1 1446 146 DIGESTED CINNAMON (CINNAMOMUM VERUM J. PRESL) BARK EXTRACT MODULATES CLAUDIN-2 GENE EXPRESSION AND PROTEIN LEVELS UNDER TNFALPHA/IL-1BETA INFLAMMATORY STIMULUS. EPIGENETIC CHANGES, HOST-GUT MICROBIOTA INTERACTIONS, AND ENVIRONMENTAL FACTORS CONTRIBUTE TO INFLAMMATORY BOWEL DISEASE (IBD) ONSET AND PROGRESSION. A HEALTHY LIFESTYLE MAY HELP TO SLOW DOWN THE CHRONIC OR REMITTING/RELAPSING INTESTINAL TRACT INFLAMMATION CHARACTERISTIC OF IBD. IN THIS SCENARIO, THE EMPLOYMENT OF A NUTRITIONAL STRATEGY TO PREVENT THE ONSET OR SUPPLEMENT DISEASE THERAPIES INCLUDED FUNCTIONAL FOOD CONSUMPTION. ITS FORMULATION CONSISTS OF THE ADDITION OF A PHYTOEXTRACT ENRICHED IN BIOACTIVE MOLECULES. A GOOD CANDIDATE AS AN INGREDIENT IS THE CINNAMON VERUM AQUEOUS EXTRACT. INDEED, THIS EXTRACT, SUBJECTED TO A PROCESS OF GASTROINTESTINAL DIGESTION SIMULATION (INFOGEST), EXHIBITS BENEFICIAL ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES IN AN IN VITRO MODEL OF THE INFLAMED INTESTINAL BARRIER. HERE, WE DEEPEN THE STUDY OF THE MECHANISMS RELATED TO THE EFFECT OF DIGESTED CINNAMON EXTRACT PRE-TREATMENT, SHOWING A CORRELATION BETWEEN TRANSEPITHELIAL ELECTRICAL RESISTANCE (TEER) DECREMENT AND ALTERATIONS IN CLAUDIN-2 EXPRESSION UNDER TUMOR NECROSIS FACTOR-ALPHA/INTERLEUKIN-1BETA (TNF-ALPHA/IL-1) BETA CYTOKINE ADMINISTRATION. OUR RESULTS SHOW THAT PRE-TREATMENT WITH CINNAMON EXTRACT PREVENTS TEER LOSS BY CLAUDIN-2 PROTEIN LEVEL REGULATION, INFLUENCING BOTH GENE TRANSCRIPTION AND AUTOPHAGY-MEDIATED DEGRADATION. HENCE, CINNAMON POLYPHENOLS AND THEIR METABOLITES PROBABLY WORK AS MEDIATORS IN GENE REGULATION AND RECEPTOR/PATHWAY ACTIVATION, LEADING TO AN ADAPTIVE RESPONSE AGAINST RENEWED INSULTS. 2023 2 2947 27 GENETIC AND EPIGENETIC CHANGES INDUCED BY CHRONIC LOW DOSE EXPOSURE TO ARSENIC OF MOUSE TESTICULAR LEYDIG CELLS. ARSENIC IS AN IMPORTANT ENVIRONMENTAL CARCINOGEN THAT AFFECTS MILLIONS OF PEOPLE WORLDWIDE THROUGH CONTAMINATED WATER SUPPLIES. GENOTOXICITY OF ARSENIC HAS BEEN A TOPIC OF CONTROVERSY. BOTH GENETIC ALTERATIONS (MUTATIONS) AND EPIGENETIC CHANGES (METHYLATION) HAVE BEEN SHOWN TO PLAY A CRUCIAL ROLE IN ENVIRONMENTAL CARCINOGENESIS. CHRONIC EXPOSURE TO ARSENIC HAS BEEN SHOWN TO INDUCE MALIGNANT TRANSFORMATION OF MAMMALIAN CELLS. HOWEVER, THE GENETIC ABERRATIONS INDUCED BY ARSENIC IN THIS PROCESS ARE UNCLEAR. THE PURPOSE OF THIS STUDY WAS TO DETERMINE IF BOTH LOWER (1 PG/ML) AND HIGHER CONCENTRATIONS (100 NG/ML) OF ARSENIC INDUCES EITHER MUTATIONS OR METHYLATION CHANGES THAT COULD LEAD TO THE DEVELOPMENT OF GENOMIC INSTABILITY IN TM3 CELLS, IMMORTALIZED LEYDIG CELLS DERIVED FROM NORMAL MOUSE TESTIS. TWO INDEPENDENT EXPOSURE TIMES WERE USED IN THIS STUDY WHICH RESULTED IN CELLS OF 33 AND 100 GENERATIONS IN AGE. ARSENIC-INDUCED GENETIC AND EPIGENETIC CHANGES WERE SCREENED AT A GENOME-WIDE LEVEL BY RANDOM AMPLIFIED POLYMORPHIC DNA (RAPD), ALSO KNOWN AS AP-PCR METHOD WITH UNDIGESTED DNA AS WELL AS DNA DIGESTED BY THE METHYLATION SENSITIVE ISOSIZOMERIC RESTRICTION ENZYMES MSPI AND HPAII AND UNTREATED CONTROLS. CHANGES IN THE DNA FINGERPRINT OF BOTH, THE RESTRICTION ENZYME DIGESTED DNA (INDICATING METHYLATION CHANGES) AS WELL AS UNDIGESTED DNA (INDICATING MUTATIONS) FROM ARSENIC-TREATED (LOW AS WELL AS HIGH DOSE) SAMPLES WERE OBSERVED AS COMPARED TO THEIR CONTROLS. THUS, THIS STUDY PROVIDES THE FIRST EVIDENCE AT DNA SEQUENCE LEVEL FOR MUTAGENIC POTENTIAL OF ARSENIC. FURTHER CHARACTERIZATION OF THESE ALTERED GENOMIC REGIONS IS UNDERWAY. THE UNDERSTANDING OF THESE GENETIC AND EPIGENETIC CHANGES IN ARSENIC-INDUCED CARCINOGENESIS WILL PROVIDE A BASIS FOR BETTER INTERVENTIONAL APPROACHES IN BOTH THE TREATMENT AND PREVENTION OF ARSENIC-INDUCED CANCER. 2007 3 3411 37 HP1GAMMA PREVENTS ACTIVATION OF THE CGAS/STING PATHWAY BY PRESERVING NUCLEAR ENVELOPE AND GENOMIC INTEGRITY IN COLON ADENOCARCINOMA CELLS. CHRONIC INFLAMMATORY PROCESSES IN THE INTESTINE RESULT IN SERIOUS CONDITIONS SUCH AS INFLAMMATORY BOWEL DISEASE (IBD) AND CANCER. AN INCREASED DETECTION OF CYTOPLASMIC DNA SENSORS HAS BEEN REPORTED IN THE IBD COLON MUCOSA, SUGGESTING THEIR CONTRIBUTION IN MUCOSAL INFLAMMATION. YET, THE MECHANISMS ALTERING DNA HOMEOSTASIS AND TRIGGERING THE ACTIVATION OF DNA SENSORS REMAIN POORLY UNDERSTOOD. IN THIS STUDY, WE SHOW THAT THE EPIGENETIC REGULATOR HP1GAMMA PLAYS A ROLE IN PRESERVING NUCLEAR ENVELOPE AND GENOMIC INTEGRITY IN ENTEROCYTIC CELLS, THEREBY PROTECTING AGAINST THE PRESENCE OF CYTOPLASMIC DNA. ACCORDINGLY, HP1 LOSS OF FUNCTION LED TO THE INCREASED DETECTION OF CGAS/STING, A CYTOPLASMIC DNA SENSOR THAT TRIGGERS INFLAMMATION. THUS, IN ADDITION TO ITS ROLE AS A TRANSCRIPTIONAL SILENCER, HP1GAMMA MAY ALSO EXERT ANTI-INFLAMMATORY PROPERTIES BY PREVENTING THE ACTIVATION OF THE ENDOGENOUS CYTOPLASMIC DNA RESPONSE IN THE GUT EPITHELIUM. 2023 4 3804 25 INTESTINAL MICROBIOTA, CHRONIC INFLAMMATION, AND COLORECTAL CANCER. IN ADDITION TO GENETIC AND EPIGENETIC FACTORS, VARIOUS ENVIRONMENTAL FACTORS, INCLUDING DIET, PLAY IMPORTANT ROLES IN THE DEVELOPMENT OF COLORECTAL CANCER (CRC). RECENTLY, THERE IS INCREASING INTEREST IN THE INTESTINAL MICROBIOTA AS AN ENVIRONMENTAL RISK FACTOR FOR CRC, BECAUSE DIET ALSO INFLUENCES THE COMPOSITION OF THE INTESTINAL MICROBIOTA. THE HUMAN INTESTINAL MICROBIOTA COMPRISES ABOUT 100 TRILLION MICROBES. THIS MICROBIOME THRIVES ON UNDIGESTED DIETARY RESIDUES IN THE INTESTINAL LUMEN AND PRODUCES VARIOUS METABOLITES. IT IS WELL KNOWN THAT THE DIETARY RISK FACTORS FOR CRC ARE MEDIATED BY DYSBIOSIS OF THE INTESTINAL MICROBIOTA AND THEIR METABOLITES. IN THIS REVIEW, WE DESCRIBE THE BACTERIAL TAXA ASSOCIATED WITH CRC, INCLUDING FUSOBACTERIUM NUCLEATUM, ENTEROTOXIGENIC BACTEROIDES FRAGILIS, ESCHERICHIA COLI, AND BUTYRATE-PRODUCING BACTERIA. WE ALSO DISCUSS THE HOST-DIET INTERACTION IN COLORECTAL CARCINOGENESIS. 2018 5 5592 32 ROLE OF TUMOR NECROSIS FACTOR-ALPHA IN THE HUMAN SYSTEMIC ENDOTOXIN-INDUCED TRANSCRIPTOME. TNFALPHA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES. DIFFERENT STRATEGIES TO INHIBIT TNFALPHA IN PATIENTS WITH SEPSIS AND CHRONIC INFLAMMATORY CONDITIONS HAVE SHOWN CONTRASTING OUTCOMES. ALTHOUGH TNFALPHA INHIBITORS ARE WIDELY USED IN CLINICAL PRACTICE, THE IMPACT OF TNFALPHA ANTAGONISM ON WHITE BLOOD CELL GENE EXPRESSION PROFILES DURING ACUTE INFLAMMATION IN HUMANS IN VIVO HAS NOT BEEN ASSESSED. WE HERE LEVERAGED THE ESTABLISHED MODEL OF HUMAN ENDOTOXEMIA TO EXAMINE THE EFFECT OF THE TNFALPHA ANTAGONIST, ETANERCEPT, ON THE GENOME-WIDE TRANSCRIPTIONAL RESPONSES IN CIRCULATING LEUKOCYTES INDUCED BY INTRAVENOUS LPS ADMINISTRATION IN MALE SUBJECTS. ETANERCEPT PRE-TREATMENT RESULTED IN A MARKEDLY DAMPENED TRANSCRIPTIONAL RESPONSE TO LPS. GENE CO-EXPRESSION NETWORK ANALYSIS REVEALED THIS LPS-INDUCED TRANSCRIPTOME CAN BE CATEGORIZED AS TNFALPHA RESPONSIVE AND NON-RESPONSIVE MODULES. HIGHLY SIGNIFICANT TNFALPHA RESPONSIVE MODULES INCLUDE NF-KB SIGNALING, ANTIVIRAL RESPONSES AND T-CELL MEDIATED RESPONSES. WITHIN THESE TNFALPHA RESPONSIVE MODULES WE DELINEATE FUNDAMENTAL GENES INVOLVED IN EPIGENETIC MODIFICATIONS, TRANSCRIPTIONAL INITIATION AND ELONGATION. THUS, WE PROVIDE COMPREHENSIVE INFORMATION ABOUT MOLECULAR PATHWAYS THAT MIGHT BE TARGETED BY THERAPEUTIC INTERVENTIONS THAT SEEK TO INHIBIT TNFALPHA ACTIVITY DURING HUMAN INFLAMMATORY DISEASES. 2013 6 3246 26 HEPATITIS B VIRUS (HBV) INDUCES THE EXPRESSION OF INTERLEUKIN-8 THAT IN TURN REDUCES HBV SENSITIVITY TO INTERFERON-ALPHA. HIGH LEVELS OF SERUM INTERLEUKIN-8 (IL-8) HAVE BEEN DETECTED IN CHRONIC HEPATITIS B (CHB) PATIENTS DURING EPISODES OF HEPATITIS FLARES. WE INVESTIGATED WHETHER HEPATITIS B VIRUS (HBV) MAY DIRECTLY INDUCE IL-8 PRODUCTION AND WHETHER IL-8 MAY ANTAGONIZE INTERFERON-ALPHA (IFN-ALPHA) ANTIVIRAL ACTIVITY AGAINST HBV. WE SHOWED THAT CHB PATIENTS HAD SIGNIFICANTLY HIGHER IL-8 LEVELS BOTH IN SERUM AND IN LIVER TISSUE THAN CONTROLS. IN HBV-REPLICATING HEPG2 CELLS, IL-8 TRANSCRIPTION WAS SIGNIFICANTLY ACTIVATED. AP-1, C/EBP AND NF-KB TRANSCRIPTION FACTORS WERE CONCURRENTLY NECESSARY FOR MAXIMUM IL-8 INDUCTION. MOREOVER, HBX VIRAL PROTEIN WAS RECRUITED ONTO THE IL-8 PROMOTER AND THIS WAS PARALLELED BY IL8-BOUND HISTONE HYPERACETYLATION AND BY ACTIVE RECRUITMENT OF TRANSCRIPTIONAL COACTIVATORS. INHIBITION OF IL-8 INCREASES THE ANTIVIRAL ACTIVITY OF IFN-ALPHA AGAINST HBV. OUR RESULTS INDICATE THAT HBV ACTIVATES IL-8 GENE EXPRESSION BY TARGETING THE EPIGENETIC REGULATION OF THE IL-8 PROMOTER AND THAT IL-8 MAY CONTRIBUTE TO REDUCE HBV SENSITIVITY TO IFN-ALPHA. 2013 7 2065 34 EPIGENETIC CONTROL OF INTESTINAL BARRIER FUNCTION AND INFLAMMATION IN ZEBRAFISH. THE INTESTINAL EPITHELIUM FORMS A BARRIER PROTECTING THE ORGANISM FROM MICROBES AND OTHER PROINFLAMMATORY STIMULI. THE INTEGRITY OF THIS BARRIER AND THE PROPER RESPONSE TO INFECTION REQUIRES PRECISE REGULATION OF POWERFUL IMMUNE HOMING SIGNALS SUCH AS TUMOR NECROSIS FACTOR (TNF). DYSREGULATION OF TNF LEADS TO INFLAMMATORY BOWEL DISEASES (IBD), BUT THE MECHANISM CONTROLLING THE EXPRESSION OF THIS POTENT CYTOKINE AND THE EVENTS THAT TRIGGER THE ONSET OF CHRONIC INFLAMMATION ARE UNKNOWN. HERE, WE SHOW THAT LOSS OF FUNCTION OF THE EPIGENETIC REGULATOR UBIQUITIN-LIKE PROTEIN CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IN ZEBRAFISH LEADS TO A REDUCTION IN TNFA PROMOTER METHYLATION AND THE INDUCTION OF TNFA EXPRESSION IN INTESTINAL EPITHELIAL CELLS (IECS). THE INCREASE IN IEC TNFA LEVELS IS MICROBE-DEPENDENT AND RESULTS IN IEC SHEDDING AND APOPTOSIS, IMMUNE CELL RECRUITMENT, AND BARRIER DYSFUNCTION, CONSISTENT WITH CHRONIC INFLAMMATION. IMPORTANTLY, TNFA KNOCKDOWN IN UHRF1 MUTANTS RESTORES IEC MORPHOLOGY, REDUCES CELL SHEDDING, AND IMPROVES BARRIER FUNCTION. WE PROPOSE THAT LOSS OF EPIGENETIC REPRESSION AND TNF INDUCTION IN THE INTESTINAL EPITHELIUM CAN LEAD TO IBD ONSET. 2015 8 6126 37 THE EPIGENETIC MODIFIER PBRM1 RESTRICTS THE BASAL ACTIVITY OF THE INNATE IMMUNE SYSTEM BY REPRESSING RETINOIC ACID-INDUCIBLE GENE-I-LIKE RECEPTOR SIGNALLING AND IS A POTENTIAL PROGNOSTIC BIOMARKER FOR COLON CANCER. IT HAS LONG BEEN KNOWN THAT PATIENTS SUFFERING FROM INFLAMMATORY BOWEL DISEASE (IBD) HAVE AN INCREASED RISK OF DEVELOPING COLORECTAL CANCER (CRC). THE INNATE IMMUNE SYSTEM OF HOST CELLS PROVIDES A FIRST-LINE DEFENCE AGAINST PATHOGENIC INFECTION, WHEREAS AN UNCONTROLLED INFLAMMATORY RESPONSE UNDER HOMEOSTATIC CONDITIONS USUALLY LEADS TO PATHOLOGICAL CONSEQUENCES, AS EXEMPLIFIED BY THE CHRONIC INFLAMMATION OF IBD. THE KEY MOLECULES AND PATHWAYS KEEPING INNATE IMMUNITY IN CHECK ARE STILL POORLY DEFINED. HERE, WE REPORT THAT THE CHROMATIN REMODELLER POLYBROMO-1 (PBRM1) IS A REPRESSOR OF INNATE IMMUNE SIGNALLING MEDIATED BY RETINOIC ACID-INDUCIBLE GENE-I (RIG-I)-LIKE RECEPTORS (RLRS). KNOCKDOWN OF PBRM1 IN COLON CANCER CELLS INCREASED THE EXPRESSION OF TWO RECEPTOR GENES (RIG-I AND MDA5) AND UPREGULATED INTERFERON (IFN)-RELATED AND INFLAMMATION-RELATED GENE SIGNATURES. THE INNATE IMMUNE SIGNAL STIMULATED BY A DOUBLE-STRANDED RNA VIRAL MIMIC WAS EXAGGERATED BY PBRM1 SUPPRESSION. PBRM1 COOPERATED WITH POLYCOMB PROTEIN EZH2 TO DIRECTLY BIND THE CIS-REGULATORY ELEMENTS OF RIG-I AND MDA5, THEREBY SUPPRESSING THEIR TRANSCRIPTION. MOREOVER, UPREGULATION OF RIG-I AND MDA5 IS REQUIRED FOR IFN RESPONSE ACTIVATION INDUCED BY PBRM1 SILENCING. TRIM25, A PROTEIN STIMULATED BY THE RLR PATHWAY AND IFN PRODUCTION, PHYSICALLY INTERACTED WITH PBRM1 AND INDUCED PBRM1 PROTEIN DESTABILIZATION BY PROMOTING ITS UBIQUITINATION. THESE FINDINGS REVEAL A PBRM1-RLR REGULATORY CIRCUIT THAT CAN KEEP INNATE IMMUNE ACTIVITY AT A MINIMAL LEVEL IN RESTING CELLS, AND ALSO ENSURE A ROBUST INFLAMMATORY RESPONSE IN THE CASE OF PATHOGEN INVASION. PBRM1 WAS FOUND TO BE DOWNREGULATED IN PRIMARY TISSUES FROM PATIENTS WITH CRC OR IBD, AND ITS EXPRESSION CORRELATED NEGATIVELY WITH THAT OF RLR GENES AND INTERFERON-STIMULATED GENES IN CRC SAMPLES. LOWER PBRM1 EXPRESSION WAS ASSOCIATED WITH ADVANCED PATHOLOGICAL GRADE AND POORER SURVIVAL OF CRC PATIENTS, INDICATING THAT PBRM1 COULD SERVE AS A POTENTIAL PROGNOSTIC BIOMARKER FOR CRC. COPYRIGHT (C) 2017 PATHOLOGICAL SOCIETY OF GREAT BRITAIN AND IRELAND. PUBLISHED BY JOHN WILEY & SONS, LTD. 2018 9 1701 41 DYNAMIC IMMUNE/INFLAMMATION PRECISION MEDICINE: THE GOOD AND THE BAD INFLAMMATION IN INFECTION AND CANCER. NORMAL OR "GOOD" INFLAMMATION PROCESS STARTS FROM A LOCAL CELLULAR RESPONSE AGAINST INJURY OR ANY INFECTIOUS AGENT, WITH THE ACTIVATION OF NEUTROPHILS, MACROPHAGES, LANGERHANS CELLS, DENDRITIC CELLS, AND INNATE IMMUNE CELLS. CYTOKINES AND CHEMOKINES ARE PRODUCED TO AMPLIFY THE LOCAL INFLAMMATORY PROCESS FOLLOWED BY THE MIGRATION OF IMMUNE CELLS TO THE REGIONAL LYMPH NODES WHERE ADAPTIVE IMMUNE RESPONSE IS INITIATED. SYSTEMIC INFLAMMATION ENHANCES THE BIOLOGICAL RESPONSE TO MOBILIZE ADDITIONAL CELLS FROM CENTRAL AND PERIPHERAL IMMUNE/HEMATOPOIETIC SYSTEM. LOCAL MECHANISMS TO LIMIT INFLAMMATION ARE INITIATED AND LEAD TO HEALING. DURING THE NORMAL INFLAMMATORY PROCESS, THERE IS A BALANCE BETWEEN THE PRODUCTION OF INFLAMMATORY CHEMOKINES/CYTOKINES SUCH AS TUMOR NECROSIS FACTOR (TNF)-ALPHA, INTERLEUKIN (IL)-6 AND IL-1 AND THE PRODUCTION OF COMPOUNDS THAT LIMIT INFLAMMATION AND HAVE AN IMMUNE SUPPRESSIVE EFFECT, SUCH AS IL-10 AND TRANSFORMING FACTOR (TGF) BETA. IL-6 AND IL-6/SOLUBLE IL-6 RECEPTOR (R) COMPLEX STIMULATE LIVER CELLS TO PRODUCE INFLAMMATORY PROTEINS, WHICH REPRESENTS THE SYSTEMIC INFLAMMATION RESPONSE. THE MAGNITUDE AND THE DURATION OF THE SYSTEMIC INFLAMMATORY RESPONSE ARE LINKED TO THE CAUSE, UNDER GENETIC AND EPIGENETIC CONTROL. SIGNIFICANT INFLAMMATION AS SEEN IN SEPTIC SHOCK, IN SEVERE FORMS OF INFECTIONS OR IN CERTAIN ACTIVE CANCERS, REPRESENTS THE "BAD INFLAMMATION", CORRELATED WITH A POOR PROGNOSIS. IN ADDITION, THE PERSISTENCE OF A CHRONIC SMOLDERING INFLAMMATION MAY LEAD TO PATHOLOGICAL SITUATIONS WHICH ARE OBSERVED IN THE MAJORITY OF INFLAMMATORY, DEGENERATIVE, DYSMETABOLIC, OR DYSIMMUNE DISEASES AND CANCER. CHRONIC SMOLDERING INFLAMMATION IS A CROSS BETWEEN DIFFERENT PATHOLOGICAL SITUATIONS POSSIBLY LINKED. IN ADDITION, WITHIN THE TUMOR MICROENVIRONMENT, INFLAMMATORY PROCESS RESULTS FROM DIFFERENT CELLULAR MECHANISMS MODULATED BY METABOLIC AND VASCULAR CHANGES. ON THE CONTRARY, A LIMITED AND BALANCED INFLAMMATION INITIATES THE NORMAL IMMUNE RESPONSE, INCLUDING THE ADAPTIVE RESPONSE WHICH AMPLIFIES ANY IMMUNOTHERAPY, INCLUDING VACCINES. IMMUNE CHECKPOINT INHIBITORS AND CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS ARE ASSOCIATED WITH CYTOKINE RELEASE SYNDROME, A CLINICAL RISK LEADING TO THE USE OF ANTI-CYTOKINE DRUGS. NOWADAYS, IT IS TIME TO MONITOR THE DYNAMIC INFLAMMATORY PROCESS FOR A BETTER IMMUNE PRECISION MEDICINE IN BOTH INFECTIONS AND CANCER. 2021 10 5602 24 RORGAMMAT(+) HEMATOPOIETIC CELLS ARE NECESSARY FOR TUMOR CELL PROLIFERATION DURING COLITIS-ASSOCIATED TUMORIGENESIS IN MICE. COLORECTAL CANCER (CRC) IS ONE OF THE MOST COMMON TUMOR ENTITIES. IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES, THE DEVELOPMENT OF COLITIS-ASSOCIATED COLON CANCER IS CONSIDERED A DANGEROUS LONG-TERM COMPLICATION. IL-17A AND THE TRANSCRIPTION FACTOR RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR GAMMAT (RORGAMMAT) PLAY FUNDAMENTAL ROLES IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASES; IN HUMAN STUDIES, WE DETECTED A DENSE INFILTRATION OF RORGAMMAT-DEPENDENT CD4(+) IL17A(+) T HELPER (TH)17 CELLS IN SPECIMENS OF CRC, ULCERATIVE COLITIS, AND ULCERATIVE COLITIS-ASSOCIATED COLORECTAL CANCER. HOWEVER, THE MECHANISTIC ROLE OF RORGAMMAT(+) HEMATOPOIETIC CELLS IN COLITIS-ASSOCIATED TUMORIGENESIS REMAINS UNCLEAR. TO INVESTIGATE COLITIS-ASSOCIATED COLON TUMORIGENESIS, WE CONDUCTED STUDIES IN THE AOM+DSS MOUSE MODEL THAT REVEALED THE IMPORTANCE OF RORGAMMAT FOR COLON TUMOR PROGRESSION. IN THE ABSENCE OF RORGAMMAT-DEPENDENT TH17 LYMPHOCYTES, MICE SHOWED SIGNS OF INTENSE CHRONIC COLITIS, BUT DEVELOPED SIGNIFICANTLY FEWER MACROSCOPIC TUMOR NODULES. THE REDUCTION OF TUMOR DEVELOPMENT IN RORGAMMAT(-/-) MICE WAS NOT DUE TO REDUCED COLON TUMOR INITIATION. HOWEVER, THE PROLIFERATION RATE OF TUMOR CELLS WAS REDUCED IN THE ABSENCE OF RORGAMMAT-DEPENDENT TH17 CELLS AND TUMOR CELLS SHOWED PRONOUNCED SIGNS OF SENESCENCE-ASSOCIATED EPIGENETIC AND LYSOSOMAL CHANGES. THESE RESULTS INDICATE AN IMPORTANT ROLE FOR THE IMMUNOLOGICAL MILIEU IN COLITIS-ASSOCIATED CANCER, WHICH IS SHAPED IN-PART BY RORGAMMAT-DEPENDENT TH17 LYMPHOCYTES THAT SUPPORT CRC GROWTH. 2015 11 4154 33 MECHANISTIC ROLES OF EPITHELIAL AND IMMUNE CELL SIGNALING DURING THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER. TO DATE, SUBSTANTIAL EVIDENCE HAS SHOWN A SIGNIFICANT ASSOCIATION BETWEEN INFLAMMATORY BOWEL DISEASES (IBD) AND DEVELOPMENT OF COLITIS-ASSOCIATED CANCER (CAC). THE INCIDENCE/PREVALENCE OF IBD IS HIGHER IN WESTERN COUNTRIES INCLUDING THE US, AUSTRALIA, AND THE UK. ALTHOUGH CAC DEVELOPMENT IS GENERALLY CHARACTERIZED BY STEPWISE ACCUMULATION OF GENETIC AS WELL AS EPIGENETIC CHANGES, PRECISE MECHANISMS OF HOW CHRONIC INFLAMMATION LEADS TO THE DEVELOPMENT OF CAC ARE LARGELY UNKNOWN. PRECEDING INTESTINAL INFLAMMATION IS ONE OF THE MAJOR INFLUENTIAL FACTORS FOR CAC TUMORIGENESIS. MUCOSAL IMMUNE RESPONSES INCLUDING ACTIVATION OF ABERRANT SIGNALING PATHWAYS BOTH IN INNATE AND ADAPTIVE IMMUNE CELLS PLAY A PIVOTAL ROLE IN CAC. TUMOR PROGRESSION AND METASTASIS ARE SHAPED BY A TIGHTLY CONTROLLED TUMOR MICROENVIRONMENT WHICH IS ORCHESTRATED BY SEVERAL IMMUNE CELLS AND STROMAL CELLS INCLUDING MACROPHAGES, NEUTROPHILS, DENDRITIC CELLS, MYELOID DERIVED SUPPRESSOR CELLS, T CELLS, AND MYOFIBROBLASTS. IN THIS ARTICLE, WE WILL DISCUSS THE CONTRIBUTING FACTORS OF EPITHELIAL AS WELL AS IMMUNE CELL SIGNALING IN INITIATION OF CAC TUMORIGENESIS AND MUCOSAL IMMUNE REGULATORY FACTORS IN THE COLONIC TUMOR MICROENVIRONMENT. IN DEPTH UNDERSTANDING OF THESE FACTORS IS NECESSARY TO DEVELOP NOVEL ANTI-INFLAMMATORY AND ANTI-CANCER THERAPIES FOR CAC IN THE NEAR FUTURE. 2016 12 1905 43 ENHANCER OF ZESTE HOMOLOG 2 CONTRIBUTES TO APOPTOSIS BY INACTIVATING JANUS KINASE 2/ SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION SIGNALING IN INFLAMMATORY BOWEL DISEASE. BACKGROUND: INFLAMMATORY BOWEL DISEASE (IBD) IS A PREVALENT WORLDWIDE HEALTH PROBLEM FEATURED BY RELAPSING, CHRONIC GASTROINTESTINAL INFLAMMATION. ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS A CRITICAL EPIGENETIC REGULATOR IN DIFFERENT PATHOLOGICAL MODELS, SUCH AS CANCER AND INFLAMMATION. HOWEVER, THE ROLE OF EZH2 IN THE IBD DEVELOPMENT IS STILL OBSCURE. AIM: TO EXPLORE THE EFFECT OF EZH2 ON IBD PROGRESSION AND THE UNDERLYING MECHANISM. METHODS: THE IBD MOUSE MODEL WAS CONDUCTED BY ADDING DEXTRAN SODIUM SULFATE (DSS), AND THE EFFECT OF EZH2 ON DSS-INDUCED COLITIS WAS ASSESSED IN THE MODEL. THE FUNCTION OF EZH2 IN REGULATING APOPTOSIS AND PERMEABILITY WAS EVALUATED BY ANNEXIN V-FITC APOPTOSIS DETECTION KIT, TRANSEPITHELIAL ELECTRICAL RESISTANCE ANALYSIS, AND WESTERN BLOT ANALYSIS OF RELATED MARKERS, INCLUDING ZONA OCCLUDENS 1, CLAUDIN-5, AND OCCLUDIN, IN NCM460 AND FETAL HUMAN COLON (FHC) CELLS. THE MECHANICAL INVESTIGATION WAS PERFORMED BY QUANTITATIVE REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION, WESTERN BLOT ANALYSIS, AND CHROMATIN IMMUNOPRECIPITATION ASSAYS. RESULTS: THE COLON LENGTH WAS INHIBITED IN THE DSS-TREATED MICE AND WAS ENHANCED BY THE EZH2 DEPLETION IN THE SYSTEM. DSS TREATMENT CAUSED A DECREASED HISTOLOGICAL SCORE IN THE MICE, WHICH WAS REVERSED BY EZH2 DEPLETION. THE INFLAMMATORY CYTOKINES, SUCH AS TUMOR NECROSIS FACTOR-ALPHA, INTERLEUKIN-6, AND INTERLEUKIN-1BETA, WERE INDUCED IN THE DSS-TREATED MICE, IN WHICH THE DEPLETION OF EZH2 COULD REVERSE THIS EFFECT. MOREOVER, THE TUMOR NECROSIS FACTOR-ALPHA TREATMENT INDUCED THE APOPTOSIS OF NCM460 AND FHC CELLS, IN WHICH EZH2 DEPLETION COULD REVERSE THIS EFFECT IN THE CELLS. MOREOVER, THE DEPLETION OF EZH2 ATTENUATED PERMEABILITY OF COLONIC EPITHELIAL CELLS. MECHANICALLY, THE DEPLETION OF EZH2 OR EZH2 INHIBITOR GSK343 WAS ABLE TO ENHANCE THE EXPRESSION AND THE PHOSPHORYLATION OF JANUS KINASE 2 (JK2) AND SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION IN THE NCM460 AND FHC CELLS. SPECIFICALLY, EZH2 INACTIVATED JAK2 EXPRESSION BY REGULATING HISTONE H3K27ME3. JAK2 INHIBITOR TG101348 WAS ABLE TO REVERSE EZH2 KNOCKDOWN-MEDIATED COLONIC EPITHELIAL CELL PERMEABILITY AND APOPTOSIS. CONCLUSION: THUS, WE CONCLUDED THAT EZH2 CONTRIBUTED TO APOPTOSIS AND INFLAMMATORY RESPONSE BY INACTIVATING JAK2/ SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION SIGNALING IN IBD. EZH2 MAY BE APPLIED AS A POTENTIAL TARGET FOR IBD THERAPY. 2021 13 482 29 ARSENITE BINDS TO THE ZINC FINGER MOTIF OF TIP60 HISTONE ACETYLTRANSFERASE AND INDUCES ITS DEGRADATION VIA THE 26S PROTEASOME. ARSENIC IS A UBIQUITOUS ENVIRONMENTAL CONTAMINANT WITH WIDESPREAD PUBLIC HEALTH CONCERN. EPIDEMIOLOGICAL STUDIES HAVE REVEALED THAT CHRONIC HUMAN EXPOSURE TO ARSENIC IN DRINKING WATER IS ASSOCIATED WITH THE PREVALENCE OF SKIN, LUNG, AND BLADDER CANCERS. ABERRANT HISTONE MODIFICATIONS (E.G., METHYLATION, ACETYLATION, AND UBIQUITINATION) WERE PREVIOUSLY FOUND TO BE ACCOMPANIED BY ARSENIC EXPOSURE; THUS, PERTURBATION OF EPIGENETIC PATHWAYS IS THOUGHT TO CONTRIBUTE TO ARSENIC CARCINOGENESIS. ARSENITE IS KNOWN TO INTERACT WITH ZINC FINGER MOTIFS OF PROTEINS, AND ZINC FINGER MOTIF IS PRESENT IN AND INDISPENSABLE FOR THE ENZYMATIC ACTIVITIES OF CRUCIAL HISTONE-MODIFYING ENZYMES ESPECIALLY THE MYST FAMILY OF HISTONE ACETYLTRANSFERASES (E.G., TIP60). HENCE, WE REASONED THAT TRIVALENT ARSENIC MAY TARGET THE ZINC FINGER MOTIF OF THESE ENZYMES, DISTURB THEIR ENZYMATIC ACTIVITIES, AND ALTER HISTONE ACETYLATION. HEREIN, WE FOUND THAT AS(3+) COULD BIND DIRECTLY TO THE ZINC-FINGER MOTIF OF TIP60 IN VITRO AND IN CELLS. IN ADDITION, EXPOSURE TO AS(3+) COULD LEAD TO A DOSE-DEPENDENT DECREASE IN TIP60 PROTEIN LEVEL VIA THE UBIQUITIN-PROTEASOME PATHWAY. THUS, THE RESULTS FROM THE PRESENT STUDY REVEALED, FOR THE FIRST TIME, THAT ARSENITE MAY TARGET CYSTEINE RESIDUES IN THE ZINC-FINGER MOTIF OF THE TIP60 HISTONE ACETYLTRANSFERASE, THEREBY ALTERING THE H4K16AC HISTONE EPIGENETIC MARK. OUR RESULTS ALSO SHED SOME NEW LIGHT ON THE MECHANISMS UNDERLYING THE ARSENIC-INDUCED EPIGENOTOXICITY AND CARCINOGENESIS IN HUMANS. 2017 14 192 35 ACETYLATED H4K16 BY MYST1 PROTECTS UROTSA CELLS FROM ARSENIC TOXICITY AND IS DECREASED FOLLOWING CHRONIC ARSENIC EXPOSURE. ARSENIC, A HUMAN CARCINOGEN THAT IS ASSOCIATED WITH AN INCREASED RISK OF BLADDER CANCER, IS COMMONLY FOUND IN DRINKING WATER. AN IMPORTANT MECHANISM BY WHICH ARSENIC IS THOUGHT TO BE CARCINOGENIC IS THROUGH THE INDUCTION OF EPIGENETIC CHANGES THAT LEAD TO ABERRANT GENE EXPRESSION. PREVIOUSLY, WE REPORTED THAT THE SAS2 GENE IS REQUIRED FOR OPTIMAL GROWTH OF YEAST IN THE PRESENCE OF ARSENITE (AS(III)). YEAST SAS2P IS ORTHOLOGOUS TO HUMAN MYST1, A HISTONE 4 LYSINE 16 (H4K16) ACETYLTRANSFERASE. HERE, WE SHOW THAT H4K16 ACETYLATION IS NECESSARY FOR THE RESISTANCE OF YEAST TO AS(III) THROUGH THE MODULATION OF CHROMATIN STATE. WE FURTHER EXPLORED THE ROLE OF MYST1 AND H4K16 ACETYLATION IN ARSENIC TOXICITY AND CARCINOGENESIS IN HUMAN BLADDER EPITHELIAL CELLS. THE EXPRESSION OF MYST1 WAS KNOCKED DOWN IN UROTSA CELLS, A MODEL OF BLADDER EPITHELIUM THAT HAS BEEN USED TO STUDY ARSENIC-INDUCED CARCINOGENESIS. SILENCING OF MYST1 REDUCED ACETYLATION OF H4K16 AND INDUCED SENSITIVITY TO AS(III) AND TO ITS MORE TOXIC METABOLITE MONOMETHYLARSONOUS ACID (MMA(III)) AT DOSES RELEVANT TO HIGH ENVIRONMENTAL HUMAN EXPOSURES. IN ADDITION, BOTH AS(III) AND MMA(III) TREATMENTS DECREASED GLOBAL H4K16 ACETYLATION LEVELS IN A DOSE- AND TIME-DEPENDENT MANNER. THIS INDICATES THAT ACETYLATED H4K16 IS REQUIRED FOR RESISTANCE TO ARSENIC AND THAT A REDUCTION IN ITS LEVELS AS A CONSEQUENCE OF ARSENIC EXPOSURE MAY CONTRIBUTE TO TOXICITY IN UROTSA CELLS. BASED ON THESE FINDINGS, WE PROPOSE A NOVEL ROLE FOR THE MYST1 GENE IN HUMAN SENSITIVITY TO ARSENIC. 2009 15 3218 34 HELICOBACTER INFECTION IS REQUIRED FOR INFLAMMATION AND COLON CANCER IN SMAD3-DEFICIENT MICE. ACCUMULATING EVIDENCE SUGGESTS THAT INTESTINAL MICROBIAL ORGANISMS MAY PLAY AN IMPORTANT ROLE IN TRIGGERING AND SUSTAINING INFLAMMATION IN INDIVIDUALS AFFLICTED WITH INFLAMMATORY BOWEL DISEASE (IBD). MOREOVER, INDIVIDUALS WITH IBD ARE AT INCREASED RISK FOR DEVELOPING COLORECTAL CANCER, SUGGESTING THAT CHRONIC INFLAMMATION MAY INITIATE GENETIC OR EPIGENETIC CHANGES ASSOCIATED WITH CANCER DEVELOPMENT. WE TESTED THE HYPOTHESIS THAT BACTERIA MAY CONTRIBUTE TO THE DEVELOPMENT OF COLON CANCER BY SYNERGIZING WITH DEFECTIVE TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) SIGNALING, A PATHWAY COMMONLY MUTATED IN HUMAN COLON CANCER. ALTHOUGH OTHERS HAVE REPORTED THAT MICE DEFICIENT IN THE TGF-BETA SIGNALING MOLECULE SMAD3 DEVELOP COLON CANCER, WE FOUND THAT SMAD3-DEFICIENT MICE MAINTAINED FREE OF THE GRAM-NEGATIVE ENTEROHEPATIC BACTERIA HELICOBACTER SPP. FOR UP TO 9 MONTHS DO NOT DEVELOP COLON CANCER. FURTHERMORE, INFECTION OF SMAD3(-/-) MICE WITH HELICOBACTER TRIGGERS COLON CANCER IN 50% TO 66% OF THE ANIMALS. USING REAL-TIME PCR, WE FOUND THAT HELICOBACTER ORGANISMS CONCENTRATE IN THE CECUM, THE PREFERRED SITE OF TUMOR DEVELOPMENT. MUCINOUS ADENOCARCINOMAS DEVELOP 5 TO 30 WEEKS AFTER INFECTION AND ARE PRECEDED BY AN EARLY INFLAMMATORY PHASE, CONSISTING OF INCREASED PROLIFERATION OF EPITHELIAL CELLS; INCREASED NUMBERS OF CYCLOOXYGENASE-2-POSITIVE CELLS, CD4(+) T CELLS, MACROPHAGES; AND INCREASED MHC CLASS II EXPRESSION. COLONIC TISSUE REVEALED INCREASED TRANSCRIPTS FOR THE ONCOGENE C-MYC AND THE PROINFLAMMATORY CYTOKINES INTERLEUKIN-1ALPHA (IL-1ALPHA), IL-1BETA, IL-6, IFN-GAMMA, AND TUMOR NECROSIS FACTOR-ALPHA, SOME OF WHICH HAVE BEEN IMPLICATED IN COLON CANCER. THESE RESULTS SUGGEST THAT BACTERIA MAY BE IMPORTANT IN TRIGGERING COLORECTAL CANCER, NOTABLY IN THE CONTEXT OF GENE MUTATIONS IN THE TGF-BETA SIGNALING PATHWAY, ONE OF THE MOST COMMONLY AFFECTED CELLULAR PATHWAYS IN COLORECTAL CANCER IN HUMANS. 2006 16 4462 30 MOLECULAR MECHANISMS OF HBV-ASSOCIATED HEPATOCARCINOGENESIS. HEPATITIS B VIRUS (HBV) CONTRIBUTES TO HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT THROUGH DIRECT AND INDIRECT MECHANISMS. HBV-DNA INTEGRATION INTO THE HOST GENOME OCCURS AT EARLY STEPS OF CLONAL TUMOR EXPANSION AND INDUCES BOTH GENOMIC INSTABILITY AND DIRECT INSERTIONAL MUTAGENESIS OF DIVERSE CANCER-RELATED GENES. PROLONGED EXPRESSION OF THE VIRAL REGULATORY PROTEIN HBX AND THE LARGE ENVELOPE PROTEIN DEREGULATE THE CELLULAR TRANSCRIPTION PROGRAM AND PROLIFERATION CONTROL AND SENSITIZE LIVER CELLS TO CARCINOGENIC FACTORS. EPIGENETIC CHANGES TARGETING THE EXPRESSION OF TUMOR SUPPRESSOR GENES OCCUR EARLY IN THE DEVELOPMENT OF HCC. A MAJOR ROLE IS PLAYED BY HBX THAT IS RECRUITED ON CELLULAR CHROMATIN AND MODULATES CHROMATIN DYNAMICS AT SPECIFIC GENE LOCI. COMPARED WITH TUMORS ASSOCIATED WITH OTHER RISK FACTORS, HBV-RELATED TUMORS HAVE A HIGHER RATE OF CHROMOSOMAL ALTERATIONS AND P53 INACTIVATION BY MUTATIONS, OVEREXPRESS FETAL LIVER/HEPATIC PROGENITOR CELLS GENES, AND SHOW A SPECIFIC ACTIVATION OF THE AKT PATHWAY. THE WNT/BETA-CATENIN PATHWAY IS ALSO OFTEN ACTIVATED, BUT HBV-RELATED TUMORS DISPLAY A LOW RATE OF ACTIVATING BETA-CATENIN MUTATIONS. ALL AVAILABLE EVIDENCE STRONGLY SUPPORTS THE NOTION THAT CHRONIC HBV INFECTION TRIGGERS BOTH COMMON AND ETIOLOGY-SPECIFIC ONCOGENIC PATHWAYS, THUS PLAYING A DIRECT ROLE BEYOND STIMULATION OF HOST IMMUNE RESPONSES AND CHRONIC NECROINFLAMMATORY LIVER DISEASE. 2013 17 1122 31 COMPARISON OF GENE EXPRESSION PROFILES IN CHROMATE TRANSFORMED BEAS-2B CELLS. BACKGROUND: HEXAVALENT CHROMIUM [CR(VI)] IS A POTENT HUMAN CARCINOGEN. OCCUPATIONAL EXPOSURE HAS BEEN ASSOCIATED WITH INCREASED RISK OF RESPIRATORY CANCER. MULTIPLE MECHANISMS HAVE BEEN SHOWN TO CONTRIBUTE TO CR(VI) INDUCED CARCINOGENESIS, INCLUDING DNA DAMAGE, GENOMIC INSTABILITY, AND EPIGENETIC MODULATION, HOWEVER, THE MOLECULAR MECHANISM AND DOWNSTREAM GENES MEDIATING CHROMIUM'S CARCINOGENICITY REMAIN TO BE ELUCIDATED. METHODS/RESULTS: WE ESTABLISHED CHROMATE TRANSFORMED CELL LINES BY CHRONIC EXPOSURE OF NORMAL HUMAN BRONCHIAL EPITHELIAL BEAS-2B CELLS TO LOW DOSES OF CR(VI) FOLLOWED BY ANCHORAGE-INDEPENDENT GROWTH. THESE TRANSFORMED CELL LINES NOT ONLY EXHIBITED CONSISTENT MORPHOLOGICAL CHANGES BUT ALSO ACQUIRED ALTERED AND DISTINCT GENE EXPRESSION PATTERNS COMPARED WITH NORMAL BEAS-2B CELLS AND CONTROL CELL LINES (UNTREATED) THAT AROSE SPONTANEOUSLY IN SOFT AGAR. INTERESTINGLY, THE GENE EXPRESSION PROFILES OF SIX CR(VI) TRANSFORMED CELL LINES WERE REMARKABLY SIMILAR TO EACH OTHER YET DIFFERED SIGNIFICANTLY FROM THAT OF EITHER CONTROL CELL LINES OR NORMAL BEAS-2B CELLS. A TOTAL OF 409 DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED IN CR(VI) TRANSFORMED CELLS COMPARED TO CONTROL CELLS. GENES RELATED TO CELL-TO-CELL JUNCTION WERE UPREGULATED IN ALL CR(VI) TRANSFORMED CELLS, WHILE GENES ASSOCIATED WITH THE INTERACTION BETWEEN CELLS AND THEIR EXTRACELLULAR MATRICES WERE DOWN-REGULATED. ADDITIONALLY, EXPRESSION OF GENES INVOLVED IN CELL PROLIFERATION AND APOPTOSIS WERE ALSO CHANGED. CONCLUSION: THIS STUDY IS THE FIRST TO REPORT GENE EXPRESSION PROFILING OF CR(VI) TRANSFORMED CELLS. THE GENE EXPRESSION CHANGES ACROSS INDIVIDUAL CHROMATE EXPOSED CLONES WERE REMARKABLY SIMILAR TO EACH OTHER BUT DIFFERED SIGNIFICANTLY FROM THE GENE EXPRESSION FOUND IN ANCHORAGE-INDEPENDENT CLONES THAT AROSE SPONTANEOUSLY. OUR ANALYSIS IDENTIFIED MANY NOVEL GENE EXPRESSION CHANGES THAT MAY CONTRIBUTE TO CHROMATE INDUCED CELL TRANSFORMATION, AND COLLECTIVELY THIS TYPE OF INFORMATION WILL PROVIDE A BETTER UNDERSTANDING OF THE MECHANISM UNDERLYING CHROMATE CARCINOGENICITY. 2011 18 1826 27 EFFECTS OF HISTONE DEACETYLASE INHIBITOR ON EXTRACELLULAR MATRIX PRODUCTION IN HUMAN NASAL POLYP ORGAN CULTURES. BACKGROUND: NASAL POLYPOSIS IS ASSOCIATED WITH A CHRONIC INFLAMMATORY CONDITION OF THE SINONASAL MUCOSA AND INVOLVES MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX (ECM) ACCUMULATION. EPIGENETIC MODULATION BY HISTONE DEACETYLASE (HDAC) INHIBITORS INCLUDING TRICHOSTATIN A (TSA) HAS BEEN REPORTED TO HAVE INHIBITORY EFFECTS ON MYOFIBROBLAST DIFFERENTIATION IN LUNG AND RENAL FIBROBLASTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE INHIBITORY EFFECT OF TSA ON MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION IN NASAL POLYP ORGAN CULTURES. METHODS: NASAL POLYP TISSUES FROM 18 PATIENTS WERE ACQUIRED DURING ENDOSCOPIC SINUS SURGERY. AFTER ORGAN CULTURE, NASAL POLYPS WERE STIMULATED WITH TGF-BETA1 AND THEN TREATED WITH TSA. ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), FIBRONECTIN, AND COLLAGEN TYPE I EXPRESSION LEVELS WERE EXAMINED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (PCR), REAL-TIME PCR, WESTERN BLOT, AND IMMUNOFLUORESCENT STAINING. HDAC2, HDAC4, AND ACETYLATED H4 EXPRESSION LEVELS WERE ASSAYED BY WESTERN BLOT. CYTOTOXICITY WAS ANALYZED BY THE TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE BIOTIN-DUTP NICK END LABELING ASSAY. RESULTS: THE EXPRESSION LEVELS OF ALPHA-SMA, FIBRONECTIN, AND COLLAGEN TYPE 1 WERE INCREASED IN NASAL POLYP AFTER TRANSFORMING GROWTH FACTOR (TGF) BETA1 TREATMENT. TSA-INHIBITED TGF-BETA1 INDUCED THESE GENE AND PROTEIN EXPRESSION LEVELS. FURTHERMORE, TSA SUPPRESSED PROTEIN EXPRESSION LEVELS OF HDAC2 AND HDAC4. HOWEVER, TSA INDUCED HYPERACETYLATION OF HISTONES H4. TREATMENT WITH TGF-BETA1 WITH OR WITHOUT TSA DID NOT HAVE CYTOTOXIC EFFECT. CONCLUSION: THESE FINDINGS PROVIDE NOVEL INSIGHTS INTO THE EPIGENETIC REGULATION IN MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION OF NASAL POLYP. TSA COULD BE A CANDIDATE OF A THERAPEUTIC AGENT FOR REVERSING THE TGF-BETA1-INDUCED ECM SYNTHESIS THAT LEADS TO NASAL POLYP DEVELOPMENT. 2013 19 3553 27 IMMUNOTOLERANCE OF DAIRY HEIFERS IN RESPONSE TO REPEATED EXPOSURE TO BACTERIAL LIPOPOLYSACCHARIDE ENDOTOXIN. DAIRY CATTLE FACE A VARIETY OF STRESSFUL EVENTS ON A DAILY BASIS. MORE SPECIFICALLY, CLIMATE CHANGE HAS RESULTED IN MORE FREQUENT HEAT STRESS EVENTS THAT INCREASE THE INCIDENCE OF CHRONIC BACTERIAL INFECTIONS BY INDUCING CONDITIONS LIKE LEAKY GUT SYNDROME, WHEREBY THE INTEGRITY OF THE INTESTINAL EPITHELIUM IS COMPROMISED ALLOWING FOR LUMINAL BACTERIAL LIPOPOLYSACCHARIDE (LPS) ENDOTOXIN TO INFILTRATE THE HOST'S BLOODSTREAM RESULTING IN ACUTE OR CHRONIC SYSTEMIC STIMULATION OF THE INNATE IMMUNE SYSTEM. REPEATED EXPOSURE TO LPS OVER A SHORT PERIOD OF TIME IS REPORTED TO INDUCE IMMUNOTOLERANCE WITHIN THE HOST. THIS LPS TOLERANCE IS AN ESSENTIAL IMMUNOHOMEOSTATIC RESPONSE THAT CAN PROTECT AGAINST OVER ACTIVATION OF THE INFLAMMATORY RESPONSE DURING SUBSEQUENT EXPOSURE TO LPS. IN THE PRESENT STUDY, HOLSTEIN CALVES (N = 20) WERE INITIALLY STRESS CHALLENGED WITH EITHER SALINE, OR 100, 200 OR 400 NG/KG OF LPS ADMINISTERED INTRAMUSCULAR, AND AGAIN RE-CHALLENGED WITH 200 NG/KG OF LPS 2-WEEKS LATER. SERUM WAS COLLECTED EVERY 2 HR FOR 6 HR TO PROFILE CHANGES IN CIRCULATORY STRESS BIOMARKERS AFTER THE REPEATED LPS EXPOSURES. HEIFERS THAT WERE INITIALLY CHALLENGED WITH 100, 200 AND 400 NG/KG OF LPS DEMONSTRATED SIGNIFICANTLY ATTENUATED CORTISOL RESPONSES IN THE SECOND CHALLENGE (P < 0.01, 0.01 AND 0.05, RESPECTIVELY), WHEREAS CONTROL ANIMALS WHO PREVIOUSLY RECEIVED SALINE DEMONSTRATED A STRONG CORTISOL RESPONSE AT 2 HR AFTER RECEIVING 200 NG/KG OF LPS (P < 0.05). THE CYTOKINE/CHEMOKINE (IL-6, CCL2, CCL3 AND CCL4) RESPONSES WERE ALSO ATTENUATED DURING THE LPS RECHALLENGE (P < 0.05). FINALLY, MICRORNA EXPRESSION PROFILES WERE DETERMINED TO ASSESS THE EPIGENETIC RESPONSE TO REPEATED LPS EXPOSURE. INTERESTINGLY, MIR-31 AND MIR-223 WERE DOWNREGULATED IN RESPONSE TO THE SECOND LPS CHALLENGE. THE PRESENT STUDY DEMONSTRATES THE DYNAMIC NATURE OF THE STRESS RESPONSE IN DAIRY CATTLE AS IT RELATES TO THE DEVELOPMENT OF LPS TOLERANCE. UNDERSTANDING THE ROLES OF VARIOUS STRESS BIOMARKERS IN THE CONTEXT OF INNATE IMMUNE CELL TOLERANCE IS ESSENTIAL FOR EVALUATING THEIR IMPACT ON IMMUNE SYSTEM HOMEOSTASIS. 2023 20 6486 27 TP53 AND LIVER CARCINOGENESIS. PRIMARY HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON MALIGNANCIES AND HAS THE FOURTH HIGHEST MORTALITY RATE WORLDWIDE. THE MAJOR RISK FACTORS, INCLUDING CHRONIC INFECTIONS WITH THE HEPATITIS B OR C VIRUS, ARE EXPOSURE TO DIETARY AFLATOXIN B1(AFB1), VINYL CHLORIDE, OR ALCOHOL CONSUMPTION. SOUTHERN CHINA AND SUB-SAHARAN AFRICA HAVE THE HIGHEST DIETARY AFB1 EXPOSURE, MAKING IT AND HEPATITIS B VIRUS (HBV) THE MAJOR CAUSES OF CANCER MORTALITY IN THESE GEOGRAPHIC AREAS. RECENT STUDIES HAVE DISCOVERED GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE MOLECULAR PATHOGENESIS OF HCC, INCLUDING SOMATIC MUTATIONS IN THE P53 TUMOR SUPPRESSOR GENE (TP53). AFB1 INDUCES TYPICAL G:C TO T:A TRANSVERSIONS AT THE THIRD BASE IN CODON 249 OF P53. CHRONIC ACTIVE HEPATITIS B AND C (HCV) INFECTION, AND FURTHER INFLAMMATORY AND OXYRADICAL DISORDERS INCLUDING WILSON DISEASE (WD) OR HEMOCHROMATOSIS, GENERATE REACTIVE OXYGEN/NITROGEN SPECIES THAT CAN DAMAGE DNA AND MUTATE THE P53 GENE. THE X GENE OF HBV (HBX) IS THE MOST COMMON OPEN READING FRAME INTEGRATED INTO THE HOST GENOME IN HCC. THE INTEGRATED HBX IS FREQUENTLY MUTATED AND HAS A DIMINISHED ABILITY TO FUNCTION AS A TRANSCRIPTIONAL COTRANSACTIVATOR AND TO ACTIVATE THE NF-KAPPA B PATHWAY. HOWEVER, THE MUTANT HBX PROTEINS STILL RETAIN THEIR ABILITY TO BIND TO AND ABROGATE P53-MEDIATED APOPTOSIS. IN SUMMARY, BOTH VIRUSES AND CHEMICALS ARE IMPLICATED IN THE ETIOLOGY AND MOLECULAR PATHOGENESIS OF HCC. THE RESULTANT MOLECULAR CHANGES IN THE RAS AND WNT SIGNAL-TRANSDUCTION PATHWAYS, AND THE P53 AND RB TUMOR SUPPRESSOR PATHWAYS SIGNIFICANTLY CONTRIBUTE TO LIVER CARCINOGENESIS 2003