1 1013 235 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	

2  460  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3 2080  41 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 5863  43 SUPPRESSION OF ALLERGIC ASTHMA BY LOSS OF FUNCTION OF MIZ1-MEDIATED TH1 SKEWING. ASTHMA IS THE MOST PREVALENT CHRONIC RESPIRATORY DISEASE WORLDWIDE. THERE IS CURRENTLY NO CURE, AND IT REMAINS AN IMPORTANT CAUSE OF MORBIDITY AND MORTALITY. HERE WE REPORT THAT LUNG-SPECIFIC LOSS OF FUNCTION OF THE TRANSCRIPTION FACTOR MIZ1 (C-MYC-INTERACTING ZINC FINGER PROTEIN-1) UPREGULATES THE PRO-T-HELPER CELL TYPE 1 CYTOKINE IL-12. UPREGULATION OF IL-12 IN TURN STIMULATES A TH1 RESPONSE, THEREBY COUNTERACTING T-HELPER CELL TYPE 2 RESPONSE AND PREVENTING THE ALLERGIC RESPONSE IN MOUSE MODELS OF HOUSE DUST MITE- AND OVA (OVALBUMIN)-INDUCED ASTHMA. USING TRANSGENIC MICE EXPRESSING CRE UNDER A CELL-SPECIFIC PROMOTER, WE DEMONSTRATE THAT MIZ1 ACTS IN LUNG EPITHELIAL CELLS AND DENDRITIC CELLS IN ASTHMA. CHROMATIN IMMUNOPRECIPITATION COUPLED WITH HIGH-THROUGHPUT DNA SEQUENCING OR QUANTITATIVE PCR REVEALS THE BINDING OF MIZ1 ON THE IL12 PROMOTER INDICATING DIRECT REPRESSION OF IL-12 BY MIZ1. IN ADDITION, HDAC1 (HISTONE DEACETYLASE 1) IS RECRUITED TO THE IL12 PROMOTER IN A MIZ1-DEPDENENT MANNER, SUGGESTING EPIGENETIC REPRESSION OF IL12 BY MIZ1. FURTHERMORE, MIZ1 IS UPREGULATED IN THE LUNGS OF ASTHMATIC MICE. OUR DATA TOGETHER SUGGEST THAT MIZ1 IS UPREGULATED DURING ASTHMA, WHICH IN TURN PROMOTES ASTHMA PATHOGENESIS BY PREVENTING TH1 SKEWING THROUGH THE TRANSCRIPTIONAL REPRESSION OF IL-12.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
5   35  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
6 5601  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  768  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8 1951  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9  368  53 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
10 6636  52 UNRAVELING A NEW PLAYER IN MULTIPLE SCLEROSIS PATHOGENESIS: THE RNA-BINDING PROTEIN HUR. BACKGROUND: ELAV-LIKE PROTEINS ARE A SMALL FAMILY OF RNA-BINDING PROTEINS THAT ARE FUNDAMENTAL PLAYERS IN POST-TRANSCRIPTIONAL MECHANISMS AND ARE INVOLVED IN THE PATHOGENESIS OF NEUROLOGIC AND PSYCHIATRIC DISORDERS. HUR, THE UBIQUITOUSLY EXPRESSED MEMBER OF THE FAMILY, IS ALSO IMPLICATED IN SUSTAINING INFLAMMATION AND INFLAMMATORY DISEASES, SUPPORTING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. INFLAMMATION PLAYS A CENTRAL ROLE IN MULTIPLE SCLEROSIS (MS), WHICH REPRESENTS THE MOST COMMON CAUSE OF PERMANENT PHYSICAL DISABILITY IN YOUNG ADULTS. MS IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM, WITH A COMPLEX AETIOLOGY INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. NO DATA ARE AVAILABLE ON THE POTENTIAL ENTANGLEMENT OF HUR IN MS PATHOGENESIS IN PATIENTS. IN THE PRESENT WORK, WE AIMED AT EXPLORING HUR PROTEIN LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM MS PATIENTS, COMPARED TO HEALTHY CONTROLS. TO FURTHER ELUCIDATE THE POSSIBLE INVOLVEMENT OF HUR IN MS, WE ALSO INVESTIGATED THE RELATIONSHIP BETWEEN THIS SPECIFIC RNA-BINDING PROTEIN AND HSP70-2 PROTEIN, ALSO CONSIDERING THE HSP70-2 RS1061581 POLYMORPHISM, GIVEN THAT HSP70-2 MRNA HAS BEEN REPORTED AS A HUR TARGET AND THIS SPECIFIC POLYMORPHISM TO BE ASSOCIATED WITH MS RISK. METHODS: ALLELES AND GENOTYPES FOR HSP70-2 RS1061581 POLYMORPHISM WERE ASSESSED, BY USING A POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM, FOLLOWED BY DIGESTION WITH RESTRICTION ENZYME, IN MS PATIENTS AND HEALTHY CONTROLS. PBMCS FROM A SUBGROUP OF PATIENTS AND CONTROLS WERE USED TO EVALUATE HUR AND HSP70-2 PROTEIN CONTENT BY WESTERN BLOT. RESULTS: PBMCS FROM 52 MS PATIENTS HAD A LOWER HUR AND HIGHER HSP70-2 PROTEIN CONTENT COMPARED TO 43 HEALTHY CONTROLS. AN INCREASE OF 100 UNITS OF HUR SIGNIFICANTLY DECREASED THE RISK OF DEVELOPING MS BY 9.8% (OR: 0.902, 95% CI: 0.83-0.98), CONTROLLING FOR HSP70-2 PROTEIN EXPRESSION, HSP70-2 RS1061581 GENOTYPE, AGE AND SEX. MOREOVER, HOLDING HUR LEVELS, AN INCREASE OF 100 UNITS OF HSP70-2 PROTEIN SIGNIFICANTLY INCREASED THE MS RISK BY 18.1% (OR: 1.181, 95% CI: 1.03-1.36) AND THE GENETIC SUSCEPTIBILITY OF DEVELOPING MS FOR HSP70-2 RS1061581 GG CARRIERS IS CONFIRMED. OF INTEREST, MS PATIENTS WITH A MODERATE TO SEVERE FORM OF MS (MSSS >/= 3) SHOWED A TREND TOWARDS A REDUCTION OF HUR PROTEIN LEVELS COMPARED TO PATIENTS WITH MILD DISEASE SEVERITY (MSSS < 3). CONCLUSIONS: HUR PROTEIN LEVELS ARE REDUCED IN MS PATIENTS COMPARED TO HEALTHY SUBJECTS, AND THE PROTEIN AMOUNT MAY CONTINUE TO DECLINE WITH DISEASE PROGRESSION, SUGGESTING A PUTATIVE ROLE OF THIS RNA-BINDING PROTEIN. MOREOVER, OUR RESULTS SUGGEST THAT MS PATHOLOGY MAY HAVE DISRUPTED THE LINK BETWEEN HUR AND ITS TARGET TRANSCRIPT HSP70-2. IT WILL BE IMPORTANT TO FURTHER EXPLORE THE EXACT ROLE OF HUR IN MS, CONSIDERING THE COMPLEX INTERPLAY WITH OTHER RNA-BINDING FACTORS AND TARGET MRNAS.	2020	
                                                                               
11 1016  37 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  238  32 ADENOSINE KINASE: A KEY REGULATOR OF PURINERGIC PHYSIOLOGY. ADENOSINE (ADO) IS AN ESSENTIAL BIOMOLECULE FOR LIFE THAT PROVIDES CRITICAL REGULATION OF ENERGY UTILIZATION AND HOMEOSTASIS. ADENOSINE KINASE (ADK) IS AN EVOLUTIONARY ANCIENT RIBOKINASE DERIVED FROM BACTERIAL SUGAR KINASES THAT IS WIDELY EXPRESSED IN ALL FORMS OF LIFE, TISSUES AND ORGAN SYSTEMS THAT TIGHTLY REGULATES INTRACELLULAR AND EXTRACELLULAR ADO CONCENTRATIONS. THE FACILE ABILITY OF ADK TO ALTER ADO AVAILABILITY PROVIDES A "SITE AND EVENT" SPECIFICITY TO THE ENDOGENOUS PROTECTIVE EFFECTS OF ADO IN SITUATIONS OF CELLULAR STRESS. IN ADDITION TO MODULATING THE ABILITY OF ADO TO ACTIVATE ITS COGNATE RECEPTORS (P1 RECEPTORS), NUCLEAR ADK ISOFORM ACTIVITY HAS BEEN LINKED TO EPIGENETIC MECHANISMS BASED ON TRANSMETHYLATION PATHWAYS. PREVIOUS DRUG DISCOVERY RESEARCH HAS TARGETED ADK INHIBITION AS A THERAPEUTIC APPROACH TO MANAGE EPILEPSY, PAIN, AND INFLAMMATION. THESE EFFORTS GENERATED MULTIPLE CLASSES OF HIGHLY POTENT AND SELECTIVE INHIBITORS. HOWEVER, CLINICAL DEVELOPMENT OF EARLY ADK INHIBITORS WAS STOPPED DUE TO APPARENT MECHANISTIC TOXICITY AND THE LACK OF SUITABLE TRANSLATIONAL MARKERS. NEW INSIGHTS REGARDING THE POTENTIAL ROLE OF THE NUCLEAR ADK ISOFORM (ADK-LONG) IN THE EPIGENETIC MODULATION OF MALADAPTIVE DNA METHYLATION OFFERS THE POSSIBILITY OF IDENTIFYING NOVEL ADK-ISOFORM SELECTIVE INHIBITORS AND NEW INTERVENTIONAL STRATEGIES THAT ARE INDEPENDENT OF ADO RECEPTOR ACTIVATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13 1668  52 DOWNREGULATION OF SOCS1 INCREASES INTERFERON-INDUCED ISGYLATION DURING DIFFERENTIATION OF INDUCED-PLURIPOTENT STEM CELLS TO HEPATOCYTES. BACKGROUND & AIMS: INCREASED EXPRESSION OF IFN-STIMULATED GENE 15 (ISG15) AND SUBSEQUENTLY INCREASED ISGYLATION ARE KEY FACTORS IN THE HOST RESPONSE TO VIRAL INFECTION. IN THIS STUDY, WE SOUGHT TO CHARACTERIZE THE EXPRESSION OF ISG15, ISGYLATION, AND ASSOCIATED ENZYMES AT EACH STAGE OF DIFFERENTIATION FROM INDUCED PLURIPOTENT STEM CELLS (IPSCS) TO HEPATOCYTES. METHODS: TO STUDY THE REGULATION OF ISGYLATION, WE UTILIZED PATIENT SAMPLES AND IN VITRO CELL CULTURE MODELS INCLUDING IPSCS, HEPATOCYTES-LIKE CELLS, IMMORTALIZED CELL LINES, AND PRIMARY HUMAN HEPATOCYTES. PROTEIN/MRNA EXPRESSION WERE MEASURED FOLLOWING TREATMENT WITH POLY(I:C), IFNALPHA AND HCV INFECTION. RESULTS: WHEN COMPARED TO HLCS, WE OBSERVED SEVERAL NOVEL ASPECTS OF THE ISGYLATION PATHWAY IN IPSCS. THESE INCLUDE A LOWER BASELINE EXPRESSION OF THE ISGYLATION-ACTIVATING ENZYME, UBE1L, A LACK OF IFN-INDUCED EXPRESSION OF THE ISGYLATION-CONJUGATION ENZYME UBE2L6, AN ATTENUATED ACTIVATION OF THE TRANSCRIPTION FACTOR STAT1 AND CONSTITUTIVE EXPRESSION OF SOCS1. ISGYLATION WAS OBSERVED IN IPSCS FOLLOWING DOWNREGULATION OF SOCS1, WHICH FACILITATED STAT1 ACTIVATION AND SUBSEQUENTLY INCREASED EXPRESSION OF UBE2L6. INTRIGUINGLY, HCV PERMISSIVE TRANSFORMED HEPATOMA CELL LINES DEMONSTRATED HIGHER INTRINSIC EXPRESSION OF SOCS1 AND WEAKER ISGYLATION FOLLOWING IFN TREATMENT. SOCS1 DOWNREGULATION IN HCV-INFECTED HUH 7.5.1 CELLS LED TO INCREASED ISGYLATION. CONCLUSIONS: HEREIN, WE SHOW THAT HIGH BASAL LEVELS OF SOCS1 INHIBIT STAT1 ACTIVATION AND SUBSEQUENTLY IFN-INDUCED UBE2L6 AND ISGYLATION IN IPSCS. FURTHERMORE, AS IPSCS DIFFERENTIATE INTO HEPATOCYTES, EPIGENETIC MECHANISMS REGULATE ISGYLATION BY MODIFYING UBE1L AND SOCS1 EXPRESSION LEVELS. OVERALL, THIS STUDY DEMONSTRATES THAT THE DEVELOPMENT OF CELL-INTRINSIC INNATE IMMUNITY DURING THE DIFFERENTIATION OF IPSCS TO HEPATOCYTES PROVIDES INSIGHT INTO CELL TYPE-SPECIFIC REGULATION OF HOST DEFENSE RESPONSES AND RELATED ONCOGENIC PROCESSES. IMPACT AND IMPLICATIONS: TO ELUCIDATE THE MECHANISM UNDERLYING REGULATION OF ISGYLATION, A KEY PROCESS IN THE INNATE IMMUNE RESPONSE, WE STUDIED CHANGES IN ISGYLATION-ASSOCIATED GENES AT THE DIFFERENT STAGES OF DIFFERENTIATION FROM IPSCS TO HEPATOCYTES. WE FOUND THAT HIGH BASAL LEVELS OF SOCS1 INHIBIT STAT1 ACTIVATION AND SUBSEQUENTLY IFN-INDUCED UBE2L6 AND ISGYLATION IN IPSCS. IMPORTANTLY, EPIGENETIC REGULATION OF SOCS1 AND SUBSEQUENTLY ISGYLATION MAY BE IMPORTANT FACTORS IN THE DEVELOPMENT OF CELL TYPE-SPECIFIC HOST DEFENSE RESPONSES IN HEPATOCYTES THAT SHOULD BE CONSIDERED WHEN STUDYING CHRONIC INFECTIONS AND ONCOGENIC PROCESSES IN THE LIVER.	2022	
                                                                                                                                                                                                                                                                                                                            
14 1950  41 EPIGENETIC ACTIVATION OF TENSIN 4 PROMOTES GASTRIC CANCER PROGRESSION. GASTRIC CANCER (GC) IS A COMPLEX DISEASE INFLUENCED BY MULTIPLE GENETIC AND EPIGENETIC FACTORS. CHRONIC INFLAMMATION CAUSED BY HELICOBACTER PYLORI INFECTION AND DIETARY RISK FACTORS CAN RESULT IN THE ACCUMULATION OF ABERRANT DNA METHYLATION IN GASTRIC MUCOSA, WHICH PROMOTES GC DEVELOPMENT. TENSIN 4 (TNS4), A MEMBER OF THE TENSIN FAMILY OF PROTEINS, IS LOCALIZED TO FOCAL ADHESION SITES, WHICH CONNECT THE EXTRACELLULAR MATRIX AND CYTOSKELETAL NETWORK. WE IDENTIFIED UPREGULATION OF TNS4 IN GC USING QUANTITATIVE REVERSE TRANSCRIPTION PCR WITH 174 PAIRED SAMPLES OF GC TUMORS AND ADJACENT NORMAL TISSUES. TRANSCRIPTIONAL ACTIVATION OF TNS4 OCCURRED EVEN DURING THE EARLY STAGE OF TUMOR DEVELOPMENT. TNS4 DEPLETION IN GC CELL LINES THAT EXPRESSED HIGH TO MODERATE LEVELS OF TNS4, I.E., SNU-601, KATO III, AND MKN74, REDUCED CELL PROLIFERATION AND MIGRATION, WHEREAS ECTOPIC EXPRESSION OF TNS4 IN THOSE LINES THAT EXPRESSED LOWER LEVELS OF TNS4, I.E., SNU-638, MKN1, AND MKN45 INCREASED COLONY FORMATION AND CELL MIGRATION. THE PROMOTER REGION OF TNS4 WAS HYPOMETHYLATED IN GC CELL LINES THAT SHOWED UPREGULATION OF TNS4. WE ALSO FOUND A SIGNIFICANT NEGATIVE CORRELATION BETWEEN TNS4 EXPRESSION AND CPG METHYLATION IN 250 GC TUMORS BASED ON THE CANCER GENOME ATLAS (TCGA) DATA. THIS STUDY ELUCIDATES THE EPIGENETIC MECHANISM OF TNS4 ACTIVATION AND FUNCTIONAL ROLES OF TNS4 IN GC DEVELOPMENT AND PROGRESSION AND SUGGESTS A POSSIBLE APPROACH FOR FUTURE GC TREATMENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15 3945  53 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16 1843  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17 1777  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18 5511  27 RIBONUCLEASES IN TUMOR GROWTH. THIS REVIEW SUMMARIZES DATA ON AMBIGUOUS BIOLOGICAL FUNCTIONS OF RIBONUCLEASES (RNASES) AT TUMOR GROWTH. IN SOME CASES THE RAISED LEVEL OF ENZYME ACTIVITY IN BIOLOGICAL FLUIDS CAN BE REGARDED AS AN ADDITIONAL MARKER OF MALIGNANT GROWTH (PANCREAS CANCER, CHRONIC MYELOID LEUKEMIA, ETC.). AT THE SAME TIME THE ACTIVITY OF RNASES IS OFTEN LOWERED IN TUMOR TISSUE. HIGH SUBSTRATE SPECIFICITY OF PARTICULAR RNASES PROVIDES METABOLIC BALANCE BETWEEN VARIOUS KINDS OF RNAS WITH VARIOUS HALF-TIME EXCHANGE TURN. RNASES ARE THE IMPORTANT FACTORS OF EPIGENETIC REGULATION OF GENE ACTIVITY IN CELLS. THE ACTIVITY OF RNASES IS ADJUSTABLE BY INHIBITORS AND OTHER FACTORS, AND DEFINES TIME OF EXISTENCE OF DIFFERENT KINDS OF RNAS. RNASES (THE MODIFIED VARIANTS OF RNASE A, RNASES OF SEMEN FLUID OF THE CATTLE, RNASE OF AMPHIBIA OOCYTES) CAN BE USED AS ANTI-TUMOR THERAPEUTIC AGENTS. ON THE OTHER HAND, SOME INHIBITORS OF RNASES OF NATURAL OR SYNTHETIC ORIGIN WERE DEMONSTRATED TO BE PERSPECTIVE DRUGS THAT INHIBIT TUMOR GROWTH.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19 1282  42 DECIPHERING THE ACTIVE CONSTITUENTS OF DABUSHEN DECOCTION OF AMELIORATING OSTEOARTHRITIS VIA PPARGAMMA PRESERVATION BY TARGETING DNMT1. OSTEOARTHRITIS (OA) IS A MULTIFACTORIAL AND CHRONIC DEGENERATIVE JOINT DISEASE. DUE TO THE ADVERSE EFFECTS OF CURRENTLY USED DRUGS, A SAFER AND MORE EFFECTIVE THERAPY FOR TREATING OA IS NEEDED. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA) IS A KEY PROTEIN PROTECTING CARTILAGE. DNMT1-MEDIATED HYPERMETHYLATION OF PPARGAMMA PROMOTER LEADS TO ITS SUPPRESSION. THEREFORE, DNMT1 MIGHT BE AN EFFECTIVE TARGET FOR EXERTING CARTILAGE PROTECTIVE EFFECTS BY REGULATING THE EPIGENETIC EXPRESSION OF PPARGAMMA. DABUSHEN DECOCTION (DD) IS A REPRESENTATIVE PRESCRIPTION OF DUNHUANG ANCIENT MEDICAL PRESCRIPTION, WHICH HAS A POTENTIAL THERAPEUTIC EFFECT ON OA. SO FAR, THE RESEARCH OF THE EFFICACY AND MATERIAL BASIS OF DD IN THE TREATMENT OF OA REMAINS UNCLEAR. IN THIS STUDY, MICRO-CT, HE STAINING, S-O STAINING, AND IMMUNOHISTOCHEMISTRY ANALYSIS WERE USED TO DEMONSTRATE THAT DD INCREASED THE EXPRESSION OF PPARGAMMA AND COLLAGEN SYNTHESIS IN AN OA RAT MODEL. NEXT, THE STRUCTURE OF DNMT1 WAS USED TO SCREEN THE ACTIVE CONSTITUENTS OF DD BY MOLECULAR DOCKING METHOD FOR TREATMENT OA. SEVEN POTENTIAL ACTIVE CONSTITUENTS, INCLUDING ISOLIQUIRITIGENIN, EMODIN, TAXIFOLIN, CATALPOL, ALISOL A, ZINGERONE, AND SCHISANDRIN C WERE HITED. THE PROTECTIVE EFFECT OF THE POTENTIAL ACTIVE CONSTITUENTS TO CHONDROCYTES WERE EVALUATED BY PROTEIN CAPILLARY ELECTROPHORESIS, IMMUNOFLUORESCENCE ASSAYS, AND EX VIVO CULTURE OF RAT KNEE CARTILAGE. THE FIVE CONSTITUENTS, SUCH AS ALISOL A, EMODIN, TAXIFOLIN, ISOLIQUIRITIGENIN, AND SCHISANDRIN C COULD PROMOTE THE EXPRESSION OF PPARGAMMA AND AMELIORATE IL-1BETA-INDUCED DOWNREGULATION OF COLLAGEN II AND THE PRODUCTION OF MMP-13. ALISOL A AND EMODIN COULD EFFECTIVELY MITIGATE CARTILAGE DAMAGE. AT LAST, MOLECULAR DYNAMICS SIMULATIONS WITH MM-GBSA METHOD WAS APPLIED TO INVESTIGATE THE INTERACTION PATTERN OF THE ACTIVE CONSTITUENTS AND DNMT1 COMPLEXES. THE FIVE CONSTITUENTS, SUCH AS ALISOL A, EMODIN, TAXIFOLIN, ISOLIQUIRITIGENIN, AND SCHISANDRIN C ACHIEVED A STABLE BINDING PATTERN WITH DNMT1, IN WHICH ALISOL A HAS A RELATIVELY HIGH BINDING FREE ENERGY. IN CONCLUSION, THIS STUDY ELUCIDATES THAT THE ACTIVE CONSTITUENTS OF DD (ALISOL A, EMODIN, TAXIFOLIN, ISOLIQUIRITIGENIN, AND SCHISANDRIN C) COULD AMELIORATE OSTEOARTHRITIS VIA PPARGAMMA PRESERVATION BY TARGETING DNMT1.THESE FINDINGS FACILITATED CLINICAL USE OF DD AND PROVIDED A VALUABLE STRATEGY FOR DEVELOPING NATURAL EPIGENETIC MODULATORS FROM CHINESE HERBAL FORMULA.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
20 1806  39 EFFECT OF TRANSCRIPTION INHIBITION AND GENERATION OF SUPPRESSIVE VIRAL NON-CODING RNAS. BACKGROUND: HIV-1 PATIENTS RECEIVING COMBINATION ANTIRETROVIRAL THERAPY (CART) SURVIVE INFECTION BUT REQUIRE LIFE-LONG ADHERENCE AT HIGH EXPENSE. IN CHRONIC CART-TREATED PATIENTS WITH UNDETECTABLE VIRAL TITERS, CELL-ASSOCIATED VIRAL RNA IS STILL DETECTABLE, POINTING TO LOW-LEVEL VIRAL TRANSCRIPTIONAL LEAKINESS. TO DATE, THERE ARE NO FDA-APPROVED DRUGS AGAINST HIV-1 TRANSCRIPTION. WE HAVE PREVIOUSLY SHOWN THAT F07#13, A THIRD GENERATION TAT PEPTIDE MIMETIC WITH COMPETITIVE ACTIVITY AGAINST CDK9/T1-TAT BINDING SITES, INHIBITS HIV-1 TRANSCRIPTION IN VITRO AND IN VIVO. RESULTS: HERE, WE DEMONSTRATE THAT INCREASING CONCENTRATIONS OF F07#13 (0.01, 0.1, 1 MICROM) CAUSE A DECREASE IN TAT LEVELS IN A DOSE-DEPENDENT MANNER BY INHIBITING THE CDK9/T1-TAT COMPLEX FORMATION AND SUBSEQUENT UBIQUITIN-MEDIATED TAT SEQUESTRATION AND DEGRADATION. OUR DATA INDICATE THAT COMPLEXES I AND IV CONTAIN DISTINCT PATTERNS OF UBIQUITINATED TAT AND THAT TRANSCRIPTIONAL INHIBITION INDUCED BY F07#13 CAUSES AN OVERALL REDUCTION IN TAT LEVELS. THIS REDUCTION MAY BE TRIGGERED BY F07#13 BUT ULTIMATELY IS MEDIATED BY TAR-GAG VIRAL RNAS THAT BIND SUPPRESSIVE TRANSCRIPTION FACTORS (SIMILAR TO 7SK, NRON, HOTAIR, AND XIST LNCRNAS) TO ENHANCE TRANSCRIPTIONAL GENE SILENCING AND LATENCY. THESE RNAS COMPLEX WITH PRC2, SIN3A, AND CUL4B, RESULTING IN EPIGENETIC MODIFICATIONS. FINALLY, WE OBSERVED AN F07#13-MEDIATED DECREASE OF VIRAL BURDEN BY TARGETING THE R REGION OF THE LONG TERMINAL REPEAT (HIV-1 PROMOTER REGION, LTR), PROMOTING BOTH PAUSED POLYMERASES AND INCREASED EFFICIENCY OF CRISPR/CAS9 EDITING IN INFECTED CELLS. THIS IMPLIES THAT GENE EDITING MAY BE BEST PERFORMED UNDER A REPRESSED TRANSCRIPTIONAL STATE. CONCLUSIONS: COLLECTIVELY, OUR RESULTS INDICATE THAT F07#13, WHICH CAN TERMINATE RNA POLYMERASE II AT DISTINCT SITES, CAN GENERATE SCAFFOLD RNAS, WHICH MAY ASSEMBLE INTO SPECIFIC SETS OF "RNA MACHINES" THAT CONTRIBUTE TO GENE REGULATION. IT REMAINS TO BE SEEN WHETHER THESE EFFECTS CAN ALSO BE SEEN IN VARIOUS CLADES THAT HAVE VARYING PROMOTER STRENGTH, MUTANT LTRS, AND IN PATIENT SAMPLES.	2019