1 6041 87 THE CLASS III HISTONE DEACETYLASE SIRTUIN 1 IN IMMUNE SUPPRESSION AND ITS THERAPEUTIC POTENTIAL IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC DEBILITATING DISEASE OF THE JOINTS. BOTH THE INNATE AND ADAPTIVE IMMUNE RESPONSES PARTICIPATE IN THE DEVELOPMENT AND PROGRESSION OF RA. WHILE SEVERAL THERAPEUTIC REAGENTS, SUCH AS TNF-ALPHA AGONISTS, HAVE BEEN SUCCESSFULLY DEVELOPED FOR THE CLINICAL USE IN THE TREATMENT OF RA, MORE THAN HALF OF THE PATIENTS DO NOT RESPOND TO ANTI-TNF THERAPY. THEREFORE, NEW THERAPEUTIC REAGENTS ARE NEEDED. RECENT STUDIES HAVE SHOWN THAT SIRTUIN 1 (SIRT1), A NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD)-DEPENDENT HISTONE DEACETYLASE, IS A CRITICAL NEGATIVE REGULATOR OF BOTH THE INNATE AND ADAPTIVE IMMUNE RESPONSE IN MICE, AND ITS ALTERED FUNCTIONS ARE LIKELY TO BE INVOLVED IN AUTOIMMUNE DISEASES. SMALL MOLECULES THAT MODULATE SIRT1 FUNCTIONS ARE POTENTIAL THERAPEUTIC REAGENTS FOR AUTOIMMUNE INFLAMMATORY DISEASES. THIS REVIEW HIGHLIGHTS THE ROLE OF SIRT1 IN IMMUNE REGULATION AND RA. 2013 2 4159 19 MECP2 CONTROLS AN EPIGENETIC PATHWAY THAT PROMOTES MYOFIBROBLAST TRANSDIFFERENTIATION AND FIBROSIS. BACKGROUND & AIMS: MYOFIBROBLAST TRANSDIFFERENTIATION GENERATES HEPATIC MYOFIBROBLASTS, WHICH PROMOTE LIVER FIBROGENESIS. THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPARGAMMA) IS A NEGATIVE REGULATOR OF THIS PROCESS. WE INVESTIGATED EPIGENETIC REGULATION OF PPARGAMMA AND MYOFIBROBLAST TRANSDIFFERENTIATION. METHODS: CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAYS ASSESSED THE BINDING OF METHYL-CPG BINDING PROTEIN 2 (MECP2) TO PPARGAMMA AND CHROMATIN MODIFICATIONS THAT SILENCE THIS GENE. MECP2(-/Y) MICE AND AN INHIBITOR (DZNEP) OF THE EPIGENETIC REGULATORY PROTEIN EZH2 WERE USED IN THE CARBON TETRACHLORIDE MODEL OF LIVER FIBROSIS. LIVER TISSUES FROM MICE WERE ASSESSED BY HISTOLOGIC ANALYSIS; MARKERS OF FIBROSIS WERE MEASURED BY QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR). REVERSE TRANSCRIPTION PCR DETECTED CHANGES IN EXPRESSION OF THE MICRORNA MIR132 AND ITS TARGET, ELONGATED TRANSCRIPTS OF MECP2. MYOFIBROBLASTS WERE TRANSFECTED WITH MIR132; PPARGAMMA AND MECP2 EXPRESSIONS WERE ANALYZED BY QPCR OR IMMUNOBLOTTING. RESULTS: MYOFIBROBLAST TRANSDIFFERENTIATION OF HEPATIC STELLATE CELLS IS CONTROLLED BY A COMBINATION OF MECP2, EZH2, AND MIR132 IN A RELAY PATHWAY. THE PATHWAY IS ACTIVATED BY DOWN-REGULATION OF MIR132, RELEASING THE TRANSLATIONAL BLOCK ON MECP2. MECP2 IS RECRUITED TO THE 5' END OF PPARGAMMA, WHERE IT PROMOTES METHYLATION BY H3K9 AND RECRUITS THE TRANSCRIPTION REPRESSOR HP1ALPHA. MECP2 ALSO STIMULATES EXPRESSION OF EZH2 AND METHYLATION OF H3K27 TO FORM A REPRESSIVE CHROMATIN STRUCTURE IN THE 3' EXONS OF PPARGAMMA. GENETIC AND PHARMACOLOGIC DISRUPTIONS OF MECP2 OR EZH2 REDUCED THE FIBROGENIC CHARACTERISTICS OF MYOFIBROBLASTS AND ATTENUATED FIBROGENESIS. CONCLUSIONS: LIVER FIBROSIS IS REGULATED BY AN EPIGENETIC RELAY PATHWAY THAT INCLUDES MECP2, EZH2, AND MIR132. REAGENTS THAT INTERFERE WITH THIS PATHWAY MIGHT BE DEVELOPED TO REDUCE FIBROGENESIS IN CHRONIC LIVER DISEASE. 2010 3 633 20 BIOLOGICAL EFFECTS AND EPIDEMIOLOGICAL CONSEQUENCES OF ARSENIC EXPOSURE, AND REAGENTS THAT CAN AMELIORATE ARSENIC DAMAGE IN VIVO. THROUGH CONTAMINATED DIET, WATER, AND OTHER FORMS OF ENVIRONMENTAL EXPOSURE, ARSENIC AFFECTS HUMAN HEALTH. THERE ARE MANY U.S. AND WORLDWIDE "HOT SPOTS" WHERE THE ARSENIC LEVEL IN PUBLIC WATER EXCEEDS THE MAXIMUM EXPOSURE LIMIT. THE BIOLOGICAL EFFECTS OF CHRONIC ARSENIC EXPOSURE INCLUDE GENERATION OF REACTIVE OXYGEN SPECIES (ROS), LEADING TO OXIDATIVE STRESS AND DNA DAMAGE, EPIGENETIC DNA MODIFICATION, INDUCTION OF GENOMIC INSTABILITY, AND INFLAMMATION AND IMMUNOMODULATION, ALL OF WHICH CAN INITIATE CARCINOGENESIS. HIGH ARSENIC EXPOSURE IS EPIDEMIOLOGICALLY ASSOCIATED WITH SKIN, LUNG, BLADDER, LIVER, KIDNEY AND PANCREATIC CANCER, AND CARDIOVASCULAR, NEURONAL, AND OTHER DISEASES. THIS REVIEW BRIEFLY SUMMARIZES THE BIOLOGICAL EFFECTS OF ARSENIC EXPOSURE AND EPIDEMIOLOGICAL CANCER STUDIES WORLDWIDE, AND PROVIDES AN OVERVIEW FOR EMERGING RODENT-BASED STUDIES OF REAGENTS THAT CAN AMELIORATE THE EFFECTS OF ARSENIC EXPOSURE IN VIVO. THESE REAGENTS MAY BE TRANSLATED TO HUMAN POPULATIONS FOR DISEASE PREVENTION. WE PROPOSE THE IMPORTANCE OF DEVELOPING A BIOMARKER-BASED PRECISION PREVENTION APPROACH FOR THE HEALTH ISSUES ASSOCIATED WITH ARSENIC EXPOSURE THAT AFFECTS MILLIONS OF PEOPLE WORLDWIDE. 2017 4 6657 27 UPREGULATED KAT7 IN SYNOVIAL FIBROBLASTS PROMOTES TH17 CELL DIFFERENTIATION AND INFILTRATION IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE INVOLVING MULTIPLE CELLULAR PARTICIPANTS, OF WHICH SYNOVIAL FIBROBLASTS (SFS) ARE TIGHTLY CONNECTED WITH THE DEVELOPMENT AND PROGRESSION OF RA. HERE, WE PROVIDE EVIDENCE CONFIRMING THAT KAT7, AN H4-SPECIFIC HISTONE ACETYLASE, IS UPREGULATED IN SFS OF RA PATIENTS, WHICH IS AT LEAST ATTRIBUTED TO THE STIMULATION BY RA-ASSOCIATED PROINFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA, IL-1BETA OR IFN-GAMMA. IN ADDITION, KAT7 OVEREXPRESSION IN CULTURED HUMAN FIBROBLAST-LIKE SYNOVIOCYTES (HFLSS) INDUCES IL-6 AND TGF-BETA EXPRESSION THROUGH AN EPIGENETIC MECHANISM, AND IN VITRO T HELPER 17 (TH17) CELL POLARIZATION CULTURED IN THESE SUPERNATANTS SHOWS PROMOTED CELL DIFFERENTIATION. MOREOVER, KAT7 OVEREXPRESSION IN HFLSS INDUCES CCL20 EXPRESSION VIA P44/42 MAPK PATHWAY, WHEREBY PROMOTING TH17 CELL MIGRATION. THESE TWO ACTIVITIES OF KAT7 IN RA SFS INDICATE ITS POTENTIAL ROLES IN ACCELERATING RA PATHOLOGY. OVERALL, THESE RESULTS DEMONSTRATE SOME CONNECTIONS BETWEEN KAT7 UPREGULATED IN RA SFS AND RA PROGRESSION AND PRESENT THE INHIBITION OF KAT7 ACTIVITY AS A NOVEL THERAPEUTIC TARGET FOR INTERFERING RA DISEASE. 2017 5 5528 23 RNA MODIFICATION IN INFLAMMATORY BOWEL DISEASES. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC INFLAMMATORY DISORDER CHARACTERIZED BY DAMAGE TO THE INTESTINAL MUCOSA, WHICH IS CAUSED BY A COMBINATION OF FACTORS. THESE INCLUDE GENETIC AND EPIGENETIC ALTERATIONS, ENVIRONMENTAL INFLUENCE, MICROORGANISM INTERACTIONS, AND IMMUNE CONDITIONS. SOME POPULATIONS WITH IBD SHOW A CANCER-PRONE PHENOTYPE. RECENT STUDIES HAVE PROVIDED INSIGHT INTO THE INVOLVEMENT OF RNA MODIFICATIONS IN THE SPECIFIC PATHOGENESIS OF IBD THROUGH REGULATION OF RNA BIOLOGY IN EPITHELIAL AND IMMUNE CELLS. STUDIES OF SEVERAL RNA MODIFICATION-TARGETING REAGENTS HAVE SHOWN PREFERABLE OUTCOMES IN PATIENTS WITH COLITIS. HERE, WE NOTE A NEW AWARENESS OF RNA MODIFICATION IN THE TARGETING OF IBD AND RELATED DISEASES, WHICH WILL CONTRIBUTE TO EARLY DIAGNOSIS, DISEASE MONITORING, AND POSSIBLE CONTROL BY INNOVATIVE THERAPEUTIC APPROACHES. 2022 6 1861 15 EMERGENCE OF CANCER STEM CELLS IN HEPATOCELLULAR CARCINOMA. LIVER CANCER REPRESENTS THE SECOND MOST DEADLY HUMAN MALIGNANCY. THE MAJOR HISTOLOGICAL SUBTYPE CALLED HEPATOCELLULAR CARCINOMA (HCC) ARISES BY CHRONIC INFLAMMATION-TRIGGERED REGENERATIVE RESPONSES OF NORMALLY QUIESCENT HEPATOCYTES AND PROGENITORS, RESPECTIVELY. SUCH REGENERATIVE STRESS ACCELERATES THE ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES (YAMASHITA & WANG, 2013), WHILE DETAILED MECHANISMS REMAIN UNCERTAIN. IN THIS ISSUE OF THE EMBO JOURNAL, NIKOLAOU ET AL PRESENT A NOVEL HCC MODEL THAT FACILITATES BOTH ISOLATION AND MOLECULAR CHARACTERIZATION OF SELF-RENEWING, HCC-PROPAGATING CANCER STEM CELLS THAT COULD INSTRUCT FUTURE INTERVENTIONS (NIKOLAOU ET AL, 2014). 2015 7 5785 20 SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 RAT LIVER EPITHELIAL CELLS. SEVERAL STUDIES HAVE SHOWN THAT CULTURED RAT LIVER EPITHELIAL CELLS TRANSFORM SPONTANEOUSLY AFTER CHRONIC MAINTENANCE IN A CONFLUENT STATE IN VITRO. IN THE PRESENT STUDY, MULTIPLE INDEPENDENT LINEAGES OF LOW-PASSAGE WB-F344 RAT LIVER EPITHELIAL STEM-LIKE CELLS WERE INITIATED AND SUBJECTED IN PARALLEL TO SELECTION FOR SPONTANEOUS TRANSFORMATION TO DETERMINE WHETHER SPONTANEOUS ACQUISITION OF TUMORIGENICITY WAS THE RESULT OF EVENTS (GENETIC OR EPIGENETIC) THAT OCCURRED INDEPENDENTLY AND STOCHASTICALLY, OR REFLECTED THE EXPRESSION OF A PRE-EXISTING ALTERATION WITHIN THE PARENTAL WB-F344 CELL LINE. TEMPORAL ANALYSIS OF THE SPONTANEOUS ACQUISITION OF TUMORIGENICITY BY WB-F344 CELLS DEMONSTRATED LINEAGE-SPECIFIC DIFFERENCES IN THE TIME OF FIRST EXPRESSION OF THE TUMORIGENIC PHENOTYPE, FREQUENCIES AND LATENCIES OF TUMOR FORMATION, AND TUMOR DIFFERENTIATIONS. ALTHOUGH SPONTANEOUSLY TRANSFORMED WB-F344 CELLS PRODUCED DIVERSE TUMOR TYPES (INCLUDING HEPATOCELLULAR CARCINOMAS, CHOLANGIOCARCINOMAS, HEPATOBLASTOMAS, AND OSTEOGENIC SARCOMAS), INDIVIDUAL LINEAGES YIELDED TUMORS WITH CONSISTENT AND SPECIFIC PATTERNS OF DIFFERENTIATION. THESE RESULTS PROVIDE SUBSTANTIAL EVIDENCE THAT THE STOCHASTIC ACCUMULATION OF INDEPENDENT TRANSFORMING EVENTS DURING THE SELECTION REGIMEN IN VITRO WERE RESPONSIBLE FOR SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 CELLS. FURTHERMORE, CELL LINEAGE COMMITMENT TO A SPECIFIC DIFFERENTIATION PROGRAM WAS STABLE WITH TIME IN CULTURE AND WITH SITE OF TRANSPLANTATION. THIS IS THE FIRST REPORT OF A COHORT OF RELATED, BUT INDEPENDENT, RAT LIVER EPITHELIAL CELL LINES THAT COLLECTIVELY PRODUCE A SPECTRUM OF TUMOR TYPES BUT INDIVIDUALLY REPRODUCE A SPECIFIC TUMOR TYPE. THESE CELL LINES WILL PROVIDE VALUABLE REAGENTS FOR INVESTIGATION OF THE MOLECULAR MECHANISMS INVOLVED IN THE DIFFERENTIATION OF HEPATIC STEM-LIKE CELLS AND FOR EXAMINATION OF POTENTIAL CAUSAL RELATIONSHIPS IN SPONTANEOUSLY TRANSFORMED RAT LIVER EPITHELIAL CELL LINES BETWEEN MOLECULAR/CELLULAR ALTERATIONS AND THE ABILITY TO PRODUCE TUMORS IN SYNGENEIC ANIMALS. 1998 8 4233 23 METHYLATION OF SEPTIN9 MEDIATED BY DNMT3A ENHANCES HEPATIC STELLATE CELLS ACTIVATION AND LIVER FIBROGENESIS. LIVER FIBROSIS, RESULTING FROM CHRONIC AND PERSISTENT INJURY TO THE LIVER, IS A WORLDWIDE HEALTH PROBLEM. ADVANCED LIVER FIBROSIS RESULTS IN CIRRHOSIS, LIVER FAILURE AND EVEN HEPATOCELLULAR CANCER (HCC), OFTEN EVENTUALLY REQUIRING LIVER TRANSPLANTATION, POSES A HUGE HEALTH BURDEN ON THE GLOBAL COMMUNITY. HOWEVER, THE SPECIFIC PATHOGENESIS OF LIVER FIBROSIS REMAINS NOT FULLY UNDERSTOOD. NUMEROUS BASIC AND CLINICAL STUDIES HAVE PROVIDED EVIDENCE THAT EPIGENETIC MODIFICATIONS, ESPECIALLY DNA METHYLATION, MIGHT CONTRIBUTE TO THE ACTIVATION OF HEPATIC STELLATE CELLS (HSCS), THE PIVOTAL CELL TYPE RESPONSIBLE FOR THE FIBROUS SCAR IN LIVER. HERE, REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) AND BISULFITE PYROSEQUENCING PCR (BSP) ANALYSIS IDENTIFIED HYPERMETHYLATION STATUS OF SEPTIN9 (SEPT9) GENE IN LIVER FIBROGENESIS. SEPT9 PROTEIN WAS DRAMATICALLY DECREASED IN LIVERS OF CCL4-TREATED MICE AND IMMORTALIZED HSC-T6 CELLS EXPOSED TO TGF-BETA1. NEVERTHELESS, THE SUPPRESSION OF SEPT9 COULD BE BLOCKED BY DNMT3A-SIRNA AND DNA METHYLTRANSFERASE INHIBITOR, 5-AZA-2'-DEOXYCYTIDINE (5-AZADC). OVEREXPRESSED SEPT9 ATTENUATED TGF-BETA1-INDUCED EXPRESSION OF MYOFIBROBLAST MARKERS ALPHA-SMA AND COL1A1, ACCOMPANIED BY UP-REGULATION OF CELL APOPTOSIS-RELATED PROTEINS. CONVERSELY, RNAI-MEDIATED SILENCING OF SEPT9 ENHANCED ACCUMULATION OF EXTRACELLULAR MATRIX. THESE OBSERVATIONS SUGGESTED THAT SEPT9 CONTRIBUTED TO ALLEVIATE LIVER FIBROSIS MIGHT PARTIALLY THROUGH PROMOTING ACTIVATED HSCS APOPTOSIS AND THIS ANTI-FIBROGENESIS EFFECT MIGHT BE BLOCKED BY DNMT-3A MEDIATED METHYLATION OF SEPT9. THEREFORE, PHARMACOLOGICAL AGENTS THAT INHIBIT SEPT9 METHYLATION AND INCREASE ITS EXPRESSION COULD BE CONSIDERED AS VALUABLE TREATMENTS FOR LIVER FIBROSIS. 2017 9 3933 24 LIVER SINUSOIDAL ENDOTHELIAL CELLS ARE IMPLICATED IN MULTIPLE FIBROTIC MECHANISMS. CHRONIC LIVER DISEASES ARE ATTRIBUTED TO LIVER INJURY. DEVELOPMENT OF FIBROSIS FROM CHRONIC LIVER DISEASES IS A DYNAMIC PROCESS THAT INVOLVES MULTIPLE MOLECULAR AND CELLULAR PROCESSES. AS THE FIRST TO BE IMPACTED BY INJURY, LIVER SINUSOIDAL ENDOTHELIAL CELLS (LSECS) ARE INVOLVED IN THE PATHOGENESIS OF LIVER DISEASES CAUSED BY A VARIETY OF ETIOLOGIES. MOREOVER, CAPILLARIZATION OF LSECS HAS BEEN RECOGNIZED AS AN IMPORTANT EVENT IN THE DEVELOPMENT OF CHRONIC LIVER DISEASES AND FIBROSIS. STUDIES HAVE REPORTED THAT VARIOUS CYTOKINES (SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR, TRANSFORMING GROWTH FACTOR-BETA), AND PATHWAYS (SUCH AS HEDGEHOG, AND NOTCH), AS WELL AS EPIGENETIC AND METABOLIC FACTORS ARE INVOLVED IN THE DEVELOPMENT OF LSEC-MEDIATED LIVER FIBROSIS. THIS REVIEW DESCRIBES THE COMPLEXITY AND PLASTICITY OF LSECS IN FIBROTIC LIVER DISEASES FROM SEVERAL PERSPECTIVES, INCLUDING THE CROSS-TALK BETWEEN LSECS AND OTHER INTRA-HEPATIC CELLS. MOREOVER, IT SUMMARIZES THE MECHANISMS OF SEVERAL KINDS OF LSECS-TARGETING ANTI-FIBROSIS CHEMICALS, AND PROVIDES A THEORETICAL BASIS FOR FUTURE STUDIES. 2021 10 2818 16 FIBROSIS UNDER ARREST. APPROXIMATELY 5% OF PEOPLE THAT ARE HOSPITALIZED FOR ANY REASON DEVELOP ACUTE KIDNEY FAILURE, WHICH, IN SOME CASES, PROGRESSES TO A CHRONIC CONDITION RESULTING IN FIBROSIS OF THE KIDNEY AND PERMANENT CHANGES IN THE ORGAN'S FUNCTION. TWO NEW STUDIES SUGGEST THAT CELL CYCLE ARREST OF EPITHELIAL CELLS AND EPIGENETIC MODIFICATIONS HAVE KEY ROLES IN THE SWITCH TO CHRONIC DISEASE (PAGES 535-543 AND 544-550). 2010 11 4665 26 NEW INSIGHTS AND ADVANCES IN PATHOGENESIS AND TREATMENT OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE. VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE (VEO-IBD) IS CHARACTERIZED BY MULTIFACTORIAL CHRONIC RECURRENT INTESTINAL INFLAMMATION. COMPARED WITH ELDERLY PATIENTS, THOSE WITH VEO-IBD HAVE A MORE SERIOUS CONDITION, NOT RESPONSIVE TO CONVENTIONAL TREATMENTS, WITH A POOR PROGNOSIS. RECENT STUDIES FOUND THAT GENETIC AND IMMUNOLOGIC ABNORMALITIES ARE CLOSELY RELATED TO VEO-IBD. INTESTINAL IMMUNE HOMEOSTASIS MONOGENIC DEFECTS (IIHMDS) ARE CHANGED THROUGH VARIOUS MECHANISMS. RECENT STUDIES HAVE ALSO REVEALED THAT ABNORMALITIES IN GENES AND IMMUNE MOLECULAR MECHANISMS ARE CLOSELY RELATED TO VEO-IBD. IIHMDS CHANGE THROUGH VARIOUS MECHANISMS. EPIGENETIC FACTORS CAN MEDIATE THE INTERACTION BETWEEN THE ENVIRONMENT AND GENOME, AND GENETIC FACTORS AND IMMUNE MOLECULES MAY BE INVOLVED IN THE PATHOGENESIS OF THE ENVIRONMENT AND GUT MICROBIOTA. THESE DISCOVERIES WILL PROVIDE NEW DIRECTIONS AND IDEAS FOR THE TREATMENT OF VEO-IBD. 2022 12 2316 30 EPIGENETIC REGULATION OF FRUCTOSE-1,6-BISPHOSPHATASE 1 BY HOST TRANSCRIPTION FACTOR SPECKLED 110 KDA DURING HEPATITIS B VIRUS INFECTION. HEPATITIS B VIRUS (HBV) IS THE LEADING CAUSE OF LIVER DISEASE RANGING FROM ACUTE AND CHRONIC HEPATITIS TO LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). STUDIES HAVE REVEALED THAT HBV INFECTION BROADLY REPROGRAMMES THE HOST CELLULAR METABOLIC PROCESSES FOR VIRAL PATHOGENESIS. PREVIOUS REPORTS HAVE SHOWN THAT GLYCOLYSIS AND GLUCONEOGENESIS ARE AMONG THE MOST DEREGULATED PATHWAYS DURING HBV INFECTION. WE NOTED THAT DESPITE BEING ONE OF THE RATE-LIMITING ENZYMES OF GLUCONEOGENESIS, THE ROLE AND REGULATION OF FRUCTOSE-1,6-BISPHOSPHATASE 1 (FBP1) DURING HBV INFECTION IS NOT MUCH EXPLORED. IN THIS STUDY, WE REPORT FBP1 UPREGULATION UPON HBV INFECTION AND UNRAVEL A NOVEL MECHANISM OF EPIGENETIC REPROGRAMMING OF FBP1 BY HBV VIA UTILIZING HOST FACTOR SPECKLED 110 KDA (SP110). HERE, WE IDENTIFIED ACETYLATED LYSINE 18 OF HISTONE H3 (H3K18AC) AS A SELECTIVE INTERACTOR OF SP110 BROMODOMAIN. FURTHERMORE, WE FOUND THAT SP110 GETS RECRUITED ON H3K18AC-ENRICHED FBP1 PROMOTER, AND FACILITATES RECRUITMENT OF DEACETYLASE SIRTUIN 2 (SIRT2) ON THAT SITE IN THE PRESENCE OF HBV. SIRT2 IN TURN BRINGS ITS INTERACTOR AND TRANSCRIPTIONAL ACTIVATOR HEPATOCYTE NUCLEAR FACTOR 4-ALPHA TO THE PROMOTER, WHICH ULTIMATELY LEADS TO A LOSS OF DNA METHYLATION NEAR THE COGNATE SITE. INTERESTINGLY, THIS SP110 DRIVEN FBP1 REGULATION DURING INFECTION WAS FOUND TO PROMOTE VIRAL-BORNE HCC PROGRESSION. MOREOVER, SP110 CAN BE USED AS A PROGNOSTIC MARKER FOR THE HEPATITIS-MEDIATED HCC PATIENTS, WHERE HIGH SP110 EXPRESSION SIGNIFICANTLY LOWERED THEIR SURVIVAL. THUS, THE EPIGENETIC READER PROTEIN SP110 HAS POTENTIAL TO BE A THERAPEUTIC TARGET TO CHALLENGE HBV-INDUCED HCCS. 2022 13 1449 15 DIRECT LINEAGE REPROGRAMMING FOR INDUCED KERATINOCYTE STEM CELLS: A POTENTIAL APPROACH FOR SKIN REPAIR. SEVERE TRAUMA OR CHRONIC WOUNDS CAN DEPLETE THE KERATINOCYTE STEM CELLS (KSCS) PRESENT IN THE EPIDERMAL BASAL LAYER OR INHIBIT THEIR MIGRATION LEADING TO COMPROMISED WOUND HEALING. SUPPLEMENTING KSCS IS THE KEY TO SOLUTION WHILE LINEAGE REPROGRAMMING PROVIDES A NEW APPROACH TO ACQUIRING KSCS. THROUGH DIRECT LINEAGE REPROGRAMMING, INDUCED KSCS (IKSCS) CAN BE PRODUCED FROM SOMATIC CELLS, WHICH EXHIBIT GREAT APPLICATION POTENTIAL. TWO STRATEGIES ARE CURRENTLY BEING USED TO DIRECTLY GENERATE IKSCS, LINEAGE TRANSCRIPTION FACTOR (TF)-MEDIATED AND PLURIPOTENCY FACTORS-MEDIATED. THIS REVIEW FOCUSES ON LINEAGE TF-MEDIATED DIRECT REPROGRAMMING AND DESCRIBES THE CONVERSION PROCESS ALONG WITH THE UNDERLYING EPIGENETIC MECHANISMS. IT ALSO DISCUSSES OTHER POTENTIAL INDUCTION STRATEGIES TO GENERATE IKSCS AND CHALLENGES ASSOCIATED WITH IN SITU REPROGRAMMING FOR SKIN REPAIR. 2023 14 5510 22 RIBAVIRIN RESTORES IFNALPHA RESPONSIVENESS IN HCV-INFECTED LIVERS BY EPIGENETIC REMODELLING AT INTERFERON STIMULATED GENES. OBJECTIVES: CAVEATS IN THE UNDERSTANDING OF RIBAVIRIN (RBV) MECHANISMS OF ACTION HAS SOMEHOW PREVENTED THE DEVELOPMENT OF BETTER ANALOGUES ABLE TO FURTHER IMPROVE ITS THERAPEUTIC CONTRIBUTION IN INTERFERON (IFN)-BASED AND DIRECT ANTIVIRAL AGENT-BASED REGIMENS FOR CHRONIC HCV OR OTHER INDICATIONS. HERE, WE DESCRIBE A NEW MECHANISM BY WHICH RBV MODULATES IFN-STIMULATED GENES (ISGS) AND CONTRIBUTES TO RESTORE HEPATIC IMMUNE RESPONSIVENESS. DESIGN: RBV EFFECT ON ISG EXPRESSION WAS MONITORED IN VITRO AND IN VIVO, THAT IS, IN NON-TRANSFORMED HEPATOCYTES AND IN THE LIVER OF RBV MONO-TREATED PATIENTS, RESPECTIVELY. MODULATION OF HISTONE MODIFICATIONS AND RECRUITMENT OF HISTONE-MODIFYING ENZYMES AT TARGET PROMOTERS WAS ANALYSED BY CHROMATIN IMMUNOPRECIPITATION IN RBV-TREATED PRIMARY HUMAN HEPATOCYTES AND IN PATIENTS' LIVER BIOPSIES. RESULTS: RBV DECREASES THE MRNA LEVELS OF SEVERAL ABNORMALLY PREACTIVATED ISGS IN PATIENTS WITH HCV, WHO ARE NON-RESPONDERS TO IFN THERAPY. RBV INCREASES G9A HISTONE METHYLTRANSFERASE RECRUITMENT AND HISTONE-H3 LYSINE-9 DIMETHYLATION/TRIMETHYLATION AT SELECTED ISG PROMOTERS IN VITRO AND IN VIVO. G9A PHARMACOLOGICAL BLOCKADE ABOLISHES RBV-INDUCED ISG DOWNREGULATION AND SEVERELY IMPAIRS RBV ABILITY TO POTENTIATE IFN ANTIVIRAL ACTION AND INDUCTION OF ISGS FOLLOWING HCV INFECTION OF PRIMARY HUMAN HEPATOCYTES. CONCLUSIONS: RBV-INDUCED EPIGENETIC CHANGES, LEADING TO DECREASED ISG EXPRESSION, RESTORE AN IFN-RESPONSIVE HEPATIC ENVIRONMENT IN PATIENTS WITH HCV, WHICH MAY ALSO PROVE USEFUL IN IFN-FREE REGIMENS. 2016 15 4867 18 OSSIFYING FIBROMA TUMOR STEM CELLS ARE MAINTAINED BY EPIGENETIC REGULATION OF A TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. ABNORMAL STEM CELL FUNCTION MAKES A KNOWN CONTRIBUTION TO MANY MALIGNANT TUMORS, BUT THE ROLE OF STEM CELLS IN BENIGN TUMORS IS NOT WELL UNDERSTOOD. HERE, WE SHOW THAT OSSIFYING FIBROMA (OF) CONTAINS A STEM CELL POPULATION THAT RESEMBLES MESENCHYMAL STEM CELLS (OFMSCS) AND IS CAPABLE OF GENERATING OF-LIKE TUMOR XENOGRAFTS. MECHANISTICALLY, OFMSCS SHOW ENHANCED TGF-BETA SIGNALING THAT INDUCES ABERRANT PROLIFERATION AND DEFICIENT OSTEOGENESIS VIA NOTCH AND BMP SIGNALING PATHWAYS, RESPECTIVELY. THE ELEVATED TGF-BETA ACTIVITY IS TIGHTLY REGULATED BY JHDM1D-MEDIATED EPIGENETIC REGULATION OF THROMBOSPONDIN-1 (TSP1), FORMING A JHDM1D/TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. INHIBITION OF TGF-BETA SIGNALING IN OFMSCS CAN RESCUE THEIR ABNORMAL OSTEOGENIC DIFFERENTIATION AND ELEVATED PROLIFERATION RATE. FURTHERMORE, CHRONIC ACTIVATION OF TGF-BETA CAN CONVERT NORMAL MSCS INTO OF-LIKE MSCS VIA ESTABLISHMENT OF THIS JHDM1D/TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. THESE RESULTS REVEAL THAT EPIGENETIC REGULATION OF TGF-BETA SIGNALING IN MSCS GOVERNS THE BENIGN TUMOR PHENOTYPE IN OF AND HIGHLIGHT TGF-BETA SIGNALING AS A CANDIDATE THERAPEUTIC TARGET. 2013 16 4143 18 MECHANISMS OF SCARRING IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS. FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) PRESENTS WITH SCAR IN PARTS OF SOME GLOMERULI AND OFTEN PROGRESSES TO GLOBAL AND DIFFUSE GLOMERULOSCLEROSIS. PODOCYTE INJURY IS THE INITIAL TARGET IN PRIMARY FSGS, INDUCED BY A CIRCULATING FACTOR. SEVERAL GENE VARIANTS, FOR EXAMPLE, APOL1, ARE ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO FSGS. PRIMARY FSGS MAY BE DUE TO GENETIC MUTATION IN KEY PODOCYTE GENES. INCREASED WORK STRESS AFTER LOSS OF NEPHRONS, EPIGENETIC MECHANISMS, AND VARIOUS PROFIBROTIC PATHWAYS CAN CONTRIBUTE TO PROGRESSIVE SCLEROSIS, REGARDLESS OF THE INITIAL INJURY. THE PROGRESSION OF FSGS LESIONS ALSO INVOLVES CROSSTALK BETWEEN PODOCYTES AND OTHER KIDNEY CELLS, SUCH AS PARIETAL EPITHELIAL CELLS, GLOMERULAR ENDOTHELIAL CELLS, AND EVEN TUBULAR EPITHELIAL CELLS. NEW INSIGHTS RELATED TO THESE MECHANISMS COULD POTENTIALLY LEAD TO NEW THERAPEUTIC STRATEGIES TO PREVENT PROGRESSION OF FSGS. 2019 17 3330 20 HISTONE DEACETYLASE INHIBITOR GIVINOSTAT ALLEVIATES LIVER FIBROSIS BY REGULATING HEPATIC STELLATE CELL ACTIVATION. HEPATIC FIBROSIS, A COMMON PATHOLOGICAL MANIFESTATION OF CHRONIC LIVER INJURY, IS GENERALLY CONSIDERED TO BE THE END RESULT OF AN INCREASE IN EXTRACELLULAR MATRIX PRODUCED BY ACTIVATED HEPATIC STELLATE CELLS (HSCS). THE AIM OF THE PRESENT STUDY WAS TO TARGET THE MECHANISMS UNDERLYING HSC ACTIVATION IN ORDER TO PROVIDE A POWERFUL THERAPEUTIC STRATEGY FOR THE PREVENTION AND TREATMENT OF LIVER FIBROSIS. IN THE PRESENT STUDY, A HIGH?THROUGHPUT SCREENING ASSAY WAS ESTABLISHED, AND THE HISTONE DEACETYLASE INHIBITOR GIVINOSTAT WAS IDENTIFIED AS A POTENT INHIBITOR OF HSC ACTIVATION IN VITRO. GIVINOSTAT SIGNIFICANTLY INHIBITED HSC ACTIVATION IN VIVO, AMELIORATED CARBON TETRACHLORIDE?INDUCED MOUSE LIVER FIBROSIS AND LOWERED PLASMA AMINOTRANSFERASES. TRANSCRIPTOMIC ANALYSIS REVEALED THE MOST SIGNIFICANTLY REGULATED GENES IN THE GIVINOSTAT TREATMENT GROUP IN COMPARISON WITH THOSE IN THE SOLVENT GROUP, AMONG WHICH, DERMOKINE (DMKN), MESOTHELIN (MSLN) AND UROPLAKIN?3B (UPK3B) WERE IDENTIFIED AS POTENTIAL REGULATORS OF HSC ACTIVATION. GIVINOSTAT SIGNIFICANTLY REDUCED THE MRNA EXPRESSION OF DMKN, MSLN AND UPK3B IN BOTH A MOUSE LIVER FIBROSIS MODEL AND IN HSC?LX2 CELLS. KNOCKDOWN OF ANY OF THE AFOREMENTIONED GENES INHIBITED THE TGF?BETA1?INDUCED EXPRESSION OF ALPHA?SMOOTH MUSCLE ACTIN AND COLLAGEN TYPE I, INDICATING THAT THEY ARE CRUCIAL FOR HSC ACTIVATION. IN SUMMARY, USING A NOVEL STRATEGY TARGETING HSC ACTIVATION, THE PRESENT STUDY IDENTIFIED A POTENTIAL EPIGENETIC DRUG FOR THE TREATMENT OF HEPATIC FIBROSIS AND REVEALED NOVEL REGULATORS OF HSC ACTIVATION. 2021 18 6741 23 WHERE TO STAND WITH STROMAL CELLS AND CHRONIC SYNOVITIS IN RHEUMATOID ARTHRITIS? THE SYNOVIUM EXERCISES ITS MAIN FUNCTION IN JOINT HOMEOSTASIS THROUGH THE SECRETION OF FACTORS (SUCH AS LUBRICIN AND HYALURONIC ACID) THAT ARE CRITICAL FOR THE JOINT LUBRICATION AND FUNCTION. THE MAIN SYNOVIUM CELL COMPONENTS ARE FIBROBLAST-LIKE SYNOVIOCYTES, MESENCHYMAL STROMAL/STEM CELLS AND MACROPHAGE-LIKE SYNOVIAL CELLS. IN THE SYNOVIUM, CELLS OF MESENCHYMAL ORIGIN MODULATE LOCAL INFLAMMATION AND FIBROSIS, AND INTERACT WITH DIFFERENT FIBROBLAST SUBTYPES AND WITH RESIDENT MACROPHAGES. IN PATHOLOGIC CONDITIONS, SUCH AS RHEUMATOID ARTHRITIS, FIBROBLAST-LIKE SYNOVIOCYTES PROLIFERATE ABNORMALLY, RECRUIT MESENCHYMAL STEM CELLS FROM SUBCHONDRAL BONE MARROW, AND INFLUENCE IMMUNE CELL ACTIVITY THROUGH EPIGENETIC AND METABOLIC ADAPTATIONS. THE RESULTING SYNOVIAL HYPERPLASIA LEADS TO SECONDARY CARTILAGE DESTRUCTION, JOINT SWELLING, AND PAIN. IN THE PRESENT REVIEW, WE SUMMARIZE RECENT FINDINGS ON THE MOLECULAR SIGNATURE AND THE ROLES OF STROMAL CELLS DURING SYNOVIAL PANNUS FORMATION AND RHEUMATOID ARTHRITIS PROGRESSION. 2019 19 3157 23 GLYCEMIC MEMORY. PURPOSE OF REVIEW: THE MISTAKE OF PREDICTING THE FUTURE IS PERHAPS NOT TENDING TO REPRESSED OR PAST MEMORIES. HAMLET'S 17TH-CENTURY SOLILOQUY 'THE HEARTACHE AND THE THOUSAND NATURAL SHOCKS, THAT FLESH IS HEIR TO', (3.1. 7-8) IS A TALE THAT LOOKS BEYOND THE PRESENT BY LINKING THE PAST WITH THE FUTURE. THE PRESENT ARTICLE EXAMINES THE RESURGENCE IN THE FIELD TO UNDERSTAND GENE-REGULATING EPIGENETIC CHANGES CONFERRING GLYCEMIC MEMORY. RECENT FINDINGS: CHROMATIN MODIFICATIONS ARE CRITICAL IN REGULATING GENOME STRUCTURE AND FUNCTION AND DESPITE THE SIGNIFICANT ADVANCES OF RECENT YEARS IN IDENTIFYING THE ENZYMES-MEDIATING CHEMICAL CHANGES TO HISTONE TAILS AND THE DNA TEMPLATE, THE PRECISE REGULATION OF GENE EXPRESSION REMAINS INCOMPLETE IN MODELS OF HEALTH AND DIABETIC COMPLICATIONS. SUMMARY: DISPELLING THE MYTH THAT ALL GENOMES ARE DRIVEN AND RESPOND EQUALLY, EXPERIMENTAL RESEARCH IS NOW UNCOVERING THE FUNCTION OF ENZYMES CONFERRING CHROMATIN MODIFICATIONS. WHATEVER THE ROLE OF THE EPIGENOME, SHOWING ITS INVOLVEMENT IN GLYCEMIC SIGNALING IS THE FIRST STEP TO NEW STRATEGIES AND TARGETS TO DEVELOP THERAPIES THAT PREVENT, RETARD OR REVERSE THE LONG-TERM DELETERIOUS END-ORGAN EFFECTS OF CHRONIC, INTERMITTENT AND PRIOR HYPERGLYCEMIA. 2012 20 5501 28 REWRITING THE EPIGENETIC CODE FOR TUMOR RESENSITIZATION: A REVIEW. IN CANCER CHEMOTHERAPY, ONE AXIOM, WHICH HAS PRACTICALLY SOLIDIFIED INTO DOGMA, IS THAT ACQUIRED RESISTANCE TO ANTITUMOR AGENTS OR REGIMENS, NEARLY INEVITABLE IN ALL PATIENTS WITH METASTATIC DISEASE, REMAINS UNALTERABLE AND IRREVERSIBLE, RENDERING THERAPEUTIC RECHALLENGE FUTILE. HOWEVER, THE INTRODUCTION OF EPIGENETIC THERAPIES, INCLUDING HISTONE DEACETYLASE INHIBITORS (HDACIS) AND DNA METHYLTRANSFERASE INHIBITORS (DNMTIS), PROVIDES ONCOLOGISTS, LIKE COMPUTER PROGRAMMERS, WITH NEW TECHNIQUES TO "OVERWRITE" THE MODIFIABLE SOFTWARE PATTERN OF GENE EXPRESSION IN TUMORS AND CHALLENGE THE "ONE AND DONE" TREATMENT PRESCRIPTION. TAKING THE EPIGENETIC CODE-AS-SOFTWARE ANALOGY A STEP FURTHER, IF CHEMORESISTANCE IS THE PRODUCT OF MULTIPLE NONGENETIC ALTERATIONS, WHICH DEVELOP AND ACCUMULATE OVER TIME IN RESPONSE TO TREATMENT, THEN THE POSSIBILITY TO HACK OR TWEAK THE OPERATING SYSTEM AND FALL BACK ON A "SYSTEM RESTORE" OR "UNDO" FEATURE, LIKE THE ARROW ICON IN THE WINDOWS XP TOOLBAR, RECONFIGURING THE TUMOR TO ITS BASELINE NONRESISTANT STATE, HOLDS TREMENDOUS PROMISE FOR TURNING ADVANCED, METASTATIC CANCER FROM A FATAL DISEASE INTO A CHRONIC, LIVABLE CONDITION. THIS REVIEW AIMS 1) TO EXPLORE THE POTENTIAL MECHANISMS BY WHICH A GROUP OF SMALL MOLECULE AGENTS INCLUDING HDACIS (ENTINOSTAT AND VORINOSTAT), DNMTIS (DECITABINE AND 5-AZACYTIDINE), AND REDOX MODULATORS (RRX-001) MAY REPROGRAM THE TUMOR MICROENVIRONMENT FROM A REFRACTORY TO A NONREFRACTORY STATE, 2) HIGHLIGHT SOME RECENT FINDINGS, AND 3) DISCUSS WHETHER THE CURRENT "ONCE BURNED FOREVER SPURNED" PARADIGM IN THE TREATMENT OF METASTATIC DISEASE SHOULD BE REVISED TO PROMOTE ACTIVE RESENSITIZATION ATTEMPTS WITH FORMERLY FAILED CHEMOTHERAPIES. 2014