1 875 132 CHRONIC AND TRANSIENT HYPERGLYCEMIA INDUCES CHANGES IN THE EXPRESSION PATTERNS OF IL6 AND ADIPOQ GENES AND THEIR ASSOCIATED EPIGENETIC MODIFICATIONS IN DIFFERENTIATING HUMAN VISCERAL ADIPOCYTES. ADIPOKINES SECRETED BY HYPERTROPHIC VISCERAL ADIPOSE TISSUE (VAT) INSTIGATE LOW-GRADE INFLAMMATION, FOLLOWED BY HYPERGLYCEMIA (HG)-RELATED METABOLIC DISORDERS. THE LATTER MAY DEVELOP WITH THE PARTICIPATION OF EPIGENETIC MODIFICATIONS. OUR AIM WAS TO ASSESS HOW HG INFLUENCES SELECTED EPIGENETIC MODIFICATIONS AND THE EXPRESSION OF INTERLEUKIN 6 (IL-6) AND ADIPONECTIN (APN; GENE SYMBOL ADIPOQ) DURING THE ADIPOGENESIS OF HUMAN VISCERAL PREADIPOCYTES (HPA-V). ADIPOCYTES (ADS) WERE CHRONICALLY OR TRANSIENTLY HG-TREATED DURING THREE STAGES OF ADIPOGENESIS (PROLIFERATION, DIFFERENTIATION, MATURATION). WE MEASURED ADIPOKINE MRNA, PROTEIN, PROVEN OR PREDICTED MICRORNA EXPRESSION (RT-QPCR AND ELISA), AND ENRICHMENT OF H3K9/14AC, H3K4ME3, AND H3K9ME3 AT GENE PROMOTER REGIONS (CHROMATIN IMMUNOPRECIPITATION). IN CHRONIC HG, WE DETECTED DIFFERENT EXPRESSION PATTERNS OF THE STUDIED ADIPOKINES AT THE MRNA AND PROTEIN LEVELS. CHRONIC AND TRANSIENT HG-INDUCED CHANGES IN MIRNA (MIR-26A-5P, MIR-26B-5P, LET-7D-5P, LET-7E-5P, MIR-365A-3P, MIR-146A-5P) WERE MOSTLY CONVERGENT TO ALTERED IL-6 TRANSCRIPTION. ALTERATIONS IN HISTONE MARKS AT THE IL6 PROMOTER WERE ALSO IN AGREEMENT WITH IL-6 MRNA. THE OPEN CHROMATIN MARKS AT THE ADIPOQ PROMOTER MOSTLY REFLECTED THE APN TRANSCRIPTION DURING NG ADIPOGENESIS, WHILE, IN THE DIFFERENTIATION STAGE, HG-INDUCED CHANGES IN ALL STUDIED MARKS WERE IN LINE WITH APN MRNA LEVELS. IN SUMMARY, HG DYSREGULATED ADIPOKINE EXPRESSION, PROMOTING INFLAMMATION. EPIGENETIC CHANGES COEXISTED WITH ALTERED EXPRESSION OF ADIPOKINES, ESPECIALLY FOR IL-6; THEREFORE, EPIGENETIC MARKS INDUCED BY TRANSIENT HG MAY ACT AS EPI-MEMORY IN ADS. SUCH CHANGES IN THE EPIGENOME AND EXPRESSION OF ADIPOKINES COULD BE INSTRUMENTAL IN THE DEVELOPMENT OF INFLAMMATION AND METABOLIC DEREGULATION OF VAT. 2021 2 188 22 ACETYL TRANSFERASE EP300 DEFICIENCY LEADS TO CHRONIC REPLICATION STRESS MEDIATED BY DEFECTIVE FORK PROTECTION AT STALLED REPLICATION FORKS. MUTATIONS IN THE EPIGENETIC REGULATOR AND GLOBAL TRANSCRIPTIONAL ACTIVATOR, E1A BINDING PROTEIN (EP300), IS BEING INCREASINGLY REPORTED IN AGGRESSIVE HEMATOLOGICAL MALIGNANCIES INCLUDING ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL). HOWEVER, THE MECHANISTIC CONTRIBUTION OF EP300 DYSREGULATION TO CANCER INITIATION AND PROGRESSION ARE CURRENTLY UNKNOWN. INDEPENDENT INHIBITION OF EP300 IN HUMAN CELLS RESULTS IN THE DIFFERENTIAL EXPRESSION OF GENES INVOLVED IN REGULATING THE CELL CYCLE, DNA REPLICATION AND DNA DAMAGE RESPONSE. NEVERTHELESS, SPECIFIC FUNCTION PLAYED BY EP300 IN DNA REPLICATION INITIATION, PROGRESSION AND REPLICATION FORK INTEGRITY HAS NOT BEEN STUDIED. HERE, USING ATLL CELLS AS A MODEL TO STUDY EP300 DEFICIENCY AND AN P300-SELECTIVE PROTAC DEGRADER, DEGRADER AS A PHARMACOLOGIC TOOL, WE REVEAL THAT EP300-MUTATED CELLS DISPLAY PROLONGED CELL CYCLE KINETICS, DUE TO PRONOUNCED DYSREGULATIONS IN DNA REPLICATION DYNAMICS LEADING TO PERSISTENT GENOMIC INSTABILITY. ABERRANT DNA REPLICATION IN EP300-MUTATED CELLS IS CHARACTERIZED BY ELEVATED REPLICATION ORIGIN FIRING DUE TO INCREASED REPLISOME PAUSING GENOME-WIDE. WE DEMONSTRATE THAT EP300 DEFICIENCY RESULTS IN NUCLEOLYTIC DEGRADATION OF NASCENTLY SYNTHESIZED DNA AT STALLED FORKS DUE TO A PROMINENT DEFECT IN FORK STABILIZATION AND PROTECTION. THIS IN TURN RESULTS IN THE ACCUMULATION OF SINGLE STRANDED DNA GAPS AT COLLAPSED REPLICATION FORKS, IN EP300-DEFICIENT CELLS. INHIBITION OF MRE11 NUCLEASE RESCUES THE SSDNA ACCUMULATION INDICATING A DYSREGULATION IN DOWNSTREAM MECHANISMS THAT RESTRAIN NUCLEASE ACTIVITY AT STALLED FORKS. IMPORTANTLY, WE FIND THAT THE ABSENCE OF EP300 RESULTS IN DECREASED EXPRESSION OF BRCA2 PROTEIN EXPRESSION AND A DEPENDENCY ON POLD3-MEDIATED ERROR-PRONE REPLICATION RESTART MECHANISMS. THE OVERALL S-PHASE ABNORMALITIES OBSERVED LEAD TO UNDER-REPLICATED DNA IN G2/M THAT INSTIGATES MITOTIC DNA SYNTHESIS. THIS IN TURN IS ASSOCIATED WITH MITOTIC SEGREGATION DEFECTS CHARACTERIZED BY ELEVATED MICRONUCLEI FORMATION, ACCUMULATION OF CYTOSOLIC DNA AND TRANSMISSION OF UNREPAIRED INHERITED DNA LESIONS IN THE SUBSEQUENT G1-PHASE IN EP300-DEFICIENT CELLS. WE DEMONSTRATE THAT THE DNA REPLICATION DYNAMICS OF EP300-MUTATED CELLS ATLL CELLS RECAPITULATE FEATURES OF BRCA-DEFICIENT CANCERS. ALTOGETHER THESE RESULTS SUGGEST THAT MUTATIONS IN EP300 CAUSE CHRONIC DNA REPLICATION STRESS AND DEFECTIVE REPLICATION FORK RESTART RESULTS IN PERSISTENT GENOMIC INSTABILITY THAT UNDERLIE AGGRESSIVE CHEMO-RESISTANT TUMORIGENESIS IN HUMANS. 2023 3 4661 12 NEW ASPECTS OF THE EPIGENETIC REGULATION OF EMT RELATED TO PULMONARY FIBROSIS. PULMONARY FIBROSIS IS A CHRONIC AND PROGRESSIVE FIBROTIC DISEASE THAT RESULTS IN IMPAIRED GAS EXCHANGE, VENTILATION, AND EVENTUAL DEATH. THE PRO-FIBROTIC ENVIRONMENT IS INSTIGATED BY VARIOUS FACTORS, LEADING TO THE TRANSFORMATION OF EPITHELIAL CELLS INTO MYOFIBROBLASTS AND/OR FIBROBLASTS THAT TRIGGER FIBROSIS. EPITHELIAL MESENCHYMAL TRANSITION (EMT) IS A BIOLOGICAL PROCESS THAT PLAYS A CRITICAL ROLE IN THE PATHOGENESIS OF PULMONARY FIBROSIS. EPIGENETIC REGULATION OF TISSUE-STROMAL CROSSTALK INVOLVING DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNA, AND CHROMATIN REMODELING PLAYS A KEY ROLE IN THE CONTROL OF EMT. THE REVIEW INVESTIGATES THE EPIGENETIC REGULATION OF EMT AND ITS SIGNIFICANCE IN PULMONARY FIBROSIS. 2023 4 5352 21 RE-ESTABLISHING THE COMPREHENSION OF PHYTOMEDICINE AND NANOMEDICINE IN INFLAMMATION-MEDIATED CANCER SIGNALING. RECENT MOUNTING EVIDENCE HAS REVEALED EXTENSIVE GENETIC HETEROGENEITY WITHIN TUMORS THAT DRIVE PHENOTYPIC VARIATION AFFECTING KEY CANCER PATHWAYS, MAKING CANCER TREATMENT EXTREMELY CHALLENGING. DIVERSE CANCER TYPES DISPLAY RESISTANCE TO TREATMENT AND SHOW PATTERNS OF RELAPSE FOLLOWING THERAPY. THEREFORE, EFFORTS ARE REQUIRED TO ADDRESS TUMOR HETEROGENEITY BY DEVELOPING A BROAD-SPECTRUM THERAPEUTIC APPROACH THAT COMBINES TARGETED THERAPIES. INFLAMMATION HAS BEEN PROGRESSIVELY DOCUMENTED AS A VITAL FACTOR IN TUMOR ADVANCEMENT AND HAS CONSEQUENCES IN EPIGENETIC VARIATIONS THAT SUPPORT TUMOR INSTIGATION, ENCOURAGING ALL THE TUMORIGENESIS PHASES. INCREASED DNA DAMAGE, DISRUPTED DNA REPAIR MECHANISMS, CELLULAR PROLIFERATION, APOPTOSIS, ANGIOGENESIS, AND ITS INCURSION ARE A FEW PRO-CANCEROUS OUTCOMES OF CHRONIC INFLAMMATION. A CLEAR UNDERSTANDING OF THE CELLULAR AND MOLECULAR SIGNALING MECHANISMS OF TUMOR-ENDORSING INFLAMMATION IS NECESSARY FOR FURTHER EXPANSION OF ANTI-CANCER THERAPEUTICS TARGETING THE CROSSTALK BETWEEN TUMOR DEVELOPMENT AND INFLAMMATORY PROCESSES. MULTIPLE INFLAMMATORY SIGNALING PATHWAYS, SUCH AS THE NF-KAPPAB SIGNALING PATHWAY, JAK-STAT SIGNALING PATHWAY, MAPK SIGNALING, PI3K/AKT/MTOR SIGNALING, WNT SIGNALING CASCADE, AND TGF-BETA/SMAD SIGNALING, HAVE BEEN FOUND TO REGULATE INFLAMMATION, WHICH CAN BE MODULATED USING VARIOUS FACTORS SUCH AS SMALL MOLECULE INHIBITORS, PHYTOCHEMICALS, RECOMBINANT CYTOKINES, AND NANOPARTICLES (NPS) IN CONJUGATION TO PHYTOCHEMICALS TO TREAT CANCER. RESEARCHERS HAVE IDENTIFIED MULTIPLE TARGETS TO SPECIFICALLY ALTER INFLAMMATION IN CANCER THERAPY TO RESTRICT MALIGNANT PROGRESSION AND IMPROVE THE EFFICACY OF CANCER THERAPY. SIRNA-AND SHRNA-LOADED NPS HAVE BEEN OBSERVED TO DOWNREGULATE STAT3 SIGNALING PATHWAYS AND HAVE BEEN EMPLOYED IN STUDIES TO TARGET TUMOR MALIGNANCIES. THIS REVIEW HIGHLIGHTS THE PATHWAYS INVOLVED IN THE INTERACTION BETWEEN TUMOR ADVANCEMENT AND INFLAMMATORY PROGRESSION, ALONG WITH THE NOVEL APPROACHES OF NANOTECHNOLOGY-BASED DRUG DELIVERY SYSTEMS CURRENTLY USED TO TARGET INFLAMMATORY SIGNALING PATHWAYS TO COMBAT CANCER. 2022 5 4858 20 ORAL ANTIBIOTIC USE AND CHRONIC DISEASE: LONG-TERM HEALTH IMPACT BEYOND ANTIMICROBIAL RESISTANCE AND CLOSTRIDIOIDES DIFFICILE. WE RECENTLY REPORTED AN INCREASED COLON CANCER RISK ASSOCIATED WITH ORAL ANTIBIOTIC USE IN A LARGE UNITED KINGDOM POPULATION. THIS ASSOCIATION BETWEEN ANTIBIOTIC EXPOSURE AND CANCER RISK ADDS TO A GROWING BODY OF EVIDENCE THAT ANTIBIOTIC USE HAS UNINTENDED OFF-TARGET LONG-TERM HEALTH CONSEQUENCES. THIS ADDENDUM HIGHLIGHTS MAJOR STUDIES LINKING ANTIBIOTIC USE AND CHRONIC DISEASE IN PEDIATRIC AND ADULT POPULATIONS. MICROBIOTA DYSBIOSIS IS THE KEY PROPOSED MECHANISM UNDERLYING ANTIBIOTIC:DISEASE ASSOCIATIONS, RESULTING IN ALTERATIONS IN GENE EXPRESSION, EPIGENETIC MODIFICATION, COLONIZATION BY PATHOGENIC BACTERIA, INSTIGATION OF BIOFILMS, AND IMMUNE REGULATION AND INFLAMMATION. THESE ADVERSE OUTCOMES OF ANTIBIOTIC EXPOSURE UNDERSCORE THE NEED FOR DIAGNOSTIC AND ANTIBIOTIC STEWARDSHIP, AS WELL AS THE URGENCY FOR FURTHER DEVELOPMENT OF NON-ANTIBIOTIC THERAPIES FOR BACTERIAL INFECTIONS. 2020 6 3927 26 LIVER ABNORMALITIES AFTER ELIMINATION OF HCV INFECTION: PERSISTENT EPIGENETIC AND IMMUNOLOGICAL PERTURBATIONS POST-CURE. CHRONIC HEPATITIS C (CHC) IS A MAJOR CAUSE OF HEPATOCELLULAR CARCINOMA (HCC) WORLDWIDE. WHILE DIRECTLY ACTING ANTIVIRAL (DAA) DRUGS ARE NOW ABLE TO CURE VIRTUALLY ALL HEPATITIS C VIRUS (HCV) INFECTIONS, EVEN IN SUBJECTS WITH ADVANCED LIVER DISEASE, WHAT HAPPENS TO THE LIVER AND PROGRESSION OF THE DISEASE AFTER DAA-INDUCED CURE OF VIREMIA IS ONLY BEGINNING TO EMERGE. SEVERAL LARGE-SCALE CLINICAL STUDIES IN DIFFERENT PATIENT POPULATIONS HAVE SHOWN THAT PATIENTS WITH ADVANCED LIVER DISEASE MAINTAIN A RISK FOR DEVELOPING HCC EVEN WHEN THE ORIGINAL INSTIGATOR, THE VIRUS, IS ELIMINATED BY DAAS. HERE WE REVIEW EMERGING STUDIES DERIVED FROM MULTIPLE, COMPLEMENTARY EXPERIMENTAL SYSTEMS INVOLVING PATIENT LIVER TISSUES, HUMAN LIVER CELL CULTURES, HUMAN LIVER SLICE CULTURES, AND ANIMAL MODELS, SHOWING THAT HCV INFECTION INDUCES EPIGENETIC, SIGNALING, AND GENE EXPRESSION CHANGES IN THE LIVER ASSOCIATED WITH ALTERED HEPATIC INNATE IMMUNITY AND LIVER CANCER RISK. OF CRITICAL IMPORTANCE IS THE FACT THAT THESE VIRUS-INDUCED ABNORMALITIES PERSIST AFTER DAA CURE OF HCV. THESE NASCENT FINDINGS PORTEND THE DISCOVERY OF PATHWAYS INVOLVED IN POST-HCV IMMUNOPATHOGENESIS, WHICH MAY BE CLINICALLY ACTIONABLE TARGETS FOR MORE COMPREHENSIVE CARE OF DAA-CURED INDIVIDUALS. 2021 7 2334 23 EPIGENETIC REGULATION OF INFLAMMATORY CYTOKINE-INDUCED EPITHELIAL-TO-MESENCHYMAL CELL TRANSITION AND CANCER STEM CELL GENERATION. THE NEOPLASTIC TRANSFORMATION OF NORMAL TO METASTATIC CANCER CELLS IS A COMPLEX MULTISTEP PROCESS INVOLVING THE PROGRESSIVE ACCUMULATION OF INTERACTING GENETIC AND EPIGENETIC CHANGES THAT ALTER GENE FUNCTION AND AFFECT CELL PHYSIOLOGY AND HOMEOSTASIS. EPIGENETIC CHANGES INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND CHANGES IN NONCODING RNA EXPRESSION, AND DEREGULATION OF EPIGENETIC PROCESSES CAN ALTER GENE EXPRESSION DURING THE MULTISTEP PROCESS OF CARCINOGENESIS. CANCER PROGRESSION AND METASTASIS THROUGH AN 'INVASION-METASTASIS CASCADE' INVOLVING AN EPITHELIAL-TO-MESENCHYMAL CELL TRANSITION (EMT), THE GENERATION OF CANCER STEM CELLS (CSCS), INVASION OF ADJACENT TISSUES, AND DISSEMINATION ARE FUELED BY INFLAMMATION, WHICH IS CONSIDERED A HALLMARK OF CANCER. CHRONIC INFLAMMATION IS GENERATED BY INFLAMMATORY CYTOKINES SECRETED BY THE TUMOR AND THE TUMOR-ASSOCIATED CELLS WITHIN THE TUMOR MICROENVIRONMENT. INFLAMMATORY CYTOKINE SIGNALING INITIATES SIGNALING PATHWAYS LEADING TO THE ACTIVATION OF MASTER TRANSCRIPTION FACTORS (TFS) SUCH AS SMADS, STAT3, AND NF-KAPPAB. MOREOVER, THE SAME INFLAMMATORY RESPONSES ALSO ACTIVATE EMT-INDUCING TF (EMT-TF) FAMILIES SUCH AS SNAIL, TWIST, AND ZEB, AND EPIGENETIC REGULATORS INCLUDING DNA AND HISTONE MODIFYING ENZYMES AND MICORNAS, THROUGH COMPLEX INTERCONNECTED POSITIVE AND NEGATIVE FEEDBACK LOOPS TO REGULATE EMT AND CSC GENERATION. HERE, WE REVIEW THE MOLECULAR REGULATORY FEEDBACK LOOPS AND NETWORKS INVOLVED IN INFLAMMATORY CYTOKINE-INDUCED EMT AND CSC GENERATION. 2019 8 3116 20 GEROSCIENCE: ADDRESSING THE MISMATCH BETWEEN ITS EXCITING RESEARCH OPPORTUNITIES, ITS ECONOMIC IMPERATIVE AND ITS CURRENT FUNDING CRISIS. THERE IS AT PRESENT A HUGE DISCONNECT BETWEEN LEVELS OF FUNDING FOR BASIC RESEARCH ON FUNDAMENTAL MECHANISMS OF BIOLOGICAL AGING AND, GIVEN DEMOGRAPHIC PROJECTIONS, THE ANTICIPATED ENORMOUS SOCIAL AND ECONOMIC IMPACTS OF A LITANY OF CHRONIC DISEASES FOR WHICH AGING IS BY FAR THE MAJOR RISK FACTOR: ONE VALUABLE APPROACH, RECENTLY INSTIGATED BY FELIPE SIERRA & COLLEAGUES AT THE US NATIONAL INSTITUTE ON AGING, IS THE DEVELOPMENT OF A GEROSCIENCE INTEREST GROUP AMONG VIRTUALLY ALL OF THE NIH INSTITUTES. A COMPLEMENTARY APPROACH WOULD BE TO SEEK MAJOR ESCALATIONS OF PRIVATE FUNDING. THE AMERICAN FEDERATION FOR AGING RESEARCH, THE PAUL GLENN FOUNDATION AND THE ELLISON MEDICAL FOUNDATION PIONEERED EFFORTS BY THE PRIVATE SECTOR TO PROVIDE SUBSTANTIAL SUPPLEMENTS TO PUBLIC SOURCES OF FUNDING. IT IS TIME FOR OUR COMMUNITY TO ORGANIZE EFFORTS TOWARDS THE ENHANCEMENTS OF SUCH CRUCIAL CONTRIBUTIONS, ESPECIALLY IN SUPPORT OF THE EMERGING GENERATION OF YOUNG INVESTIGATORS, MANY OF WHOM ARE LEAVING OUR RANKS TO SEEK ALTERNATIVE EMPLOYMENT. TO DO SO, WE MUST PROVIDE POTENTIAL DONORS WITH STRONG ECONOMIC, HUMANITARIAN AND SCIENTIFIC RATIONALES. AN INITIAL APPROACH TO SUCH EFFORTS IS BRIEFLY OUTLINED IN THIS MANUSCRIPT AS A BASIS FOR WIDER DISCUSSIONS WITHIN OUR COMMUNITY. 2017 9 1255 22 CURRENT STATUS OF NOVEL ANTIFIBROTIC THERAPIES IN PATIENTS WITH CHRONIC LIVER DISEASE. FIBROSIS ACCUMULATION IS A DYNAMIC PROCESS RESULTING FROM A WOUND-HEALING RESPONSE TO ACUTE OR CHRONIC LIVER INJURY OF ALL CAUSES. THE CASCADE STARTS WITH HEPATOCYTE NECROSIS AND APOPTOSIS, WHICH INSTIGATE INFLAMMATORY SIGNALING BY CHEMOKINES AND CYTOKINES, RECRUITMENT OF IMMUNE CELL POPULATIONS, AND ACTIVATION OF FIBROGENIC CELLS, CULMINATING IN THE DEPOSITION OF EXTRACELLULAR MATRIX. THESE KEY ELEMENTS, ALONG WITH PATHWAYS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION, REPRESENT FERTILE THERAPEUTIC TARGETS. NEW THERAPIES INCLUDE DRUGS SPECIFICALLY DESIGNED AS ANTIFIBROTICS, AS WELL AS DRUGS ALREADY AVAILABLE WITH WELL-ESTABLISHED SAFETY PROFILES, WHOSE MECHANISM OF ACTION MAY ALSO BE ANTIFIBROTIC. AT THE SAME TIME, THE DEVELOPMENT OF NONINVASIVE FIBROGENIC MARKERS, AND TECHNIQUES (E.G. FIBROSCAN), AS WELL AS COMBINED SCORING SYSTEMS INCORPORATING SERUM AND CLINICAL FEATURES WILL ALLOW IMPROVED ASSESSMENT OF THERAPY RESPONSE. IN AGGREGATE, THE ADVANCES IN THE ELUCIDATION OF THE BIOLOGY OF FIBROSIS, COMBINED WITH IMPROVED TECHNOLOGIES FOR ASSESSMENT WILL PROVIDE A COMPREHENSIVE FRAMEWORK FOR DESIGN OF ANTIFIBROTICS AND THEIR ANALYSIS IN WELL-DESIGNED CLINICAL TRIALS. THESE EFFORTS MAY ULTIMATELY YIELD SUCCESS IN HALTING THE PROGRESSION OF, OR REVERSING, LIVER FIBROSIS. 2011 10 2241 29 EPIGENETIC MODULATION IN PERIODONTITIS: INTERACTION OF ADIPONECTIN AND JMJD3-IRF4 AXIS IN MACROPHAGES. EMERGING EVIDENCE SUGGESTS AN IMPORTANT ROLE FOR EPIGENETIC MECHANISMS IN MODULATING SIGNALS DURING MACROPHAGE POLARIZATION AND INFLAMMATION. JMJD3, A JMJC FAMILY HISTONE DEMETHYLASE NECESSARY FOR M2 POLARIZATION IS ALSO REQUIRED FOR EFFECTIVE INDUCTION OF MULTIPLE M1 GENES BY LIPOPOLYSACCHARIDE (LPS). HOWEVER, THE EFFECTS OF JMJD3 TO INFLAMMATION IN THE CONTEXT OF OBESITY REMAINS UNKNOWN. TO ADDRESS THIS DEFICIENCY, WE FIRSTLY EXAMINED THE EXPRESSION OF JMJD3 IN MACROPHAGE ISOLATED FROM BONE MARROW AND ADIPOSE TISSUE OF DIET INDUCED OBESITY (DIO) MICE. THE RESULTS INDICATED THAT JMJD3 WAS DOWN-REGULATED IN OBESITY. ADIPONECTIN (APN), A FACTOR SECRETED BY ADIPOSE TISSUE WHICH IS DOWN-REGULATED IN OBESITY, FUNCTIONS TO SWITCH MACROPHAGE POLARIZATION FROM M1 TO M2, THEREBY ATTENUATING CHRONIC INFLAMMATION. INTRIGUINGLY, OUR RESULTS INDICATED THAT APN CONTRIBUTED TO JMJD3 UP-REGULATION, REDUCED MACROPHAGE INFILTRATION IN OBESE ADIPOSE TISSUE, AND ABOLISHED THE UP-REGULATION OF JMJD3 IN PERITONEAL MACROPHAGES ISOLATED FROM DIO MICE WHEN CHALLENGED WITH PORPHYROMONAS GINGIVALIS LPS (PG.LPS). TO ELUCIDATE THE INTERACTION OF APN AND JMJD3 INVOLVED IN MACROPHAGE TRANSFORMATION IN THE CONTEXT OF INFLAMMATION, WE DESIGNED THE LOSS AND GAIN-FUNCTION EXPERIMENTS OF APN IN VIVO WITH APN(-/-) MICE WITH EXPERIMENTAL PERIODONTITIS AND IN VITRO WITH MACROPHAGE ISOLATED FROM APN(-/-) MICE. FOR THE FIRST TIME, WE FOUND THAT APN CAN HELP TO REDUCE PERIODONTITIS-RELATED BONE LOSS, MODULATE JMJD3 AND IRF4 EXPRESSION, AND MACROPHAGE INFILTRATION. THEREFORE, IT CAN BE INFERRED THAT APN MAY CONTRIBUTE TO ANTI-INFLAMMATION MACROPHAGE POLARIZATION BY REGULATING JMJD3 EXPRESSION, WHICH PROVIDES A BASIS FOR MACROPHAGE-CENTERED EPIGENETIC THERAPEUTIC STRATEGIES. 2016 11 4749 20 NOVEL PROSPECTS FOR SCARLESS WOUND HEALING: THE ROLES OF MYOFIBROBLASTS AND ADIPOCYTES. DISTURBANCES OR DEFECTS IN THE PROCESS OF WOUND REPAIR CAN DISRUPT THE DELICATE BALANCE OF CELLS AND MOLECULES NECESSARY FOR COMPLETE WOUND HEALING, THUS LEADING TO CHRONIC WOUNDS OR FIBROTIC SCARS. MYOFIBROBLASTS ARE ONE OF THE MOST IMPORTANT CELLS INVOLVED IN FIBROTIC SCARS, AND REPROGRAMMING PROVIDES A POTENTIAL AVENUE TO INCREASE MYOFIBROBLAST CLEARANCE. ALTHOUGH MYOFIBROBLASTS HAVE LONG BEEN RECOGNIZED AS TERMINALLY DIFFERENTIATED CELLS, RECENT STUDIES HAVE SHOWN THAT MYOFIBROBLASTS HAVE THE CAPACITY TO BE REPROGRAMMED INTO ADIPOCYTES. THIS REVIEW INTENDS TO SUMMARIZE THE POTENTIAL OF REPROGRAMMING MYOFIBROBLASTS INTO ADIPOCYTES. WE WILL DISCUSS MYOFIBROBLAST LINEAGE TRACING, AS WELL AS THE KNOWN MECHANISMS UNDERLYING ADIPOCYTE REGENERATION FROM MYOFIBROBLASTS. IN ADDITION, WE INVESTIGATED DIFFERENT CHANGES IN MYOFIBROBLAST GENE EXPRESSION, TRANSCRIPTIONAL REGULATORS, SIGNALLING PATHWAYS AND EPIGENETIC REGULATORS DURING SKIN WOUND HEALING. IN THE FUTURE, MYOFIBROBLAST REPROGRAMMING IN WOUND HEALING WILL BE BETTER UNDERSTOOD AND APPRECIATED, WHICH MAY PROVIDE NEW IDEAS FOR THE TREATMENT OF SCARLESS WOUND HEALING. 2022 12 5736 13 SMOKE-INDUCED CHANGES TO THE EPIGENOME PROVIDE FERTILE GROUND FOR ONCOGENIC MUTATION. HOW GENETIC AND EPIGENETIC EVENTS SYNERGIZE TO GENERATE THE ONCOGENIC STATE IS NOT WELL UNDERSTOOD. IN THIS ISSUE OF CANCER CELL, VAZ ET AL. PROVIDE COMPELLING EVIDENCE THAT EXPOSURE TO CHRONIC CIGARETTE SMOKE CAUSES PROGRESSIVE EPIGENETIC ALTERATIONS THAT PRIME FOR KEY GENETIC EVENTS TO DRIVE THE DEVELOPMENT OF LUNG CANCER. 2017 13 2545 29 EPIGENETICS IN LIVER FIBROSIS: COULD HDACS BE A THERAPEUTIC TARGET? CHRONIC LIVER DISEASES (CLD) REPRESENT A WORLDWIDE HEALTH PROBLEM. WHILE CLDS MAY HAVE DIVERSE ETIOLOGIES, A COMMON PATHOGENIC DENOMINATOR IS THE PRESENCE OF LIVER FIBROSIS. CIRRHOSIS, THE END-STAGE OF CLD, IS CHARACTERIZED BY EXTENSIVE FIBROSIS AND IS MARKEDLY ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. THE MOST IMPORTANT EVENT IN HEPATIC FIBROGENESIS IS THE ACTIVATION OF HEPATIC STELLATE CELLS (HSC) FOLLOWING LIVER INJURY. ACTIVATED HSCS ACQUIRE A MYOFIBROBLAST-LIKE PHENOTYPE BECOMING PROLIFERATIVE, FIBROGENIC, AND CONTRACTILE CELLS. WHILE TRANSIENT ACTIVATION OF HSCS IS PART OF THE PHYSIOLOGICAL MECHANISMS OF TISSUE REPAIR, PROTRACTED ACTIVATION OF A WOUND HEALING REACTION LEADS TO ORGAN FIBROSIS. THE PHENOTYPIC CHANGES OF ACTIVATED HSCS INVOLVE EPIGENETIC MECHANISMS MEDIATED BY NON-CODING RNAS (NCRNA) AS WELL AS BY CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS. DURING CLD THESE EPIGENETIC MECHANISMS BECOME DEREGULATED, WITH ALTERATIONS IN THE EXPRESSION AND ACTIVITY OF EPIGENETIC MODULATORS. HERE WE PROVIDE AN OVERVIEW OF THE EPIGENETIC ALTERATIONS INVOLVED IN FIBROGENIC HSCS TRANSDIFFERENTIATION WITH PARTICULAR FOCUS ON HISTONES ACETYLATION CHANGES. WE ALSO DISCUSS RECENT STUDIES SUPPORTING THE PROMISING THERAPEUTIC POTENTIAL OF HISTONE DEACETYLASE INHIBITORS IN LIVER FIBROSIS. 2020 14 2322 20 EPIGENETIC REGULATION OF HEPATIC STELLATE CELL ACTIVATION AND LIVER FIBROSIS. CHRONIC LIVER INJURY TO HEPATOCYTES OR CHOLANGIOCYTES, WHEN LEFT UNMANAGED, LEADS TO THE DEVELOPMENT OF LIVER FIBROSIS, A CONDITION CHARACTERIZED BY THE EXCESSIVE INTRAHEPATIC DEPOSITION OF EXTRACELLULAR MATRIX PROTEINS. ACTIVATED HEPATIC STELLATE CELLS CONSTITUTE THE PREDOMINANT SOURCE OF EXTRACELLULAR MATRIX IN FIBROTIC LIVERS AND THEIR TRANSITION FROM A QUIESCENT STATE DURING FIBROGENESIS IS ASSOCIATED WITH IMPORTANT ALTERATIONS IN THEIR TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPE. AREAS COVERED: WE BRIEFLY DESCRIBE THE PROCESSES INVOLVED IN HEPATIC STELLATE CELL ACTIVATION AND DISCUSS OUR CURRENT UNDERSTANDING OF ALTERATIONS IN THE EPIGENETIC LANDSCAPE, I.E DNA METHYLATION, HISTONE MODIFICATIONS AND THE FUNCTIONAL ROLE OF NON-CODING RNAS THAT ACCOMPANY THIS KEY EVENT IN THE DEVELOPMENT OF CHRONIC LIVER DISEASE. EXPERT COMMENTARY: ALTHOUGH GREAT PROGRESS HAS BEEN MADE, OUR UNDERSTANDING OF THE EPIGENETIC REGULATION OF HEPATIC STELLATE CELL ACTIVATION IS LIMITED AND, THUS FAR, INSUFFICIENT TO ALLOW THE DEVELOPMENT OF EPIGENETIC DRUGS THAT CAN SELECTIVELY INTERRUPT LIVER FIBROSIS. 2016 15 2686 13 EVIDENCE FOR THE INVOLVEMENT OF EPIGENETICS IN THE PROGRESSION OF RENAL FIBROGENESIS. EPIGENETICS ARE OMNIPRESENT IN EUKARYOTIC CELLS AND INFLUENCE CELL DIFFERENTIATION AND MAINTENANCE OF CELL METABOLISM IN HEALTH AND DISEASE. HERE, WE DISCUSS HOW THE 'SECOND GENETIC CODE' IMPACTS THE FATE OF THE INJURED KIDNEY. WE PROVIDE A GLIMPSE OF HOW RECENT INSIGHTS INTO EPIGENETIC MECHANISMS OF CHRONIC KIDNEY DISEASE MIGHT LEAD TO NOVEL DIAGNOSTIC AND THERAPEUTIC TOOLS. 2014 16 3245 17 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 17 6882 10 [RESEARCH PROGRESS ON NON-CODING RNAS IN THE MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. PRIMARY LIVER CANCER ARISES FROM CHRONIC LIVER DISEASE, AND CIRRHOTIC LIVER GRADUALLY DEVELOPS INTO DYSPLASTIC NODULES THAT EVENTUALLY FORM MALIGNANT TUMORS. IN RECENT YEARS, MOLECULAR BIOTECHNOLOGY DEVELOPMENT HAS DEEPENED PEOPLE'S UNDERSTANDING ON THE PATHOGENESIS OF LIVER CANCER. EPIGENETIC MODIFICATIONS PLAY A SIGNIFICANT ROLE IN DNA METHYLATION, NON-CODING RNAS, CHROMATIN REMODELING, AND HISTONE MODIFICATION. THIS REVIEW FOCUSES ON THE PROGRESS OF CURRENTLY IMPLICATED NON-CODING RNAS IN THE MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA, AND ITS POTENTIAL APPLICATION IN IMPROVING THE DIAGNOSIS AND TREATMENT. 2018 18 6053 15 THE CRUCIAL ROLE OF NLRP3 INFLAMMASOME IN VIRAL INFECTION-ASSOCIATED FIBROSING INTERSTITIAL LUNG DISEASES. IDIOPATHIC PULMONARY FIBROSIS (IPF), ONE OF THE MOST COMMON FIBROSING INTERSTITIAL LUNG DISEASES (ILD), IS A CHRONIC-AGE-RELATED RESPIRATORY DISEASE THAT RISES FROM REPEATED MICRO-INJURY OF THE ALVEOLAR EPITHELIUM. ENVIRONMENTAL INFLUENCES, INTRINSIC FACTORS, GENETIC AND EPIGENETIC RISK FACTORS THAT LEAD TO CHRONIC INFLAMMATION MIGHT BE IMPLICATED IN THE DEVELOPMENT OF IPF. THE EXACT TRIGGERS THAT INITIATE THE FIBROTIC RESPONSE IN IPF REMAIN ENIGMATIC, BUT THERE IS NOW INCREASING EVIDENCE SUPPORTING THE ROLE OF CHRONIC EXPOSURE OF VIRAL INFECTION. DURING VIRAL INFECTION, ACTIVATION OF THE NLRP3 INFLAMMASOME BY INTEGRATING MULTIPLE CELLULAR AND MOLECULAR SIGNALING IMPLICATES ROBUST INFLAMMATION, FIBROBLAST PROLIFERATION, ACTIVATION OF MYOFIBROBLAST, MATRIX DEPOSITION, AND ABERRANT EPITHELIAL-MESENCHYMAL FUNCTION. OVERALL, THE CROSSTALK OF THE NLRP3 INFLAMMASOME AND VIRUSES CAN ACTIVATE IMMUNE RESPONSES AND INFLAMMASOME-ASSOCIATED MOLECULES IN THE DEVELOPMENT, PROGRESSION, AND EXACERBATION OF IPF. 2021 19 3581 27 IMPACT OF PHYSICAL ACTIVITY AND EXERCISE ON THE EPIGENOME IN SKELETAL MUSCLE AND EFFECTS ON SYSTEMIC METABOLISM. EXERCISE AND PHYSICAL ACTIVITY INDUCES PHYSIOLOGICAL RESPONSES IN ORGANISMS, AND ADAPTATIONS IN SKELETAL MUSCLE, WHICH IS BENEFICIAL FOR MAINTAINING HEALTH AND PREVENTING AND/OR TREATING MOST CHRONIC DISEASES. THESE ADAPTATIONS ARE MAINLY INSTIGATED BY TRANSCRIPTIONAL RESPONSES THAT ENSUE IN REACTION TO EACH INDIVIDUAL EXERCISE, EITHER RESISTANCE OR ENDURANCE. CONSEQUENTLY, CHANGES IN KEY METABOLIC, REGULATORY, AND MYOGENIC GENES IN SKELETAL MUSCLE OCCUR AS BOTH AN EARLY AND LATE RESPONSE TO EXERCISE, AND THESE EPIGENETIC MODIFICATIONS, WHICH ARE INFLUENCED BY ENVIRONMENTAL AND GENETIC FACTORS, TRIGGER THOSE ALTERATIONS IN THE TRANSCRIPTIONAL RESPONSES. DNA METHYLATION AND HISTONE MODIFICATIONS ARE THE MOST SIGNIFICANT EPIGENETIC CHANGES DESCRIBED IN GENE TRANSCRIPTION, LINKED TO THE SKELETAL MUSCLE TRANSCRIPTIONAL RESPONSE TO EXERCISE, AND MEDIATING THE EXERCISE ADAPTATIONS. NEVERTHELESS, OTHER ALTERATIONS IN THE EPIGENETICS MARKERS, SUCH AS EPITRANSCRIPTOMICS, MODIFICATIONS MEDIATED BY MIRNAS, AND LACTYLATION AS A NOVEL EPIGENETIC MODIFICATION, ARE EMERGING AS KEY EVENTS FOR GENE TRANSCRIPTION. HERE, WE PROVIDE AN OVERVIEW AND UPDATE OF THE IMPACT OF EXERCISE ON EPIGENETIC MODIFICATIONS, INCLUDING THE WELL-DESCRIBED DNA METHYLATIONS AND HISTONE MODIFICATIONS, AND THE EMERGING MODIFICATIONS IN THE SKELETAL MUSCLE. IN ADDITION, WE DESCRIBE THE EFFECTS OF EXERCISE ON EPIGENETIC MARKERS IN OTHER METABOLIC TISSUES; ALSO, WE PROVIDE INFORMATION ABOUT HOW SYSTEMIC METABOLISM OR ITS METABOLITES INFLUENCE EPIGENETIC MODIFICATIONS IN THE SKELETAL MUSCLE. 2022 20 3628 20 INACTIVATION OF NUCLEAR HISTONE DEACETYLASES BY EP300 DISRUPTS THE MICEE COMPLEX IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE, AND HIGHLY LETHAL LUNG DISEASE WITH UNKNOWN ETIOLOGY AND POOR PROGNOSIS. IPF PATIENTS DIE WITHIN 2 YEARS AFTER DIAGNOSIS MOSTLY DUE TO RESPIRATORY FAILURE. CURRENT TREATMENTS AGAINST IPF AIM TO AMELIORATE PATIENT SYMPTOMS AND TO DELAY DISEASE PROGRESSION. UNFORTUNATELY, THERAPIES TARGETING THE CAUSES OF OR REVERTING IPF HAVE NOT YET BEEN DEVELOPED. HERE WE SHOW THAT REDUCED LEVELS OF MIRNA LETHAL 7D (MIRLET7D) IN IPF COMPROMISE EPIGENETIC GENE SILENCING MEDIATED BY THE RIBONUCLEOPROTEIN COMPLEX MICEE. IN ADDITION, WE FIND THAT HYPERACTIVE EP300 REDUCES NUCLEAR HDAC ACTIVITY AND INTERFERES WITH MICEE FUNCTION IN IPF. REMARKABLY, EP300 INHIBITION REDUCES FIBROTIC HALLMARKS OF IN VITRO (PATIENT-DERIVED PRIMARY FIBROBLAST), IN VIVO (BLEOMYCIN MOUSE MODEL), AND EX VIVO (PRECISION-CUT LUNG SLICES, PCLS) IPF MODELS. OUR WORK PROVIDES THE MOLECULAR BASIS FOR THERAPIES AGAINST IPF USING EP300 INHIBITION. 2019