1 5677 153 SHORT AIP1 (ASK1-INTERACTING PROTEIN-1) ISOFORM LOCALIZES TO THE MITOCHONDRIA AND PROMOTES VASCULAR DYSFUNCTION. OBJECTIVE: VASCULAR ENDOTHELIAL CELLS (ECS) NORMALLY MAINTAIN VASCULAR HOMEOSTASIS AND ARE REGULATED BY PROINFLAMMATORY CYTOKINES AND REACTIVE OXYGEN SPECIES. A HUMAN GENOME-WIDE ASSOCIATION STUDY IDENTIFIED THAT AIP1 (ASK1 [APOPTOSIS SIGNAL-REGULATING KINASE 1]-INTERACTING PROTEIN-1; ALSO IDENTIFIED AS DAB2IP) GENE VARIANTS CONFER SUSCEPTIBILITY TO CARDIOVASCULAR DISEASE, BUT THE UNDERLYING MECHANISM IS UNKNOWN. APPROACH AND RESULTS: WE DETECTED A NORMAL AIP1 FORM (NAMED AIP1A) IN THE HEALTHY AORTA, BUT A SHORTER FORM OF AIP1 (NAMED AIP1B) WAS FOUND IN DISEASED AORTAE THAT CONTAINED ATHEROSCLEROTIC PLAQUES AND GRAFT ARTERIOSCLEROSIS. AIP1B TRANSCRIPTION IN RESTING ECS WAS SUPPRESSED THROUGH EPIGENETIC INHIBITION BY RIF1 (RAP1 [RAS-RELATED PROTEIN 1]-INTERACTING FACTOR 1)/H3K9 (HISTONE H3 LYSINE 9) METHYLTRANSFERASE-MEDIATED H3K9 TRIMETHYLATION, AND THIS INHIBITION WAS RELEASED BY PROINFLAMMATORY CYTOKINES. AIP1A, BUT NOT AIP1B, WAS DOWNREGULATED BY PROTEOLYTIC DEGRADATION THROUGH A SMURF1 (SMAD [SUPPRESSOR OF MOTHERS AGAINST DECAPENTAPLEGIC MISCELLANEOUS] UBIQUITYLATION REGULATORY FACTOR 1)-DEPENDENT PATHWAY IN ECS UNDER INFLAMMATION. THEREFORE, AIP1B WAS THE MAJOR FORM PRESENT DURING INFLAMMATORY CONDITIONS. AIP1B, WHICH LACKS THE N-TERMINAL PLECKSTRIN HOMOLOGY DOMAIN OF AIP1A, LOCALIZED TO THE MITOCHONDRIA AND AUGMENTED TNFALPHA (TUMOR NECROSIS FACTOR ALPHA)-INDUCED MITOCHONDRIAL REACTIVE OXYGEN SPECIES GENERATION AND EC ACTIVATION. AIP1B-ECTG (EC-SPECIFIC AIP1B TRANSGENIC) MICE EXHIBITED AUGMENTED REACTIVE OXYGEN SPECIES PRODUCTION, EC ACTIVATION, AND NEOINTIMA FORMATION IN VASCULAR REMODELING MODELS. CONCLUSIONS: OUR CURRENT STUDY SUGGESTS THAT A SHIFT FROM ANTI-INFLAMMATORY AIP1A TO PROINFLAMMATORY AIP1B DURING CHRONIC INFLAMMATION PLAYS A KEY ROLE IN INFLAMMATORY VASCULAR DISEASES. 2020 2 1217 37 CREG PROTECTS FROM MYOCARDIAL ISCHEMIA/REPERFUSION INJURY BY REGULATING MYOCARDIAL AUTOPHAGY AND APOPTOSIS. AIMS: HUMAN CELLULAR REPRESSOR OF E1A-STIMULATED GENES (CREG) IS A SECRETED GLYCOPROTEIN THAT REGULATES TISSUE AND CELL HOMEOSTASIS AND HAS BEEN SHOWN TO ANTAGONIZE HEART FIBROSIS, WHICH INDICATES A POTENTIAL PROTECTIVE EFFECT OF CREG AGAINST CARDIOMYOCYTE CHRONIC DAMAGE. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLE OF CREG IN MYOCARDIAL TISSUE ACUTE INJURY, IN THIS STUDY, WE AIMED TO INVESTIGATE THE ROLE OF CREG IN MYOCARDIAL ISCHEMIA/REPERFUSION (MI/R) INJURY AND CLARIFY THE MECHANISM OF ACTION. METHODS AND RESULTS: WILD-TYPE CREG (CREG(+/+)), HETEROZYGOUS CREG (CREG(+/-)) MICE AND MICE PRETREATED WITH INFUSION OF RECOMBINANT 0.3MG/KG.D CREG PROTEIN (RECREG(+/+)) WERE SUBJECTED TO 30MIN OF LEFT ASCENDING CORONARY ISCHEMIA AND 24H OF REPERFUSION. EVAN'S BLUE-TRIPHENYL- TETRAZOLIUM CHLORIDE (TTC) SOLUTION AND ECHOCARDIOGRAPHY ANALYSIS WERE USED TO EVALUATE THE EFFECTS OF CREG ON MI/R MICE. THE UNDERLYING MECHANISMS WERE FURTHER DETERMINED BY CULTURED MYOCARDIAL CELLS IN VITRO. OUR FINDINGS REVEALED THAT THE LEVEL OF CREG PROTEIN IN MOUSE HEARTS WAS SIGNIFICANTLY DECREASED AFTER MICE WERE SUBJECTED TO MI/R. MOREOVER, CREG(+/-) MICE HAD LARGER INFARCTION SIZE 2H AFTER REPERFUSION AND WORSE CARDIAC FUNCTION 28DAYS AFTER MI/R INJURY COMPARED TO THAT IN CREG(+/+) MICE. HOWEVER, RECREG(+/+) MICE COULD MAINTAIN CREG AT A HIGH LEVEL EVEN AFTER MI/R INJURY, AND MITIGATED INFARCTION SIZE AND IMPROVED CARDIAC FUNCTION SIGNIFICANTLY. IN CREG(+/-) MICE, MYOCARDIAL AUTOPHAGY WAS DYSFUNCTIONAL CHARACTERIZED BY ACCUMULATION OF LC3A AND P62, WHILE APOPTOTIC CELL NUMBER INCREASE WAS DETECTED BY CLEAVED CASPASE-3 BLOTTING AND TUNEL STAINING. CONVERSELY, DECREASED APOPTOSIS AND ACTIVATED AUTOPHAGY WERE DETECTED IN RECREG(+/+) MICE. FURTHERMORE, CHLOROQUINE, A KIND OF AUTOPHAGY BLOCKER, WAS USED TO DEMONSTRATE RECOMBINANT CREG PROTECTED CARDIOMYOCYTES AGAINST APOPTOSIS MEDIATED BY ACTIVATING AUTOPHAGY BOTH IN VIVO AND IN VITRO. FINALLY, WE FOUND CREG WAS INVOLVED INTO LYSOSOMAL PROTEIN TRANSFER AND IMPROVE CELLULAR AUTOPHAGY. CONCLUSION: CREG PROTECTS HEART AGAINST MI/R INJURY-INDUCED CARDIOMYOCYTES APOPTOSIS BY ACTIVATING LYSOSOMAL AUTOPHAGY. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: GENETIC AND EPIGENETIC CONTROL OF HEART FAILURE - EDITED BY JUN REN AND MEGAN YINGMEI ZHANG. 2017 3 2080 37 EPIGENETIC DNA METHYLATION OF EBI3 MODULATES HUMAN INTERLEUKIN-35 FORMATION VIA NFKB SIGNALING: A PROMISING THERAPEUTIC OPTION IN ULCERATIVE COLITIS. ULCERATIVE COLITIS (UC), A SEVERE CHRONIC DISEASE WITH UNCLEAR ETIOLOGY THAT IS ASSOCIATED WITH INCREASED RISK FOR COLORECTAL CANCER, IS ACCOMPANIED BY DYSREGULATION OF CYTOKINES. EPSTEIN-BARR VIRUS-INDUCED GENE 3 (EBI3) ENCODES A SUBUNIT IN THE UNIQUE HETERODIMERIC IL-12 CYTOKINE FAMILY OF EITHER PRO- OR ANTI-INFLAMMATORY FUNCTION. AFTER HAVING RECENTLY DEMONSTRATED THAT UPREGULATION OF EBI3 BY HISTONE ACETYLATION ALLEVIATES DISEASE SYMPTOMS IN A DEXTRAN SULFATE SODIUM (DSS)-TREATED MOUSE MODEL OF CHRONIC COLITIS, WE NOW AIMED TO EXAMINE A POSSIBLE FURTHER EPIGENETIC REGULATION OF EBI3 BY DNA METHYLATION UNDER INFLAMMATORY CONDITIONS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR (DNMTI) DECITABINE (DAC) AND TNFALPHA LED TO SYNERGISTIC UPREGULATION OF EBI3 IN HUMAN COLON EPITHELIAL CELLS (HCEC). USE OF DIFFERENT SIGNALING PATHWAY INHIBITORS INDICATED NFKAPPAB SIGNALING WAS NECESSARY AND PROPORTIONAL TO THE SYNERGISTIC EBI3 INDUCTION. MALDI-TOF/MS AND HPLC-ESI-MS/MS ANALYSIS OF DAC/TNFALPHA-TREATED HCEC IDENTIFIED IL-12P35 AS THE MOST PROBABLE BINDING PARTNER TO FORM A FUNCTIONAL PROTEIN. EBI3/IL-12P35 HETERODIMERS (IL-35) INDUCE THEIR OWN GENE UPREGULATION, SOMETHING THAT WAS INDEED OBSERVED IN HCEC CULTURED WITH MEDIA FROM PREVIOUSLY DAC/TNFALPHA-TREATED HCEC. THESE RESULTS SUGGEST THAT UNDER INFLAMMATORY AND DEMETHYLATING CONDITIONS THE UPREGULATION OF EBI3 RESULTS IN THE FORMATION OF ANTI-INFLAMMATORY IL-35, WHICH MIGHT BE CONSIDERED AS A THERAPEUTIC TARGET IN COLITIS. 2021 4 1016 27 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 5 768 30 CD47 (CLUSTER OF DIFFERENTIATION 47). CD47, ALSO KNOWN AS INTEGRIN-ASSOCIATED PROTEIN, IS A CONSTITUTIVELY AND UBIQUITOUSLY EXPRESSED TRANSMEMBRANE RECEPTOR. CD47 IS CONSERVED ACROSS AMNIOTES INCLUDING MAMMALS, REPTILES, AND BIRDS. EXPRESSION IS INCREASED IN MANY CANCERS AND, IN NON-MALIGNANT CELLS, BY STRESS AND WITH AGING. THE UP-REGULATION OF CD47 EXPRESSION IS GENERALLY EPIGENETIC, WHEREAS GENE AMPLIFICATION OCCURS WITH LOW FREQUENCY IN SOME CANCERS. CD47 IS A HIGH AFFINITY SIGNALING RECEPTOR FOR THE SECRETED PROTEIN THROMBOSPONDIN-1 (THBS1) AND THE COUNTER-RECEPTOR FOR SIGNAL REGULATORY PROTEIN-ALPHA (SIRPA, SIRPALPHA) AND SIRPGAMMA (SIRPG). CD47 INTERACTION WITH SIRPALPHA SERVES AS A MARKER OF SELF TO INNATE IMMUNE CELLS AND THEREBY PROTECTS CANCER CELLS FROM PHAGOCYTIC CLEARANCE. CONSEQUENTLY, HIGHER CD47 CORRELATES WITH A POOR PROGNOSIS IN SOME CANCERS, AND THERAPEUTIC BLOCKADE CAN SUPPRESS TUMOR GROWTH BY ENHANCING INNATE ANTITUMOR IMMUNITY. CD47 EXPRESSED ON CYTOTOXIC T CELLS, DENDRITIC CELLS, AND NK CELLS MEDIATES INHIBITORY THBS1 SIGNALING THAT FURTHER LIMITS ANTITUMOR IMMUNITY. CD47 LATERALLY ASSOCIATES WITH SEVERAL INTEGRINS AND THEREBY REGULATES CELL ADHESION AND MIGRATION. CD47 HAS ADDITIONAL LATERAL BINDING PARTNERS IN SPECIFIC CELL TYPES, AND LIGATION OF CD47 IN SOME CASES MODULATES THEIR FUNCTION. THBS1-CD47 SIGNALING IN NON-MALIGNANT CELLS INHIBITS NITRIC OXIDE/CGMP, CALCIUM, AND VEGF SIGNALING, MITOCHONDRIAL HOMEOSTASIS, STEM CELL MAINTENANCE, PROTECTIVE AUTOPHAGY, AND DNA DAMAGE RESPONSE, AND PROMOTES NADPH OXIDASE ACTIVITY. CD47 SIGNALING IS A PHYSIOLOGICAL REGULATOR OF PLATELET ACTIVATION, ANGIOGENESIS AND BLOOD FLOW. THBS1/CD47 SIGNALING IS FREQUENTLY DYSREGULATED IN CHRONIC DISEASES. 2021 6 1777 37 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 7 1951 30 EPIGENETIC ACTIVATION OF THE TUSC3 GENE AS A POTENTIAL THERAPY FOR XMEN DISEASE. BACKGROUND: X-LINKED MAGT1 DEFICIENCY WITH INCREASED SUSCEPTIBILITY TO EPSTEIN-BARR VIRUS INFECTION AND N-LINKED GLYCOSYLATION DEFECT (XMEN) DISEASE IS A RARE COMBINED IMMUNODEFICIENCY CAUSED BY LOSS-OF-FUNCTION MUTATIONS IN THE MAGNESIUM TRANSPORTER 1 (MAGT1) GENE. MAGT1 DEFICIENCY IMPAIRS MAGNESIUM TRANSPORT AND THE N-LINKED GLYCOSYLATION OF A PANEL OF PROTEINS, WHICH SUBSEQUENTLY ABOLISHES THE EXPRESSION OF KEY IMMUNE RECEPTORS SUCH AS NATURAL KILLER GROUP 2, MEMBER D (AKA NKG2D). THESE EFFECTS INDUCE IMMUNE SYSTEM ABNORMALITIES, CHRONIC EPSTEIN-BARR VIRUS INFECTION, AND NEOPLASIA. RECENT RESEARCH SHOWS THAT MAGT1 AND TUMOR CANDIDATE SUPPRESSOR 3 (TUSC3) SHARE HIGH SEQUENCE AND FUNCTIONAL SIMILARITY. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE FEASIBILITY OF ACTIVATING TUSC3 EXPRESSION TO PROVIDE A POTENTIAL THERAPEUTIC STRATEGY FOR XMEN DISEASE. METHODS: THE EXPRESSION PROFILES OF MAGT1 AND TUSC3 WERE ANALYZED USING MULTIPLE DATABASES, REAL-TIME QUANTITATIVE PCR, AND WESTERN BLOT. THE EFFECTS OF DECITABINE AND PANOBINOSTAT ON THE REGULATION OF TUSC3 EXPRESSION WERE EXPLORED IN BOTH MAGT1 KNOCKOUT (KO)/PATIENT-DERIVED LYMPHOCYTES AND MAGT1 KO HEPATOCYTES. RESULTS: ALTHOUGH TUSC3 IS WIDELY EXPRESSED, IT IS UNDETECTABLE SPECIFICALLY IN THE IMMUNE SYSTEM AND LIVER, CONSISTENT WITH THE MAIN DISEASED TISSUES IN PATIENTS WITH XMEN DISEASE. CRISPR/CAS9-MEDIATED KO OF MAGT1 IN THE NKL CELL LINE SUCCESSFULLY MIMICKED THE PHENOTYPES OF XMEN PATIENT-DERIVED LYMPHOCYTES, AND EXOGENOUS EXPRESSION OF TUSC3 RESCUED THE DEFICIENCIES IN KO NKL CELLS. USING THIS IN VITRO MODEL, WE IDENTIFIED 2 EPIGENETIC DRUGS, DECITABINE AND PANOBINOSTAT, BY SCREENING. COMBINATION TREATMENT USING THESE 2 DRUGS SIGNIFICANTLY UPREGULATED TUSC3 EXPRESSION AND RESCUED THE IMMUNE AND LIVER ABNORMALITIES. CONCLUSIONS: EPIGENETIC ACTIVATION OF TUSC3 EXPRESSION CONSTITUTES AN EFFECTIVE THERAPEUTIC STRATEGY FOR XMEN DISEASE. 2023 8 2640 27 EPIGENOMIC AND TRANSCRIPTIONAL PROFILING IDENTIFIES IMPAIRED GLYOXYLATE DETOXIFICATION IN NAFLD AS A RISK FACTOR FOR HYPEROXALURIA. EPIGENETIC MODIFICATIONS (E.G. DNA METHYLATION) IN NAFLD AND THEIR CONTRIBUTION TO DISEASE PROGRESSION AND EXTRAHEPATIC COMPLICATIONS ARE POORLY EXPLORED. HERE, WE USE AN INTEGRATED EPIGENOME AND TRANSCRIPTOME ANALYSIS OF MOUSE NAFLD HEPATOCYTES AND IDENTIFY ALTERATIONS IN GLYOXYLATE METABOLISM, A PATHWAY RELEVANT IN KIDNEY DAMAGE VIA OXALATE RELEASE-A HARMFUL WASTE PRODUCT AND KIDNEY STONE-PROMOTING FACTOR. DOWNREGULATION AND HYPERMETHYLATION OF ALANINE-GLYOXYLATE AMINOTRANSFERASE (AGXT), WHICH DETOXIFIES GLYOXYLATE, PREVENTING EXCESSIVE OXALATE ACCUMULATION, IS ACCOMPANIED BY INCREASED OXALATE FORMATION AFTER METABOLISM OF THE PRECURSOR HYDROXYPROLINE. VIRAL-MEDIATED AGXT TRANSFER OR INHIBITING HYDROXYPROLINE CATABOLISM RESCUES EXCESSIVE OXALATE RELEASE. IN HUMAN STEATOTIC HEPATOCYTES, AGXT IS ALSO DOWNREGULATED AND HYPERMETHYLATED, AND IN NAFLD ADOLESCENTS, STEATOSIS SEVERITY CORRELATES WITH URINARY OXALATE EXCRETION. THUS, THIS WORK IDENTIFIES A REDUCED CAPACITY OF THE STEATOTIC LIVER TO DETOXIFY GLYOXYLATE, TRIGGERING ELEVATED OXALATE, AND PROVIDES A MECHANISTIC EXPLANATION FOR THE INCREASED RISK OF KIDNEY STONES AND CHRONIC KIDNEY DISEASE IN NAFLD PATIENTS. 2021 9 216 30 ACUTE BETA-ADRENERGIC ACTIVATION TRIGGERS NUCLEAR IMPORT OF HISTONE DEACETYLASE 5 AND DELAYS G(Q)-INDUCED TRANSCRIPTIONAL ACTIVATION. DURING HEMODYNAMIC STRESS, CATECHOLAMINES AND NEUROHUMORAL STIMULI MAY INDUCE CO-ACTIVATION OF G(Q)-COUPLED RECEPTORS AND BETA-ADRENERGIC RECEPTORS (BETA-AR), LEADING TO CARDIAC REMODELING. DYNAMIC REGULATION OF HISTONE DEACETYLASE 5 (HDAC5), A TRANSCRIPTIONAL REPRESSOR, IS CRUCIAL DURING STRESS SIGNALING DUE TO ITS ROLE IN EPIGENETIC CONTROL OF FETAL GENE MARKERS. LITTLE IS KNOWN ABOUT ITS REGULATION DURING ACUTE AND CHRONIC BETA-AR STIMULATION AND ITS CROSS-INTERACTION WITH G(Q) SIGNALING IN ADULT CARDIAC MYOCYTES. HERE, WE EVALUATE THE POTENTIAL CROSS-TALK BETWEEN G(Q)-DRIVEN AND BETA-AR MEDIATED SIGNALING AT THE LEVEL OF NUCLEOCYTOPLASMIC SHUTTLING OF HDAC5. WE SHOW THE TRANSLOCATION OF GFP-TAGGED WILD TYPE HDAC5 OR MUTANTS (S279A AND S279D) IN RESPONSE TO BETA-AR OR G(Q) AGONISTS. ISOPROTERENOL (ISO) OR PKA ACTIVATION RESULTS IN STRONG NUCLEAR ACCUMULATION OF HDAC5 IN CONTRAST TO NUCLEAR EXPORT DRIVEN BY CA(2+)-CALMODULIN PROTEIN KINASE II AND PROTEIN KINASE D. MOREOVER, NUCLEAR ACCUMULATION OF HDAC5 UNDER ACUTE ISO/PKA SIGNALING IS DEPENDENT ON PHOSPHORYLATION OF SER-279 AND CAN BLOCK SUBSEQUENT G(Q)-MEDIATED NUCLEAR HDAC5 EXPORT. INTRIGUINGLY, THE ATTENUATION OF G(Q)-INDUCED EXPORT IS ABOLISHED AFTER CHRONIC PKA ACTIVATION, YET NUCLEAR HDAC5 REMAINS ELEVATED. LAST, THE EFFECT OF CHRONIC BETA-AR SIGNALING ON HDAC5 TRANSLOCATION WAS EXAMINED IN ADULT MYOCYTES FROM A RABBIT MODEL OF HEART FAILURE, WHERE ISO-INDUCED NUCLEAR IMPORT IS ABLATED, BUT G(Q)-AGONIST MEDIATED EXPORT IS PRESERVED. ACUTE BETA-AR/PKA ACTIVATION PROTECTS AGAINST HYPERTROPHIC SIGNALING BY DELAYING G(Q)-MEDIATED TRANSCRIPTIONAL ACTIVATION. THIS SERVES AS A KEY PHYSIOLOGICAL CONTROL SWITCH BEFORE ALLOWING GENETIC REPROGRAMMING VIA HDAC5 NUCLEAR EXPORT DURING MORE SEVERE STRESS, SUCH AS HEART FAILURE. 2013 10 35 26 A CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC APPROACH REVEALS A TRANSCRIPTIONAL REPRESSOME FOR GENE-SPECIFIC SILENCING. IMMUNE CELLS DEVELOP ENDOTOXIN TOLERANCE (ET) AFTER PROLONGED STIMULATION. ET INCREASES THE LEVEL OF A REPRESSION MARK H3K9ME2 IN THE TRANSCRIPTIONALLY SILENT CHROMATIN SPECIFICALLY ASSOCIATED WITH PRO-INFLAMMATORY GENES. HOWEVER, IT IS NOT CLEAR WHAT PROTEINS ARE FUNCTIONALLY INVOLVED IN THIS PROCESS. HERE WE SHOW THAT A NOVEL CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC (CHAC) APPROACH CAN DISSECT THE FUNCTIONAL CHROMATIN PROTEIN COMPLEXES THAT REGULATE ET-ASSOCIATED INFLAMMATION. USING UNC0638 THAT BINDS THE ENZYMATICALLY ACTIVE H3K9-SPECIFIC METHYLTRANSFERASE G9A/GLP, CHAC REVEALS THAT G9A IS CONSTITUTIVELY ACTIVE AT A G9A-DEPENDENT MEGA-DALTON REPRESSOME IN PRIMARY ENDOTOXIN-TOLERANT MACROPHAGES. G9A/GLP BROADLY IMPACTS THE ET-SPECIFIC REPROGRAMMING OF THE HISTONE CODE LANDSCAPE, CHROMATIN REMODELLING AND THE ACTIVITIES OF SELECT TRANSCRIPTION FACTORS. WE DISCOVER THAT THE G9A-DEPENDENT EPIGENETIC ENVIRONMENT PROMOTES THE TRANSCRIPTIONAL REPRESSION ACTIVITY OF C-MYC FOR GENE-SPECIFIC CO-REGULATION OF CHRONIC INFLAMMATION. CHAC MAY ALSO BE APPLICABLE TO DISSECT OTHER FUNCTIONAL PROTEIN COMPLEXES IN THE CONTEXT OF PHENOTYPIC CHROMATIN ARCHITECTURES. 2014 11 5017 27 PERSISTENT INFECTION OF CULTURED CELLS WITH MOUSE HEPATITIS VIRUS (MHV) RESULTS FROM THE EPIGENETIC EXPRESSION OF THE MHV RECEPTOR. THE A59 STRAIN OF MURINE CORONAVIRUS MOUSE HEPATITIS VIRUS (MHV) CAN CAUSE PERSISTENT INFECTION OF 17C1-1 CELLS AND OTHER MURINE CELL LINES. PERSISTENTLY INFECTED CULTURES RELEASED LARGE AMOUNTS OF VIRUS (10(7) TO 10(8) PFU/ML) AND WERE RESISTANT TO SUPERINFECTION WITH MHV BUT NOT TO INFECTION WITH UNRELATED SEMLIKI FOREST AND VESICULAR STOMATITIS VIRUSES. THE CULTURE MEDIUM FROM PERSISTENTLY INFECTED CULTURES DID NOT CONTAIN A SOLUBLE INHIBITOR SUCH AS INTERFERON THAT PROTECTED UNINFECTED CELLS FROM INFECTION BY MHV OR VESICULAR STOMATITIS VIRUS. THE PERSISTENT INFECTION WAS CURED IF FEWER THAN 100 CELLS WERE TRANSFERRED DURING SUBCULTURING, AND SUCH CURED CULTURES WERE SUSCEPTIBLE TO REINFECTION AND THE REESTABLISHMENT OF PERSISTENT INFECTION. CULTURES OF 17C1-1 CELLS THAT HAD BEEN NEWLY CLONED FROM SINGLE CELLS CONSISTED OF A MIXTURE OF MHV-RESISTANT AND -SUSCEPTIBLE CELLS. 17C1-1/#97 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 97 PASSAGES OF A PERSISTENTLY INFECTED CULTURE OVER A 1-YEAR PERIOD, CONTAINED 5 TO 10% OF THEIR POPULATION AS SUSCEPTIBLE CELLS, WHILE 17C1-1/#402 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 402 PASSAGES OVER A 3-YEAR PERIOD, HAD LESS THAN 1% SUSCEPTIBLE CELLS. SUSCEPTIBILITY TO INFECTION CORRELATED WITH THE EXPRESSION OF MHV RECEPTOR GLYCOPROTEIN (MHVR [BGP1A]). FLUORESCENCE-ACTIVATED CELL SORTER ANALYSIS WITH ANTIBODY TO MHVR SHOWED THAT 17C1-1/#97 CELLS CONTAINED A SMALL FRACTION OF MHVR-EXPRESSING CELLS. THESE MHVR-EXPRESSING CELLS WERE SELECTIVELY ELIMINATED WITHIN 24 H AFTER CHALLENGE WITH MHV-A59, AND PRETREATMENT OF 17C1-1/#97 CELLS WITH MONOCLONAL ANTIBODY CC1, WHICH BINDS TO THE N-TERMINAL DOMAIN OF MHVR, BLOCKED INFECTION. WE CONCLUDE THAT THE SUBPOPULATION OF MHVR-EXPRESSING CELLS WERE INFECTED AND KILLED IN ACUTELY OR PERSISTENTLY INFECTED CULTURES, WHILE THE SUBPOPULATION OF MHVR-NONEXPRESSING CELLS SURVIVED AND PROLIFERATED. THE SUBPOPULATION OF MHVR-NEGATIVE CELLS PRODUCED A SMALL PROPORTION OF PROGENY CELLS THAT EXPRESSED MHVR AND BECAME INFECTED, THEREBY MAINTAINING THE PERSISTENT INFECTION AS A STEADY-STATE CARRIER CULTURE. THUS, IN 17C1-1 CELL CULTURES, THE UNSTABLE OR EPIGENETIC EXPRESSION OF MHVR PERMITTED THE ESTABLISHMENT OF A PERSISTENT, CHRONIC INFECTION. 1995 12 2796 26 FBW7 MEDIATES SENESCENCE AND PULMONARY FIBROSIS THROUGH TELOMERE UNCAPPING. TISSUE STEM CELLS UNDERGO PREMATURE SENESCENCE UNDER STRESS, PROMOTING AGE-RELATED DISEASES; HOWEVER, THE ASSOCIATED MECHANISMS REMAIN UNCLEAR. HERE, WE REPORT THAT IN RESPONSE TO RADIATION, OXIDATIVE STRESS, OR BLEOMYCIN, THE E3 UBIQUITIN LIGASE FBW7 MEDIATES CELL SENESCENCE AND TISSUE FIBROSIS THROUGH TELOMERE UNCAPPING. FBW7 BINDING TO TELOMERE PROTECTION PROTEIN 1 (TPP1) FACILITATES TPP1 MULTISITE POLYUBIQUITINATION AND ACCELERATES DEGRADATION, TRIGGERING TELOMERE UNCAPPING AND DNA DAMAGE RESPONSE. OVEREXPRESSING TPP1 OR INHIBITING FBW7 BY GENETIC ABLATION, EPIGENETIC INTERFERENCE, OR PEPTIDOMIMETIC TELOMERE DYSFUNCTION INHIBITOR (TELODIN) REDUCES TELOMERE UNCAPPING AND SHORTENING, EXPANDING THE PULMONARY ALVEOLAR AEC2 STEM CELL POPULATION IN MICE. TELODIN, SYNTHESIZED FROM THE SEVENTH BETA STRAND BLADE OF FBW7 WD40 PROPELLER DOMAIN, INCREASES TPP1 STABILITY, LUNG RESPIRATORY FUNCTION, AND RESISTANCE TO SENESCENCE AND FIBROSIS IN ANIMALS CHRONICALLY EXPOSED TO ENVIRONMENTAL STRESS. OUR FINDINGS ELUCIDATE A PIVOTAL MECHANISM UNDERLYING STRESS-INDUCED PULMONARY EPITHELIAL STEM CELL SENESCENCE AND FIBROSIS, PROVIDING A FRAMEWORK FOR AGING-RELATED DISORDER INTERVENTIONS. 2020 13 3945 37 LNCRNA IL21-AS1 INTERACTS WITH HNRNPU PROTEIN TO PROMOTE IL21 OVEREXPRESSION AND ABERRANT DIFFERENTIATION OF TFH CELLS IN SYSTEMIC LUPUS ERYTHEMATOSUS. BACKGROUND: THE ABERRANT DIFFERENTIATION OF T FOLLICULAR HELPER (TFH) CELLS PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE). HOWEVER, THE MECHANISM OF REGULATING TFH CELLS DIFFERENTIATION REMAINS UNCLEAR. LONG NONCODING RNAS (LNCRNAS) ACT AS IMPORTANT REGULATORS IN THE PROCESSES OF INNATE AND ADAPTIVE IMMUNE RESPONSE. WHETHER LNCRNAS ARE INVOLVED IN REGULATING TFH CELL DIFFERENTIATION AND AUTOIMMUNE RESPONSES NEED TO BE FURTHER IDENTIFIED. METHODS: THE CHARACTERS AND FUNCTIONS OF HUMAN IL21-AS1 AND ITS MOUSE HOMOLOGOUS LNCRNA (MIL21-AS) WERE INVESTIGATED BY A SERIES OF BIOCHEMICAL ASSAYS AND CELL TRANSFECTION ASSAY. MIL21-AS1 REGULATING HUMORAL IMMUNE RESPONSE IN VIVO WAS EXPLORED BY KEYHOLE LIMPET HAEMOCYANIN (KLH) AND CHRONIC GRAFT VERSUS HOST DISEASE (CGVHD) MODEL. RESULTS: HUMAN IL21-AS1 AND ITS MOUSE HOMOLOGOUS LNCRNA (MIL21-AS) WERE IDENTIFIED AND CLONED. WE UNCOVERED THAT IL21-AS1 WAS HIGHLY EXPRESSED IN CD4(+) T CELLS OF SLE PATIENTS AND TFH CELLS, WHICH PROMOTED DIFFERENTIATION OF TFH CELLS. MECHANISTICALLY, IL21-AS1 BOUND HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN U AND RECRUITED ACETYLTRANSFERASES CREB-BINDING PROTEIN TO THE PROMOTER OF IL21, LEADING TO THE TRANSCRIPTIONAL ACTIVATION OF IL21 AND TFH CELLS DIFFERENTIATION THROUGH INCREASING HISTONE H3 ACETYLATION LEVEL ON IL21 PROMOTER. MOREOVER, TFH PROPORTION AND ANTIBODIES PRODUCTION WERE SIGNIFICANTLY INCREASED IN MIL21-AS KNOCK-IN MICE IMMUNIZED WITH KLH. MIL21-AS1 OVEREXPRESSION ALSO EXACERBATED THE LUPUS-LIKE PHENOTYPE IN CGVHD MICE MODEL. CONCLUSIONS: OUR RESULTS DEMONSTRATE THAT IL21-AS1 ACTIVATES IL21 TRANSCRIPTION VIA EPIGENETIC MECHANISM TO PROMOTE GERMINAL CENTRE RESPONSE, ADDING INSIGHT INTO THE MOLECULAR REGULATION OF AUTOIMMUNE PATHOGENESIS AND PROVIDING A NOVEL TARGET FOR SLE TREATMENT. 2022 14 1843 29 EFFECTS OF TELOMERASE INHIBITOR ON EPIGENETIC CHROMATIN MODIFICATION ENZYMES IN MALIGNANCIES. TELOMERASE HAS A CRITICAL ROLE IN CELL PROLIFERATION, TUMOR MAINTAINING, AND THERAPY RESISTANCE, WHICH ACT BY MODIFYING MANY SIGNALING PATHWAYS. 2-[(E)-3-NAPHTALEN-2-YL-BUT-2-ENOYLAMINO]-BENZOIC ACID (BIBR1532) IS ONE OF THE MOST STUDIED TELOMERASE INHIBITORS, AND IT TARGETS TELOMERASE COMPONENTS TERC AND TERT. IN THIS NOVEL STUDY, WE AIMED TO INVESTIGATE THE EPIGENETIC EFFECTS OF BIBR1532 ON BOTH HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS. K-562 HUMAN CHRONIC MYELOID LEUKEMIA CELL LINE AND U87MG GLIOBLASTOMA CELL LINE WERE COMPARED WITH CONTROL GROUPS WITHOUT BIBR1532 TREATMENT. CYTOTOXIC EFFECTS OF BIBR1532 WERE DETERMINED BY USING WST-1 ASSAY. APOPTOTIC EFFECTS OF BIBR1532 WERE DETECTED BY USING ANNEXIN V METHOD. TO ASSESS EXPRESSION CHANGES IN THE HUMAN EPIGENETIC CHROMATIN MODIFICATION ENZYME GENES, TOTAL RNA WAS ISOLATED FROM K-562 AND U87MG CELLS TREATED WITH BIBR1532 AND UNTREATED CONTROL CELLS. BIBR1532 INDUCED 2.41-FOLD APOPTOTIC CELL DEATH IN U87MG CELL LINES COMPARED WITH CONTROL GROUPS. APOPTOSIS WAS SLIGHTLY INDUCED IN K-562 CELLS WITH BIBR1532 TREATMENT COMPARED WITH CONTROL CELLS. WE OBSERVED THAT BIBR1532 ALSO REGULATES SIMILAR GENES IN BOTH CELL LINES, AND IT IS USEFUL ON EPIGENETIC MECHANISMS. AS A RESULT, TELOMERASE INHIBITOR BIBR1532 HAS A SIGNIFICANT EFFECT ON BOTH HEMATOLOGICAL MALIGNANCIES AND SOLID TUMORS. 2018 15 3626 26 IN-SILICO DISCOVERY OF DUAL ACTIVE MOLECULE TO RESTORE SYNAPTIC WIRING AGAINST AUTISM SPECTRUM DISORDER VIA HDAC2 AND H3R INHIBITION. METAL-DEPENDENT HISTONE DEACETYLASES (HDACS) ARE ESSENTIAL EPIGENETIC REGULATORS; THEIR MOLECULAR AND PHARMACOLOGICAL ROLES IN MEDICALLY CRITICAL DISEASES SUCH AS NEUROPSYCHIATRIC DISORDERS, NEURODEGENERATION, AND CANCER ARE BEING STUDIED GLOBALLY. HDAC2'S DIFFERENTIAL EXPRESSION IN THE CENTRAL NERVOUS SYSTEM MAKES IT AN APPEALING THERAPEUTIC TARGET FOR CHRONIC NEUROLOGICAL DISEASES LIKE AUTISM SPECTRUM DISORDER. IN THIS STUDY, WE IDENTIFIED H3R INHIBITOR MOLECULES THAT ARE COMPUTATIONALLY EFFECTIVE AT BINDING TO THE HDAC2 METAL-COORDINATED BINDING SITE. THE STUDY HIGHLIGHTS THE IMPORTANCE OF PITOLISANT IN SCREENING THE POTENTIAL H3R INHIBITORS BY USING A HYBRID WORKFLOW OF LIGAND AND RECEPTOR-BASED DRUG DISCOVERY. THE SCREENED LEAD COMPOUNDS WITH PUBCHEM SIDS 103179850, 103185945, AND 103362074 SHOW VIABLE BINDING WITH HDAC2 IN SILICO. THE IMPORTANCE OF LIGAND CONTACTS WITH THE ZN2+ ION IN THE HDAC2 CATALYTIC SITE IS ALSO DISCUSSED AND INVESTIGATED FOR A SIGNIFICANT ROLE IN ENZYME INHIBITION. THE PROPOSED H3R INHIBITORS 103179850, 103185945, AND 103362074 ARE ESTIMATED AS DUAL-ACTIVE MOLECULES TO BLOCK THE HDAC2-MEDIATED DEACETYLATION OF THE EAAT2 GENE (SLC1A2) AND H3R-MEDIATED SYNAPTIC TRANSMISSION IRREGULARITY AND ARE, THEREFORE, OPEN FOR EXPERIMENTAL VALIDATION. 2022 16 16 31 4CRNA NEAT1 SPONGE ADSORPTION OF MIR-378 MODULATES ACTIVITY OF LIPOPOLYSACCHARIDE-TREATED ARTICULAR CHONDROCYTES AND INFLUENCES THE PATHOLOGICAL DEVELOPMENT OF OSTEOARTHRITIS. CONTEXT: OSTEOARTHRITIS (OA) IS A CHRONIC JOINT DISEASE THAT CAN EVENTUALLY LEAD TO DEGENERATION, FIBROSIS, FRACTURES, AND DEFECTS OF THE ARTICULAR CARTILAGE. LONG NON-CODING RNA (LNCRNA) IS A KEY SUBSTANCE IN MANY PROCESSES, SUCH AS EPIGENETIC REGULATION AND CELL-CYCLE AND CELL-DIFFERENTIATION MODULATION, AND ITS RELATIONSHIP WITH OA HAS BEEN REPEATEDLY VERIFIED. OBJECTIVE: THE STUDY INTENDED TO CLARIFY THE INFLUENCE OF LNCRNA NUCLEAR ENRICHED ABUNDANT TRANSCRIPT 1 (NEAT1), LNCRNA NEAT1, ON LIPOPOLYSACCHARIDE (LPS)-INDUCED OA CHONDROCYTES THROUGH SPONGE ADSORPTION OF MICRORNA-378 (MIR-378) AND TO PROVIDE NOVEL INSIGHTS INTO FUTURE DIAGNOSIS AND TREATMENT OF OA. DESIGN: THE RESEARCH TEAM PERFORMED AN ANIMAL STUDY. SETTING: THE STUDY TOOK PLACE IN THE DEPARTMENT OF REHABILITATION MEDICINE AT LINYI PEOPLE'S HOSPITAL IN LINYI, SHANGDONG, CHINA. ANIMALS: THE STUDY'S ANIMALS WERE 10 SPRAGUE DAWLEY (SD) RATS, 3-5 DAYS OLD AND 10-15 G IN WEIGHT, OF THE SPECIFIC-PATHOGEN-FREE (SPF) GRADE. INTERVENTION: THE RAT CHONDROCYTES FOR THE POSITIVE CONTROL GROUP (THE MODEL GROUP) WERE TREATED WITH 500 NG/ML OF LPS TO INDUCE OA. CHONDROCYTES TREATED WITH THE SAME AMOUNT OF NORMAL SALINE WERE USED AS THE NEGATIVE CONTROL GROUP. THE CHONDROCYTES OF THE LPS-INDUCED RATS WERE INTO SIX GROUPS: (1) A POSITIVE CONTROL GROUP TRANSFECTED WITH NEAT1-INTERFERING RNA, THE SH-NEAT1 GROUP; (2) A NEGATIVE CONTROL GROUP NOT TRANSFECTED WITH NEAT1-INTERFERING RNA, THE NEAT1 EMPTY VECTOR (NC-NEAT1) GROUP; (3) AN INTERVENTION GROUP CO-TRANSFECTED WITH NEAT1 INTERFERING RNA AND THE MIR-378 INHIBITOR SEQUENCE (INH-MIR-378 THE SH-NEAT1+ INH-MIR-378 GROUP; (4) A NEGATIVE CONTROL GROUP TRANSFECTED WITH NEAT1 INTERFERING RNA BUT NOT TRANSFECTED WITH THE MIR-378 INHIBITOR SEQUENCE, THE SH-NEAT1+ MIR-378 NEGATIVE CONTROL (NC-MIR-378) GROUP; (5) A NEGATIVE CONTROL GROUP TRANSFECTED WITH THE MIR-378 INHIBITOR SEQUENCE BUT NOT TRANSFECTED WITH NEAT1 INTERFERING RNA, THE NEAT1 EMPTY VECTOR (NC-NEAT1) + INH-MIR-378 GROUP; (6) A NEGATIVE CONTROL GROUP NOT TRANSFECTED WITH EITHER NEAT1 INTERFERING RNA OR THE MIR-378 INHIBITOR SEQUENCE, THE NC-NEAT1 + NC-MIR-378 GROUP. OUTCOME MEASURES: AN OA-CHONDROCYTE MODEL WAS INDUCED BY LPS AND MEASUREMENTS OF NEAT1 AND MIR-378 EXPRESSION WERE MADE BY REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION (QRT)- POLYMERASE CHAIN REACTION (PCR). THEN, SMALL NEAT1-INTERFERING RNA (SH-NEAT1), EMPTY VECTOR NEAT1 (NC-NEAT1), INHIBITOR-SEQUENCE-MIR-378 (INH-MIR-378), AND NEGATIVE-CONTROL-MIR-378 (NC-MIR-378) WERE TRANSFECTED INTO CELLS, AND CELL VIABILITY AND APOPTOSIS RATE WERE MEASURED. FINALLY, THE STUDY VERIFIED THE RELATIONSHIP BETWEEN NEAT1 AND MIR-378. RESULTS: COMPARED TO THE CONTROL GROUP, NEAT1 WAS SIGNIFICANTLY ELEVATED IN THE MODEL GROUP, AND ITS MIR-378 WAS SIGNIFICANTLY DECREASED. SILENCING NEAT1 CAN ENHANCE OA-CHONDROCYTE ACTIVITY AND DECREASE APOPTOSIS. WHEN NEAT1 AND MIR-378 WERE INHIBITED TOGETHER, AS SHOWN FORT THE NC-NEAT1 + NC-MIR-378 GROUP, NEAT1 EXPRESSION, AS WELL AS THE MULTIPLICATION AND APOPTOSIS ABILITY OF THE OA-MODEL CELLS, WERE THE SAME AS THOSE OF CELLS TRANSFECTED WITH AN EMPTY VECTOR, THE NC-NEAT1 GROUP. ALSO, THE NEAT1 + NC-MIR-378 GROUP'S CELL ACTIVITY WAS LOWER THAN THAT OF THE SH-NEAT1+NC-MIR-378 GROUP BUT HIGHER THAN THAT OF THE NC-NEAT1 + INH-MIR-378 GROUP. FINALLY, HIGHER FLUORESCENCE ACTIVITY OCCURRED FOR NEAT1-MUTANT TYPE (MUT) TRANSFECTED WITH INH-MIR-378. CONCLUSIONS: NEAT1, WHICH IS HIGHLY EXPRESSED IN OA, MEDIATES LPS-INDUCED OA-CHONDROCYTE ACTIVITY THROUGH SPONGE ADSORPTION OF MIR-378. 2022 17 1421 24 DIFFERENTIAL BRAIN ADRA2A AND ADRA2C GENE EXPRESSION AND EPIGENETIC REGULATION IN SCHIZOPHRENIA. EFFECT OF ANTIPSYCHOTIC DRUG TREATMENT. POSTSYNAPTIC ALPHA(2A)-ADRENOCEPTOR DENSITY IS ENHANCED IN THE DORSOLATERAL PREFRONTAL CORTEX (DLPFC) OF ANTIPSYCHOTIC-TREATED SCHIZOPHRENIA SUBJECTS. THIS ALTERATION MIGHT BE DUE TO TRANSCRIPTIONAL ACTIVATION, AND COULD BE REGULATED BY EPIGENETIC MECHANISMS SUCH AS HISTONE POSTTRANSLATIONAL MODIFICATIONS (PTMS). THE AIM OF THIS STUDY WAS TO EVALUATE ADRA2A AND ADRA2C GENE EXPRESSION (CODIFYING FOR ALPHA(2)-ADRENOCEPTOR SUBTYPES), AND PERMISSIVE AND REPRESSIVE HISTONE PTMS AT GENE PROMOTER REGIONS IN THE DLPFC OF SUBJECTS WITH SCHIZOPHRENIA AND MATCHED CONTROLS (N = 24 PAIRS). WE STUDIED THE EFFECT OF ANTIPSYCHOTIC (AP) TREATMENT IN AP-FREE (N = 12) AND AP-TREATED (N = 12) SUBGROUPS OF SCHIZOPHRENIA SUBJECTS AND IN RATS ACUTELY AND CHRONICALLY TREATED WITH TYPICAL AND ATYPICAL ANTIPSYCHOTICS. ADRA2A MRNA EXPRESSION WAS SELECTIVELY UPREGULATED IN AP-TREATED SCHIZOPHRENIA SUBJECTS (+93%) WHEREAS ADRA2C MRNA EXPRESSION WAS UPREGULATED IN ALL SCHIZOPHRENIA SUBJECTS (+53%) REGARDLESS OF ANTIPSYCHOTIC TREATMENT. ACUTE AND CHRONIC CLOZAPINE TREATMENT IN RATS DID NOT ALTER BRAIN CORTEX ADRA2A MRNA EXPRESSION BUT INCREASED ADRA2C MRNA EXPRESSION. BOTH ADRA2A AND ADRA2C PROMOTER REGIONS SHOWED EPIGENETIC MODIFICATION BY HISTONE METHYLATION AND ACETYLATION IN HUMAN DLPFC. THE UPREGULATION OF ADRA2A EXPRESSION IN AP-TREATED SCHIZOPHRENIA SUBJECTS MIGHT BE RELATED TO OBSERVED BIVALENT CHROMATIN AT ADRA2A PROMOTER REGION IN SCHIZOPHRENIA (DEPICTED BY INCREASED PERMISSIVE H3K4ME3 AND REPRESSIVE H3K27ME3) AND COULD BE TRIGGERED BY THE ENHANCED H4K16AC AT ADRA2A PROMOTER. IN CONCLUSION, EPIGENETIC PREDISPOSITION DIFFERENTIALLY MODULATED ADRA2A AND ADRA2C MRNA EXPRESSION IN DLPFC OF SCHIZOPHRENIA SUBJECTS. 2021 18 5601 28 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 19 5487 29 REVERSIBLE ALTERATION IN THE EXPRESSION OF THE GAP JUNCTIONAL PROTEIN CONNEXIN 32 DURING TUMOR PROMOTION IN RAT LIVER AND ITS ROLE DURING CELL PROLIFERATION. ALTHOUGH NUMEROUS BIOCHEMICAL MARKERS CAN IDENTIFY PUTATIVE PRENEOPLASTIC ALTERED HEPATIC FOCI (AHF) IN RAT LIVER, NO CONSISTENT PATTERN OF EXPRESSION DURING HEPATOCARCINOGENESIS HAS EMERGED. USING QUANTITATIVE STEREOLOGIC ANALYSES WE DEMONSTRATED THAT DECREASED EXPRESSION OF THE MAJOR HEPATOCYTE GAP JUNCTION PROTEIN, CONNEXIN 32 (CX32), IN RAT AHF IS A CONSISTENT OBSERVATION IN SEVERAL PROTOCOLS OF MULTISTAGE HEPATOCARCINOGENESIS. THIS CHANGE WAS OBSERVED AFTER INITIATION BY EITHER ETHYLNITROSOUREA (ENU) OR DIETHYLNITROSAMINE (DEN), FOLLOWED BY PROMOTION WITH PHENOBARBITAL (PB), DIOXIN, CHLORENDIC ACID, C.I. SOLVENT YELLOW, OR TAMOXIFEN. AHF GENERATED BY WY-14,643, CIPROFIBRATE, AND A CHOLINE/METHIONINE-DEFICIENT DIETARY REGIMEN ALSO SHOWED DECREASED CX32 EXPRESSION. THE DECREASE OF CX32 IN AHF WAS RAPIDLY REVERSIBLE AFTER WITHDRAWAL OF PB, AND THIS CHANGE PRECEDED A REDUCTION IN PLACENTAL ISOZYME OF GLUTATHIONE-S-TRANSFERASE (GST) EXPRESSION IN THE SAME AHF. WITHIN 20 DAYS OF WITHDRAWAL, FEWER THAN 4% OF GST-POSITIVE AHF WERE CX32 DEFICIENT, WHILE THE VOLUME OF TOTAL AHF DECREASED 30%. CHRONIC PB TREATMENT ALSO RESULTED IN A REVERSIBLE DECREASE IN CX32 SPECIFICALLY IN MID- AND CENTRO-LOBULAR HEPATOCYTES. CONTINUOUS THYMIDINE LABELING DEMONSTRATED THAT CX32 COULD BE UNCOUPLED FROM THE CELL CYCLE, SUGGESTING THAT SOME LIVER PROMOTERS MAY ACT DIRECTLY TO ALTER THE EXPRESSION OF CX32. THESE OBSERVATIONS SUGGEST THAT A DECREASE IN CX32 CONTENT WAS A RELATIVELY COMMON EPIGENETIC CHANGE IN AHF INDUCED DURING HEPATOCARCINOGENESIS BY A NUMBER OF INITIATING AND PROMOTING AGENTS BUT THAT THIS CHANGE WAS NOT SUFFICIENT FOR CARCINOGENESIS. THIS CHANGE, HOWEVER, MAY BE NECESSARY FOR THE MECHANISM(S) OF TUMOR PROMOTION, SINCE CX32-POSITIVE AHF DID NOT PROLIFERATE AS READILY AS CX32-DEFICIENT AHF. 1990 20 1013 45 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