERSIBLE WOUND-HEALING RESPONSE CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX (ECM) DEPOSITION AND SECONDARY TO PERSISTENT CHRONIC INJURY. BROMODOMAIN PROTEIN 4 (BRD4) COMMONLY FUNCTIONS AS A "READER" TO REGULATE EPIGENETIC MODIFICATIONS INVOLVED IN VARIOUS BIOLOGICAL AND PATHOLOGICAL EVENTS, BUT THE MECHANISM OF HF REMAINS UNCLEAR. IN THIS STUDY, WE ESTABLISHED A CCL(4)-INDUCED HF MODEL AND SPONTANEOUS RECOVERY MODEL IN MICE AND FOUND ABERRANT BRD4 EXPRESSION, WHICH WAS CONSISTENT WITH THE RESULTS IN HUMAN HEPATIC STELLATE CELLS (HSCS)- LX2 CELLS IN VITRO. SUBSEQUENTLY, WE FOUND THAT DISTRICTION AND INHIBITION OF BRD4 RESTRAINED TGFBETA-INDUCED TRANS-DIFFERENTIATION OF LX2 CELLS INTO ACTIVATED, PROLIFERATIVE MYOFIBROBLASTS AND ACCELERATED APOPTOSIS, AND BRD4 OVEREXPRESSION BLOCKED MDI-INDUCED LX2 CELLS INACTIVATION AND PROMOTED THE PROLIFERATION AND INHIBITED APOPTOSIS OF INACTIVATED CELLS. ADDITIONALLY, ADENO-ASSOCIATED VIRUS SEROTYPE 8-LOADED SHORT HAIRPIN RNA-MEDIATED BRD4 KNOCKDOWN IN MICE SIGNIFICANTLY ATTENUATED CCL(4)-INDUCED FIBROTIC RESPONSES INCLUDING HSCS ACTIVATION AND COLLAGEN DEPOSITION. MECHANISTICALLY, BRD4 DEFICIENCY INHIBITED PLK1 EXPRESSION IN ACTIVATED LX2 CELLS, AND CHIP AND CO-IP ASSAYS REVEALED THAT BRD4 REGULATION OF PLK1 WAS DEPENDENT ON P300-MEDIATED ACETYLATION MODIFICATION FOR H3K27 ON THE PLK1 PROMOTER. IN CONCLUSION, BRD4 DEFICIENCY IN THE LIVER ALLEVIATES CCL(4)-INDUCED HF IN MICE, AND BRD4 PARTICIPATES IN THE ACTIVATION AND REVERSAL OF HSCS THROUGH POSITIVELY REGULATING THE P300/H3K27AC/PLK1 AXIS, PROVIDING A POTENTIAL INSIGHT FOR HF THERAPY. 2023 8 3329 18 HISTONE DEACETYLASE 6-MEDIATED SELECTIVE AUTOPHAGY REGULATES COPD-ASSOCIATED CILIA DYSFUNCTION. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) INVOLVES ABERRANT AIRWAY INFLAMMATORY RESPONSES TO CIGARETTE SMOKE (CS) THAT ARE ASSOCIATED WITH EPITHELIAL CELL DYSFUNCTION, CILIA SHORTENING, AND MUCOCILIARY CLEARANCE DISRUPTION. EXPOSURE TO CS REDUCED CILIA LENGTH AND INDUCED AUTOPHAGY IN VIVO AND IN DIFFERENTIATED MOUSE TRACHEAL EPITHELIAL CELLS (MTECS). AUTOPHAGY-IMPAIRED (BECN1+/- OR MAP1LC3B-/-) MICE AND MTECS RESISTED CS-INDUCED CILIA SHORTENING. FURTHERMORE, CS INCREASED THE AUTOPHAGIC TURNOVER OF CILIARY PROTEINS, INDICATING THAT AUTOPHAGY MAY REGULATE CILIA HOMEOSTASIS. WE IDENTIFIED CYTOSOLIC DEACETYLASE HDAC6 AS A CRITICAL REGULATOR OF AUTOPHAGY-MEDIATED CILIA SHORTENING DURING CS EXPOSURE. MICE BEARING AN X CHROMOSOME DELETION OF HDAC6 (HDAC6-/Y) AND MTECS FROM THESE MICE HAD REDUCED AUTOPHAGY AND WERE PROTECTED FROM CS-INDUCED CILIA SHORTENING. AUTOPHAGY-IMPAIRED BECN1-/-, MAP1LC3B-/-, AND HDAC6-/Y MICE OR MICE INJECTED WITH AN HDAC6 INHIBITOR WERE PROTECTED FROM CS-INDUCED MUCOCILIARY CLEARANCE (MCC) DISRUPTION. MCC WAS PRESERVED IN MICE GIVEN THE CHEMICAL CHAPERONE 4-PHENYLBUTYRIC ACID, BUT WAS DISRUPTED IN MICE LACKING THE TRANSCRIPTION FACTOR NRF2, SUGGESTING THAT OXIDATIVE STRESS AND ALTERED PROTEOSTASIS CONTRIBUTE TO THE DISRUPTION OF MCC. ANALYSIS OF HUMAN COPD SPECIMENS REVEALED EPIGENETIC DEREGULATION OF HDAC6 BY HYPOMETHYLATION AND INCREASED PROTEIN EXPRESSION IN THE AIRWAYS. WE CONCLUDE THAT AN AUTOPHAGY-DEPENDENT PATHWAY REGULATES CILIA LENGTH DURING CS EXPOSURE AND HAS POTENTIAL AS A THERAPEUTIC TARGET FOR COPD. 2013 9 5868 18 SUPPRESSIVE EFFECTS OF METFORMIN ON T-HELPER 1-RELATED CHEMOKINES EXPRESSION IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. PURPOSE OF THE STUDY: TYPE 1 AND TYPE 2 DIABETES MELLITUS (DM) ARE CHRONIC T-CELL-MEDIATED INFLAMMATORY DISEASES. METFORMIN IS A WIDELY USED DRUG FOR TYPE 2 DM THAT REDUCES THE NEED FOR INSULIN IN TYPE 1 DM. HOWEVER, WHETHER METFORMIN HAS AN ANTI-INFLAMMATORY EFFECT FOR TREATING DM IS UNKNOWN. WE INVESTIGATED THE ANTI-INFLAMMATORY MECHANISM OF METFORMIN IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. MATERIALS AND METHODS: THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1 WAS PRETREATED WITH METFORMIN AND STIMULATED WITH LIPOPOLYSACCHARIDE (LPS). THE PRODUCTION OF T-HELPER (TH)-1-RELATED CHEMOKINES INCLUDING INTERFERON-GAMMA-INDUCED PROTEIN-10 (IP-10) AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), TH2-RELATED CHEMOKINE MACROPHAGE-DERIVED CHEMOKINE, AND THE PROINFLAMMATORY CHEMOKINE TUMOR NECROSIS FACTOR-ALPHA WAS MEASURED USING ENZYME-LINKED IMMUNOSORBENT ASSAY. INTRACELLULAR SIGNALING PATHWAYS WERE INVESTIGATED USING WESTERN BLOT ANALYSIS AND CHROMATIN IMMUNOPRECIPITATION ASSAY. RESULTS: METFORMIN SUPPRESSED LPS-INDUCED IP-10 AND MCP-1 PRODUCTION AS WELL AS LPS-INDUCED PHOSPHORYLATION OF C-JUN N-TERMINAL KINASE (JNK), P38, EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK), AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB). MOREOVER, METFORMIN SUPPRESSED LPS-INDUCED ACETYLATION OF HISTONES H3 AND H4 AT THE IP-10 PROMOTER. CONCLUSIONS: METFORMIN SUPPRESSED THE PRODUCTION OF TH1-RELATED CHEMOKINES IP-10 AND MCP-1 IN THP-1 CELLS. SUPPRESSIVE EFFECTS OF METFORMIN ON IP-10 PRODUCTION MIGHT BE ATTRIBUTED AT LEAST PARTIALLY TO THE JNK, P38, ERK, AND NF-KAPPAB PATHWAYS AS WELL AS TO EPIGENETIC REGULATION THROUGH THE ACETYLATION OF HISTONES H3 AND H4. THESE RESULTS INDICATED THE THERAPEUTIC ANTI-INFLAMMATORY POTENTIAL OF METFORMIN. 2018 10 6599 14 TWIST1 AND TWIST2 INDUCE HUMAN MACROPHAGE MEMORY UPON CHRONIC INNATE RECEPTOR TREATMENT BY HDAC-MEDIATED DEACETYLATION OF CYTOKINE PROMOTERS. INTESTINAL TISSUES ARE CONTINUOUSLY EXPOSED TO MICROBIAL PRODUCTS THAT STIMULATE PATTERN-RECOGNITION RECEPTORS (PRRS). ONGOING PRR STIMULATION CAN CONFER EPIGENETIC CHANGES IN MACROPHAGES, WHICH CAN THEN REGULATE SUBSEQUENT IMMUNE OUTCOMES AND ADAPTATION TO THE LOCAL ENVIRONMENT. MECHANISMS LEADING TO THESE CHANGES ARE INCOMPLETELY UNDERSTOOD. WE FOUND THAT SHORT-TERM STIMULATION OF THE PRR NOD2 IN PRIMARY HUMAN MONOCYTE-DERIVED MACROPHAGES RESULTED IN INCREASED H3 AND H4 ACETYLATION OF CYTOKINE PROMOTERS, CONSISTENT WITH THE INCREASED CYTOKINE SECRETION OBSERVED. HOWEVER, WITH PROLONGED NOD2 STIMULATION, BOTH THE ACETYLATION AND CYTOKINE SECRETION WERE DRAMATICALLY DECREASED. CHRONIC NOD2 STIMULATION UPREGULATED THE TRANSCRIPTION FACTORS TWIST1 AND TWIST2, WHICH BOUND TO THE PROMOTERS OF THE HISTONE DEACETYLASES HDAC1 AND HDAC3 AND INDUCED HDAC1 AND HDAC3 EXPRESSION. HDAC1 AND HDAC3 THEN MEDIATED HISTONE DEACETYLATION AT CYTOKINE PROMOTERS AND, IN TURN, CYTOKINE DOWNREGULATION UNDER THESE CONDITIONS. SIMILAR REGULATION WAS OBSERVED UPON CHRONIC STIMULATION OF MULTIPLE PRRS. CONSISTENT WITH THE CHRONIC MICROBIAL EXPOSURE IN THE INTESTINAL ENVIRONMENT, TWIST1, TWIST2, HDAC1, AND HDAC3 WERE UPREGULATED IN HUMAN INTESTINAL RELATIVE TO PERIPHERAL MACROPHAGES. IMPORTANTLY, COMPLEMENTING HDAC1 AND HDAC3 IN TWIST1/TWIST2-DEFICIENT MONOCYTE-DERIVED MACROPHAGES RESTORED THE REDUCED HISTONE ACETYLATION ON CYTOKINE PROMOTERS AND THE DECREASED CYTOKINE SECRETION WITH CHRONIC NOD2 STIMULATION. TAKEN TOGETHER, WE IDENTIFY MECHANISMS WHEREIN TWIST1 AND TWIST2 PROMOTE CHROMATIN MODIFICATIONS, RESULTING IN MACROPHAGE INSTRUCTION AND ADAPTATION TO CONDITIONS IN THE INTESTINAL MICROENVIRONMENT. 2019 11 674 20 BRAHMA-RELATED GENE 1 BRIDGES EPIGENETIC REGULATION OF PROINFLAMMATORY CYTOKINE PRODUCTION TO STEATOHEPATITIS IN MICE. CHRONIC INFLAMMATION, INFLICTED BY THE SPILLOVER OF PROINFLAMMATORY MEDIATORS, LINKS METABOLIC DYSFUNCTION TO NONALCOHOLIC STEATOHEPATITIS (NASH). THE EPIGENETIC MANEUVERINGS THAT UNDERSCORE ACCELERATED SYNTHESIS OF PROINFLAMMATORY MEDIATORS IN RESPONSE TO NUTRITIONAL INPUTS ARE NOT CLEARLY DEFINED. HERE WE REPORT THAT THE ATP-DEPENDENT CHROMATIN REMODELING PROTEINS BRAHMA-RELATED GENE 1 (BRG1) AND BRAHMA (BRM) WERE UP-REGULATED IN VITRO IN CULTURED HEPATOCYTES TREATED WITH FREE FATTY ACID OR GLUCOSE AND IN VIVO IN ANIMAL MODELS OF NASH. OCCUPANCY OF BRG1 AND BRM ON THE PROMOTER REGIONS OF PROINFLAMMATORY GENES WAS INCREASED IN VITRO IN CELLS AND EX VIVO IN LIVER TISSUES. ESTRADIOL SUPPRESSED THE INDUCTION AND RECRUITMENT OF BRG1/BRM BY PALMITATE. RECRUITMENT OF BRG1 AND BRM RELIED ON NUCLEAR FACTOR KAPPA B/P65; RECIPROCALLY, BRG1 AND BRM CONTRIBUTED TO THE STABILIZATION OF P65 BINDING. IMPORTANTLY, OVEREXPRESSION OF BRG1/BRM ENHANCED, WHEREAS KNOCKDOWN OF BRG1/BRM ATTENUATED, THE INDUCTION OF PROINFLAMMATORY MEDIATORS IN HEPATOCYTES CHALLENGED WITH EXCESSIVE NUTRIENT. MECHANISTICALLY, BRG1 AND BRM WERE INVOLVED IN THE MAINTENANCE OF A CHROMATIN MICROENVIRONMENT MARKED BY ACTIVE HISTONE MODIFICATIONS AND FRIENDLY TO THE ACCESS OF THE GENERAL TRANSCRIPTIONAL MACHINERY. FINALLY, DEPLETION OF BRG1/BRM BY SHORT HAIRPIN RNA ATTENUATED THE RELEASE OF PROINFLAMMATORY MEDIATORS IN THE LIVER AND SIGNIFICANTLY AMELIORATED HEPATIC PATHOLOGY IN NASH MICE. CONCLUSION: OUR DATA ILLUSTRATE A BRG1-DEPENDENT PATHWAY THAT CONNECTS THE EPIGENETIC REGULATION OF PROINFLAMMATORY GENES TO THE PATHOGENESIS OF NASH AND POINT TO A POTENTIAL DRUGGABLE TARGET IN THE THERAPEUTIC INTERVENTION OF NASH. 2013 12 699 17 BROMODOMAIN PROTEIN 4 IS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HEPATIC STELLATE CELL ACTIVATION. LIVER FIBROSIS IS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX IN LIVER. CHRONIC LIVER INJURY INDUCES THE ACTIVATION OF HEPATIC STELLATE CELL (HSCS), A KEY STEP IN LIVER FIBROGENESIS. THE ACTIVATED HSC IS THE PRIMARY SOURCE OF ECM AND CONTRIBUTES SIGNIFICANTLY TO LIVER FIBROSIS. TGFBETA1 IS THE MOST POTENT PRO-FIBROTIC CYTOKINE. BROMODOMAIN PROTEIN 4 (BRD4), AN EPIGENETIC READER OF HISTONE ACETYLATION MARKS, WAS CRUCIAL FOR PROFIBROTIC GENE EXPRESSION IN HSCS. THE PRESENT STUDY AIMED TO INVESTIGATE THE ROLES OF BRD4 IN TGFBETA1-DEPENDENT HSC ACTIVATION AND LIVER FIBROSIS, FOCUSING ON TGFBETA1-INDUCED ALTERATIONS OF THE LEVELS OF THE FIBROTIC-RELATED IMPORTANT PROTEINS IN HSCS BY EMPLOYING THE HETEROZYGOUS TGFBETA1 KNOCKOUT MICE AND BRD4 KNOCKDOWN IN VIVO AND IN VITRO. RESULTS REVEALED THAT BRD4 PROTEIN LEVEL WAS SIGNIFICANTLY UPREGULATED BY TGFBETA1 AND BRD4 KNOCKDOWN REDUCED TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. BRD4 WAS REQUIRED FOR THE INFLUENCES OF TGFBETA1 ON PDGFBETA RECEPTOR AND ON THE PATHWAYS OF SMAD3, STAT3, AND AKT. BRD4 ALSO MEDIATED TGFBETA1-INDUCED INCREASES IN HISTONE ACETYLTRANSFERASE P300, THE PIVOTAL PRO-INFLAMMATORY NFKB P65, AND TISSUE INHIBITOR OF METALLOPROTEINASE 1 WHEREAS BRD4 REDUCED CASPASE-3 PROTEIN LEVELS IN HSCS DURING LIVER INJURY, INDEPENDENT OF TGFBETA1. FURTHER EXPERIMENTS INDICATED THE INTERACTION BETWEEN TGFBETA1-INDUCED BRD4 AND NFKB P65 IN HSCS AND IN LIVER OF TAA-INDUCED LIVER INJURY. HUMAN CIRRHOTIC LIVERS WERE DEMONSTRATED A PARALLEL INCREASE IN THE PROTEIN LEVELS OF BRD4 AND NFKB P65 IN HSCS. THIS STUDY REVEALED THAT BRD4 WAS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. 2023 13 6085 17 THE EFFECTS OF ACARBOSE ON CHEMOKINE AND CYTOKINE PRODUCTION IN HUMAN MONOCYTIC THP-1 CELLS. BACKGROUND AND OBJECTIVES: CHRONIC INFLAMMATION INDUCED BY PROINFLAMMATORY CYTOKINES AND CHEMOKINES IS POSTULATED TO BE INVOLVED IN INSULIN RESISTANCE AND BETA-CELL DYSFUNCTION IN TYPE 2 DIABETES MELLITUS (T2DM). ACARBOSE, THE ALPHA-GLUCOSIDASE INHIBITOR, IS AN ORAL ANTIDIABETIC DRUG FOR T2DM. ACARBOSE SUPPRESSES INFLAMMATORY CYTOKINE PRODUCTION IN PATIENTS WITH T2DM, THOUGH THE UNDERLYING MECHANISMS ARE UNCLEAR. IN THE PRESENT STUDY, WE AIMED TO INVESTIGATE THE ANTI-INFLAMMATORY EFFECTS AND THE EXACT MECHANISMS OF ACARBOSE IN HUMAN MONOCYTIC THP-1 CELLS. METHODS: THP-1 CELLS WERE PRETREATED WITH ACARBOSE AND THEN STIMULATED WITH LIPOPOLYSACCHARIDE (LPS). THE LEVELS OF TH1-RELATED CHEMOKINES, INCLUDING INTERFERON-GAMMA-INDUCIBLE PROTEIN-10 (IP-10), MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), TH2-RELATED CHEMOKINE MACROPHAGE-DERIVED CHEMOKINE (MDC), AND PROINFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), WERE DETERMINED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. INTRACELLULAR SIGNALING PATHWAYS WERE EXPLORED BY WESTERN BLOT ANALYSIS AND USING A CHROMATIN IMMUNOPRECIPITATION ASSAY. RESULTS: ACARBOSE SUPPRESSED THE LEVELS OF IP-10, MCP-1, MDC, AND TNF-ALPHA AND DOWNREGULATED PHOSPHORYLATION OF P38, C-JUN N-TERMINAL KINASE (JNK), EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK), AND NUCLEAR FACTOR-KAPPA B-P65 (NF-KAPPAB-P65) IN LPS-STIMULATED THP-1 CELLS. ACARBOSE SUPPRESSED LPS-INDUCED ACETYLATION OF HISTONES H3 (H3) AND H4 IN THE IP-10 AND MCP-1 PROMOTER REGIONS. THESE FINDINGS REVEALED THE SUPPRESSIVE EFFECTS OF ACARBOSE ON IP-10, MCP-1, MDC, AND TNF-ALPHA PRODUCTION IN THP-1 CELLS VIA, AT LEAST PARTIALLY, THE P38, JNK, ERK, AND NF-KAPPAB-P65 PATHWAYS, AS WELL AS THROUGH EPIGENETIC REGULATION VIA HISTONE H3 AND H4 ACETYLATION. CONCLUSION: OUR STUDY POINTS TO THE THERAPEUTIC ANTI-INFLAMMATORY POTENTIAL OF ACARBOSE. 2019 14 5915 25 TARGETING A PHOSPHO-STAT3-MIRNAS PATHWAY IMPROVES VESICULAR HEPATIC STEATOSIS IN AN IN VITRO AND IN VIVO MODEL. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A LEADING CAUSE OF CHRONIC LIVER DISEASE. ALTHOUGH GENETIC PREDISPOSITION AND EPIGENETIC FACTORS CONTRIBUTE TO THE DEVELOPMENT OF NAFLD, OUR UNDERSTANDING OF THE MOLECULAR MECHANISM INVOLVED IN THE PATHOGENESIS OF THE DISEASE IS STILL EMERGING. HERE WE INVESTIGATED A POSSIBLE ROLE OF A MICRORNAS-STAT3 PATHWAY IN THE INDUCTION OF HEPATIC STEATOSIS. DIFFERENTIATED HEPARG CELLS TREATED WITH THE FATTY ACID SODIUM OLEATE (FATTY DHEPARG) RECAPITULATED FEATURES OF LIVER VESICULAR STEATOSIS AND ACTIVATED A CELL-AUTONOMOUS INFLAMMATORY RESPONSE, INDUCING STAT3-TYROSINE-PHOSPHORYLATION. WITH A GENOME-WIDE APPROACH (CHROMATIN IMMUNOPRECIPITATION SEQUENCING), MANY PHOSPHO-STAT3 BINDING SITES WERE IDENTIFIED IN FATTY DHEPARG CELLS AND SEVERAL STAT3 AND/OR NAFLD-REGULATED MICRORNAS SHOWED INCREASED EXPRESSION LEVELS, INCLUDING MIR-21. INNOVATIVE CARS (COHERENT ANTI-STOKES RAMAN SCATTERING) MICROSCOPY REVEALED THAT CHEMICAL INHIBITION OF STAT3 ACTIVITY DECREASED LIPID ACCUMULATION AND DEREGULATED STAT3-RESPONSIVE MICRORNAS, INCLUDING MIR-21, IN LIPID OVERLOADED DHEPARG CELLS. WE WERE ABLE TO SHOW IN VIVO THAT REDUCING PHOSPHO-STAT3-MIR-21 LEVELS IN C57/BL6 MICE LIVER, BY LONG-TERM TREATMENT WITH METFORMIN, PROTECTED MICE FROM AGING-DEPENDENT HEPATIC VESICULAR STEATOSIS. OUR RESULTS IDENTIFIED A MICRORNAS-PHOSPHOSTAT3 PATHWAY INVOLVED IN THE DEVELOPMENT OF HEPATIC STEATOSIS, WHICH MAY REPRESENT A MOLECULAR MARKER FOR BOTH DIAGNOSIS AND THERAPEUTIC TARGETING. 2018 15 6456 15 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 16 4506 17 MRTF-A MEDIATES LPS-INDUCED PRO-INFLAMMATORY TRANSCRIPTION BY INTERACTING WITH THE COMPASS COMPLEX. CHRONIC INFLAMMATION UNDERSCORES THE PATHOGENESIS OF A RANGE OF HUMAN DISEASES. LIPOPOLYSACCHARIDE (LPS) ELICITS STRONG PRO-INFLAMMATORY RESPONSES IN MACROPHAGES THROUGH THE TRANSCRIPTION FACTOR NF-KAPPAB. THE EPIGENETIC MECHANISM UNDERLYING LPS-INDUCED PRO-INFLAMMATORY TRANSCRIPTION IS NOT FULLY UNDERSTOOD. HEREIN, WE DESCRIBE A ROLE FOR MYOCARDIN-RELATED TRANSCRIPTION FACTOR A (MRTF-A, ALSO KNOWN AS MKL1) IN THIS PROCESS. MRTF-A OVEREXPRESSION ENHANCED NF-KAPPAB-DEPENDENT PRO-INFLAMMATORY TRANSCRIPTION, WHEREAS MRTF-A SILENCING INHIBITED THIS PROCESS. MRTF-A DEFICIENCY ALSO REDUCED THE SYNTHESIS OF PRO-INFLAMMATORY MEDIATORS IN A MOUSE MODEL OF COLITIS. LPS PROMOTED THE RECRUITMENT OF MRTF-A TO THE PROMOTERS OF PRO-INFLAMMATORY GENES IN AN NF-KAPPAB-DEPENDENT MANNER. RECIPROCALLY, MRTF-A INFLUENCED THE NUCLEAR ENRICHMENT AND TARGET BINDING OF NF-KAPPAB. MECHANISTICALLY, MRTF-A WAS NECESSARY FOR THE ACCUMULATION OF ACTIVE HISTONE MODIFICATIONS ON NF-KAPPAB TARGET PROMOTERS BY COMMUNICATING WITH THE HISTONE H3K4 METHYLTRANSFERASE COMPLEX (COMPASS). SILENCING OF INDIVIDUAL MEMBERS OF COMPASS, INCLUDING ASH2, WDR5 AND SET1 (ALSO KNOWN AS SETD1A), DOWNREGULATED THE PRODUCTION OF PRO-INFLAMMATORY MEDIATORS AND IMPAIRED THE NF-KAPPAB KINETICS. IN SUMMARY, OUR WORK HAS UNCOVERED A PREVIOUSLY UNKNOWN FUNCTION FOR MRTF-A AND PROVIDED INSIGHTS INTO THE RATIONALIZED DEVELOPMENT OF ANTI-INFLAMMATORY THERAPEUTIC STRATEGIES. 2014 17 3619 20 IN VIVO ACUTE ON CHRONIC ETHANOL EFFECTS IN LIVER: A MOUSE MODEL EXHIBITING EXACERBATED INJURY, ALTERED METABOLIC AND EPIGENETIC RESPONSES. CHRONIC ALCOHOLICS WHO ALSO BINGE DRINK (I.E., ACUTE ON CHRONIC) ARE PRONE TO AN EXACERBATED LIVER INJURY BUT ITS MECHANISM IS NOT UNDERSTOOD. WE THEREFORE INVESTIGATED THE IN VIVO EFFECTS OF CHRONIC AND BINGE ETHANOL INGESTION AND COMPARED TO CHRONIC ETHANOL FOLLOWED BY THREE REPEAT BINGE ETHANOL ON THE LIVER OF MALE C57/BL6 MICE FED ETHANOL IN LIQUID DIET (4%) FOR FOUR WEEKS FOLLOWED BY BINGE ETHANOL (INTRAGASTRIC ADMINISTRATION, 3.5 G/KG BODY WEIGHT, THREE DOSES, 12H APART). CHRONIC FOLLOWED BY BINGE ETHANOL EXACERBATED FAT ACCUMULATION, NECROSIS, DECREASE IN HEPATIC SAM AND SAM:SAH RATIO, INCREASE IN ADENOSINE LEVELS, AND ELEVATED CYP2E1 LEVELS. HISTONE H3 LYSINE ACETYLATION (H3ACK9), DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10), AND PHOSPHORYLATED H2AX INCREASED AFTER BINGE WHEREAS PHOSPHORYLATION OF HISTONE H3 SER 10 (H3S10) AND H3 SER 28 (H3S28) INCREASED AFTER CHRONIC ETHANOL-BINGE. HISTONE H3 LYSINE 4 AND 9 DIMETHYLATION INCREASED WITH A MARKED DIMETHYLATION IN H3K9 IN CHRONIC ETHANOL BINGE GROUP. TRIMETHYLATED HISTONE H3 LEVELS DID NOT CHANGE. NUCLEAR LEVELS OF HISTONE ACETYL TRANSFERASE GCN5 AND HISTONE DEACETYLASE HDAC3 WERE ELEVATED WHEREAS PHOSPHO-CREB DECREASED IN A DISTINCTIVE MANNER. TAKEN TOGETHER, ACUTE ON CHRONIC ETHANOL INGESTION CAUSED AMPLIFICATION OF LIVER INJURY AND ELICITED CHARACTERISTIC PROFILES OF HISTONE MODIFICATIONS, METABOLIC ALTERATIONS, AND CHANGES IN NUCLEAR PROTEIN LEVELS. THESE FINDINGS DEMONSTRATE THAT CHRONIC ETHANOL EXPOSURE RENDERS LIVER MORE SUSCEPTIBLE TO REPEAT ACUTE/BINGE ETHANOL INDUCED ACCELERATION OF ALCOHOLIC LIVER DISEASE. 2015 18 328 14 ALPHA-KETOGLUTARIC ACID AMELIORATES INTERVERTEBRAL DISC DEGENERATION BY BLOCKING THE IL-6/JAK2/STAT3 PATHWAY. INTERVERTEBRAL DISC DEGENERATION (IVDD) IS THE MAJOR CAUSE OF LOW BACK PAIN. ALPHA-KETOGLUTARIC ACID (ALPHA-KG), AN IMPORTANT INTERMEDIATE IN ENERGY METABOLISM, HAS VARIOUS FUNCTIONS, INCLUDING EPIGENETIC REGULATION, MAINTENANCE OF REDOX HOMEOSTASIS, AND ANTI-AGING, BUT WHETHER IT CAN AMELIORATE IVDD HAS NOT BEEN REPORTED. HERE, WE EXAMINED THE IMPACTS OF LONG-TERM ADMINISTRATION OF A-KG ON AGING-ASSOCIATED IVDD IN ADULT RATS. IN VIVO AND IN VITRO EXPERIMENTS SHOWED THAT ALPHA-KG SUPPLEMENTATION EFFECTIVELY AMELIORATED IVDD IN RATS AND THE SENESCENCE OF NUCLEUS PULPOSUS CELLS (NPCS). ALPHA-KG SUPPLEMENTATION SIGNIFICANTLY ATTENUATED SENESCENCE, APOPTOSIS AND MMP-13 PROTEIN EXPRESSION, AND IT INCREASED THE SYNTHESIS OF AGGRECAN AND COLLAGEN II IN IL-1BETA-TREATED NPCS. IN ADDITION, ALPHA-KG SUPPLEMENTATION REDUCED THE LEVELS OF IL-6, PHOSPHORYLATED JAK2 AND STAT3, AND THE NUCLEAR TRANSLOCATION OF P-STAT3 IN IL-1BETA-INDUCED DEGENERATING NPCS. THE EFFECTS OF ALPHA-KG WERE ENHANCED BY AG490 IN NPCS. THE UNDERLYING MECHANISM MAY INVOLVE THE INHIBITION OF JAK2/STAT3 PHOSPHORYLATION AND THE REDUCTION OF IL-6 EXPRESSION. OUR FINDINGS MAY HELP IN THE DEVELOPMENT OF NEW THERAPEUTIC STRATEGIES FOR IVDD. 2023 19 3939 14 LNC-IL7R ALLEVIATES PM(2.5)-MEDIATED CELLULAR SENESCENCE AND APOPTOSIS THROUGH EZH2 RECRUITMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: LONG-TERM EXPOSURE TO PM(2.5) (PARTICULATE MATTER WITH AN AERODYNAMIC DIAMETER OF