1 66 117 A KEY ROLE FOR EZH2 IN EPIGENETIC SILENCING OF HOX GENES IN MANTLE CELL LYMPHOMA. THE CHROMATIN MODIFIER EZH2 IS OVEREXPRESSED AND ASSOCIATED WITH INFERIOR OUTCOME IN MANTLE CELL LYMPHOMA (MCL). RECENTLY, WE DEMONSTRATED PREFERENTIAL DNA METHYLATION OF HOX GENES IN MCL COMPARED WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), DESPITE THESE GENES NOT BEING EXPRESSED IN EITHER ENTITY. SINCE EZH2 HAS BEEN SHOWN TO REGULATE HOX GENE EXPRESSION, TO GAIN FURTHER INSIGHT INTO ITS POSSIBLE ROLE IN DIFFERENTIAL SILENCING OF HOX GENES IN MCL VS. CLL, WE PERFORMED DETAILED EPIGENETIC CHARACTERIZATION USING REPRESENTATIVE CELL LINES AND PRIMARY SAMPLES. WE OBSERVED SIGNIFICANT OVEREXPRESSION OF EZH2 IN MCL VS. CLL. CHROMATIN IMMUNE PRECIPITATION (CHIP) ASSAYS REVEALED THAT EZH2 CATALYZED REPRESSIVE H3 LYSINE 27 TRIMETHYLATION (H3K27ME3), WHICH WAS SUFFICIENT TO SILENCE HOX GENES IN CLL, WHEREAS IN MCL H3K27ME3 IS ACCOMPANIED BY DNA METHYLATION FOR A MORE STABLE REPRESSION. MORE IMPORTANTLY, HYPERMETHYLATION OF THE HOX GENES IN MCL RESULTED FROM EZH2 OVEREXPRESSION AND SUBSEQUENT RECRUITMENT OF THE DNA METHYLATION MACHINERY ONTO HOX GENE PROMOTERS. THE IMPORTANCE OF EZH2 UPREGULATION IN THIS PROCESS WAS FURTHER UNDERSCORED BY SIRNA TRANSFECTION AND EZH2 INHIBITOR EXPERIMENTS. ALTOGETHER, THESE OBSERVATIONS IMPLICATE EZH2 IN THE LONG-TERM SILENCING OF HOX GENES IN MCL, AND ALLUDE TO ITS POTENTIAL AS A THERAPEUTIC TARGET WITH CLINICAL IMPACT. 2013 2 5003 33 PERIODONTITIS IS AN INFLAMMATORY DISEASE OF OXIDATIVE STRESS: WE SHOULD TREAT IT THAT WAY. PERIODONTITIS IS A HIGHLY PREVALENT DISEASE. AS IT PROGRESSES, IT CAUSES SERIOUS MORBIDITY IN THE FORM OF PERIODONTAL ABSCESSES AND TOOTH LOSS AND, IN THE LATTER STAGES, PAIN. IT IS ALSO NOW KNOWN THAT PERIODONTITIS IS STRONGLY ASSOCIATED WITH SEVERAL NONORAL DISEASES. THUS, PATIENTS WITH PERIODONTITIS ARE AT GREATER RISK FOR THE DEVELOPMENT AND/OR EXACERBATION OF DIABETES, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND CARDIOVASCULAR DISEASES, AMONG OTHER CONDITIONS. ALTHOUGH IT IS WITHOUT QUESTION THAT SPECIFIC GROUPS OF ORAL BACTERIA WHICH POPULATE DENTAL PLAQUE PLAY A CAUSATIVE ROLE IN THE DEVELOPMENT OF PERIODONTITIS, IT IS NOW THOUGHT THAT ONCE THIS DISEASE HAS BEEN TRIGGERED, OTHER FACTORS PLAY AN EQUAL, AND POSSIBLY MORE IMPORTANT, ROLE IN ITS PROGRESSION, PARTICULARLY IN SEVERE CASES OR IN CASES THAT PROVE DIFFICULT TO TREAT. IN THIS REGARD, WE ALLUDE TO THE HOST RESPONSE, SPECIFICALLY THE NOTION THAT THE HOST, ONCE INFECTED WITH ORAL PERIODONTAL PATHOGENIC BACTERIA, WILL MOUNT A DEFENSE RESPONSE MEDIATED LARGELY THROUGH THE INNATE IMMUNE SYSTEM. THE MOST ABUNDANT CELL TYPE OF THE INNATE IMMUNE SYSTEM - POLYMORPHONUCLEAR NEUTROPHILS - CAN, WHEN PROTECTING THE HOST FROM MICROBIAL INVASION, MOUNT A RESPONSE THAT INCLUDES UPREGULATION OF PROINFLAMMATORY CYTOKINES, MATRIX METALLOPROTEINASES, AND REACTIVE OXYGEN SPECIES, ALL OF WHICH THEN CONTRIBUTE TO THE TISSUE DAMAGE AND LOSS OF TEETH COMMONLY ASSOCIATED WITH PERIODONTITIS. OF THE MECHANISMS REFERRED TO HERE, WE SUGGEST THAT UPREGULATION OF REACTIVE OXYGEN SPECIES MIGHT PLAY ONE OF THE MOST IMPORTANT ROLES IN THE ESTABLISHMENT AND PROGRESSION OF PERIODONTITIS (AS WELL AS IN OTHER DISEASES OF INFLAMMATION) THROUGH THE DEVELOPMENT OF OXIDATIVE STRESS. IN THIS OVERVIEW, WE DISCUSS BOTH INNATE AND EPIGENETIC FACTORS (EG, DIABETES, SMOKING) THAT LEAD TO THE DEVELOPMENT OF OXIDATIVE STRESS. THIS OXIDATIVE STRESS THEN PROVIDES AN ENVIRONMENT CONDUCIVE TO THE DESTRUCTIVE PROCESSES OBSERVED IN PERIODONTITIS. THEREFORE, WE SHALL DESCRIBE SOME OF THE FUNDAMENTAL CHARACTERISTICS OF OXIDATIVE STRESS AND ITS EFFECTS ON THE PERIODONTIUM, DISCUSS THE DISEASES AND OTHER FACTORS THAT CAUSE OXIDATIVE STRESS, AND, FINALLY, REVIEW POTENTIALLY NOVEL THERAPEUTIC APPROACHES FOR THE MANAGEMENT (AND POSSIBLY EVEN THE REVERSAL) OF PERIODONTITIS, WHICH RELY ON THE USE OF THERAPIES, SUCH AS RESVERATROL AND OTHER ANTIOXIDANTS, THAT PROVIDE INCREASED ANTIOXIDANT ACTIVITY IN THE HOST. 2020 3 6580 22 TREPONEMA DENTICOLA INCREASES MMP-2 EXPRESSION AND ACTIVATION IN THE PERIODONTIUM VIA REVERSIBLE DNA AND HISTONE MODIFICATIONS. HOST-DERIVED MATRIX METALLOPROTEINASES (MMPS) AND BACTERIAL PROTEASES MEDIATE DESTRUCTION OF EXTRACELLULAR MATRICES AND SUPPORTING ALVEOLAR BONE IN PERIODONTITIS. THE TREPONEMA DENTICOLA DENTILISIN PROTEASE INDUCES MMP-2 EXPRESSION AND ACTIVATION IN PERIODONTAL LIGAMENT (PDL) CELLS, AND DENTILISIN-MEDIATED ACTIVATION OF PRO-MMP-2 IS REQUIRED FOR CELLULAR FIBRONECTIN DEGRADATION. HERE, WE REPORT THAT T. DENTICOLA REGULATES MMP-2 EXPRESSION THROUGH EPIGENETIC MODIFICATIONS IN THE PERIODONTIUM. PDL CELLS WERE TREATED WITH EPIGENETIC ENZYME INHIBITORS BEFORE OR AFTER T. DENTICOLA CHALLENGE. FIBRONECTIN FRAGMENTATION, MMP-2 EXPRESSION, AND ACTIVATION WERE ASSESSED BY IMMUNOBLOT, ZYMOGRAPHY, AND QRT-PCR, RESPECTIVELY. CHROMATIN MODIFICATION ENZYME EXPRESSION IN T. DENTICOLA-CHALLENGED PDL CELLS AND PERIODONTAL TISSUES WERE EVALUATED USING GENE ARRAYS. SEVERAL CLASSES OF EPIGENETIC ENZYMES SHOWED SIGNIFICANT ALTERATIONS IN TRANSCRIPTION IN DISEASED TISSUE AND T. DENTICOLA-CHALLENGED PDL CELLS. T. DENTICOLA-MEDIATED MMP-2 EXPRESSION AND ACTIVATION WERE SIGNIFICANTLY REDUCED IN PDL CELLS TREATED WITH INHIBITORS OF AURORA KINASES AND HISTONE DEACETYLASES. IN CONTRAST, DNA METHYLTRANSFERASE INHIBITORS HAD LITTLE EFFECT, AND INHIBITORS OF HISTONE ACETYLTRANSFERASES, METHYLTRANSFERASES, AND DEMETHYLASES EXACERBATED T. DENTICOLA-MEDIATED MMP-2 EXPRESSION AND ACTIVATION. CHRONIC EPIGENETIC CHANGES IN PERIODONTAL TISSUES MEDIATED BY T. DENTICOLA OR OTHER ORAL MICROBES MAY CONTRIBUTE TO THE LIMITED SUCCESS OF CONVENTIONAL TREATMENT OF CHRONIC PERIODONTITIS AND MAY BE AMENABLE TO THERAPEUTIC REVERSAL. 2018 4 2273 30 EPIGENETIC REGULATION ALTERS BIOFILM ARCHITECTURE AND COMPOSITION IN MULTIPLE CLINICAL ISOLATES OF NONTYPEABLE HAEMOPHILUS INFLUENZAE. BIOFILMS PLAY A CRITICAL ROLE IN THE COLONIZATION, PERSISTENCE, AND PATHOGENESIS OF MANY HUMAN PATHOGENS. MULTIPLE MUCOSA-ASSOCIATED PATHOGENS HAVE EVOLVED A MECHANISM OF RAPID ADAPTATION, TERMED THE PHASEVARION, WHICH FACILITATES A COORDINATED REGULATION OF NUMEROUS GENES THROUGHOUT THE BACTERIAL GENOME. THIS EPIGENETIC REGULATION OCCURS VIA PHASE VARIATION OF A DNA METHYLTRANSFERASE, MOD. THE PHASEVARION OF NONTYPEABLE HAEMOPHILUS INFLUENZAE (NTHI) SIGNIFICANTLY AFFECTS THE SEVERITY OF EXPERIMENTAL OTITIS MEDIA AND REGULATES SEVERAL DISEASE-RELATED PROCESSES. HOWEVER, THE ROLE OF THE NTHI PHASEVARION IN BIOFILM FORMATION IS UNCLEAR. THE PRESENT STUDY SHOWS THAT THE PHASEVARIONS OF MULTIPLE NTHI CLINICAL ISOLATES REGULATE IN VITRO BIOFILM FORMATION UNDER DISEASE-SPECIFIC MICROENVIRONMENTAL CONDITIONS. THE IMPACT OF PHASEVARION REGULATION WAS GREATEST UNDER ALKALINE CONDITIONS THAT MIMIC THOSE KNOWN TO OCCUR IN THE MIDDLE EAR DURING DISEASE. UNDER ALKALINE CONDITIONS, NTHI STRAINS THAT EXPRESS THE MODA2 METHYLTRANSFERASE FORMED BIOFILMS WITH SIGNIFICANTLY GREATER BIOMASS AND LESS DISTINCT ARCHITECTURE THAN THOSE FORMED BY A MODA2-DEFICIENT POPULATION. THE BIOFILMS FORMED BY NTHI STRAINS THAT EXPRESS MODA2 ALSO CONTAINED LESS EXTRACELLULAR DNA (EDNA) AND SIGNIFICANTLY LESS EXTRACELLULAR HU, A DNABII DNA-BINDING PROTEIN CRITICAL FOR BIOFILM STRUCTURAL STABILITY. STABLE BIOFILM STRUCTURE IS CRITICAL FOR BACTERIAL PATHOGENESIS AND PERSISTENCE IN MULTIPLE EXPERIMENTAL MODELS OF DISEASE. THESE RESULTS IDENTIFY A ROLE FOR THE PHASEVARION IN REGULATION OF BIOFILM FORMATION, A PROCESS INTEGRAL TO THE CHRONIC NATURE OF MANY INFECTIONS. UNDERSTANDING THE ROLE OF THE PHASEVARION IN BIOFILM FORMATION IS CRITICAL TO THE DEVELOPMENT OF PREVENTION AND TREATMENT STRATEGIES FOR THESE CHRONIC DISEASES.IMPORTANCE UPPER RESPIRATORY TRACT INFECTIONS ARE THE NUMBER ONE REASON FOR A CHILD TO VISIT THE EMERGENCY DEPARTMENT, AND OTITIS MEDIA (MIDDLE EAR INFECTION) RANKS THIRD OVERALL. BIOFILMS CONTRIBUTE SIGNIFICANTLY TO THE CHRONIC NATURE OF BACTERIAL RESPIRATORY TRACT INFECTIONS, INCLUDING OTITIS MEDIA, AND MAKE THESE DISEASES PARTICULARLY DIFFICULT TO TREAT. SEVERAL MUCOSA-ASSOCIATED HUMAN PATHOGENS UTILIZE A MECHANISM OF RAPID ADAPTATION TERMED THE PHASEVARION, OR PHASEVARIABLE REGULON, TO RESIST ENVIRONMENTAL AND HOST IMMUNE PRESSURES. IN THIS STUDY, WE ASSESSED THE ROLE OF THE PHASEVARION IN REGULATION OF BIOFILM FORMATION BY NONTYPEABLE HAEMOPHILUS INFLUENZAE (NTHI), WHICH CAUSES NUMEROUS RESPIRATORY TRACT DISEASES. WE FOUND THAT THE NTHI PHASEVARION REGULATES BIOFILM STRUCTURE AND CRITICAL BIOFILM MATRIX COMPONENTS UNDER DISEASE-SPECIFIC CONDITIONS. THE FINDINGS OF THIS WORK COULD BE SIGNIFICANT IN THE DESIGN OF IMPROVED STRATEGIES AGAINST NTHI INFECTIONS, AS WELL AS DISEASES DUE TO OTHER PATHOGENS THAT UTILIZE A PHASEVARION. 2018 5 940 29 CHRONIC LYMPHOCYTIC LEUKEMIA AND MANTLE CELL LYMPHOMA: CROSSROADS OF GENETIC AND MICROENVIRONMENT INTERACTIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND MANTLE CELL LYMPHOMA (MCL) ARE 2 WELL-DEFINED ENTITIES THAT DIVERGE IN THEIR BASIC PATHOGENIC MECHANISMS AND CLINICAL EVOLUTION BUT THEY SHARE EPIDEMIOLOGICAL CHARACTERISTICS, CELLS OF ORIGIN, MOLECULAR ALTERATIONS, AND CLINICAL FEATURES THAT DIFFER FROM OTHER LYMPHOID NEOPLASMS. CLL AND MCL ARE CLASSICALLY CONSIDERED INDOLENT AND AGGRESSIVE NEOPLASMS, RESPECTIVELY. HOWEVER, THE CLINICAL EVOLUTION OF BOTH TUMORS IS VERY HETEROGENEOUS, WITH SUBSETS OF PATIENTS HAVING STABLE DISEASE FOR A LONG TIME WHEREAS OTHERS REQUIRE IMMEDIATE INTERVENTION. BOTH CLL AND MCL INCLUDE 2 MAJOR MOLECULAR SUBTYPES THAT SEEM TO DERIVE FROM ANTIGEN-EXPERIENCED CD5(+) B CELLS THAT RETAIN A NAIVE OR MEMORY-LIKE EPIGENETIC SIGNATURE AND CARRY A VARIABLE LOAD OF IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE REGION SOMATIC MUTATIONS FROM TRULY UNMUTATED TO HIGHLY MUTATED, RESPECTIVELY. THESE 2 SUBTYPES OF TUMORS DIFFER IN THEIR MOLECULAR PATHWAYS, GENOMIC ALTERATIONS, AND CLINICAL BEHAVIOR, BEING MORE AGGRESSIVE IN NAIVE-LIKE THAN MEMORY-LIKE-DERIVED TUMORS IN BOTH CLL AND MCL. THE PATHOGENESIS OF THE 2 ENTITIES INTEGRATES THE RELEVANT INFLUENCE OF B-CELL RECEPTOR SIGNALING, TUMOR CELL MICROENVIRONMENT INTERACTIONS, GENOMIC ALTERATIONS, AND EPIGENOME MODIFICATIONS THAT CONFIGURE THE EVOLUTION OF THE TUMORS AND OFFER NEW POSSIBILITIES FOR THERAPEUTIC INTERVENTION. THIS REVIEW WILL FOCUS ON THE SIMILARITIES AND DIFFERENCES OF THESE 2 TUMORS BASED ON RECENT STUDIES THAT ARE ENHANCING THE UNDERSTANDING OF THEIR PATHOGENESIS AND CREATING SOLID BASES FOR NEW MANAGEMENT STRATEGIES. 2018 6 465 31 ARE TARGETED THERAPIES FOR DIABETIC CARDIOMYOPATHY ON THE HORIZON? DIABETES INCREASES THE RISK OF HEART FAILURE APPROXIMATELY 2.5-FOLD, INDEPENDENT OF CORONARY ARTERY DISEASE AND OTHER COMORBIDITIES. THIS PROCESS, TERMED DIABETIC CARDIOMYOPATHY, IS CHARACTERIZED BY INITIAL IMPAIRMENT OF LEFT VENTRICULAR (LV) RELAXATION FOLLOWED BY LV CONTRACTILE DYSFUNCTION. POST-MORTEM EXAMINATION REVEALS THAT HUMAN DIASTOLIC DYSFUNCTION IS CLOSELY ASSOCIATED WITH LV DAMAGE, INCLUDING CARDIOMYOCYTE HYPERTROPHY, APOPTOSIS AND FIBROSIS, WITH IMPAIRED CORONARY MICROVASCULAR PERFUSION. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERPINNING THE CHARACTERISTIC FEATURES OF DIABETIC CARDIOMYOPATHY REMAIN POORLY UNDERSTOOD, ALTHOUGH MULTIPLE FACTORS INCLUDING ALTERED LIPID METABOLISM, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM (ER) STRESS, INFLAMMATION, AS WELL AS EPIGENETIC CHANGES, ARE IMPLICATED. DESPITE A RECENT RISE IN RESEARCH INTERROGATING THESE MECHANISMS AND AN INCREASED UNDERSTANDING OF THE CLINICAL IMPORTANCE OF DIABETIC CARDIOMYOPATHY, THERE REMAINS A LACK OF SPECIFIC TREATMENT STRATEGIES. HOW THE CHRONIC METABOLIC DISTURBANCES OBSERVED IN DIABETES LEAD TO STRUCTURAL AND FUNCTIONAL CHANGES REMAINS A PERTINENT QUESTION, AND IT IS HOPED THAT RECENT ADVANCES, PARTICULARLY IN THE AREA OF EPIGENETICS, AMONG OTHERS, MAY PROVIDE SOME ANSWERS. THIS REVIEW HENCE EXPLORES THE TEMPORAL ONSET OF THE PATHOLOGICAL FEATURES OF DIABETIC CARDIOMYOPATHY, AND THEIR RELATIVE CONTRIBUTION TO THE RESULTANT DISEASE PHENOTYPE, AS WELL AS BOTH CURRENT AND POTENTIAL THERAPEUTIC OPTIONS. THE EMERGENCE OF GLUCOSE-OPTIMIZING AGENTS, NAMELY GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS AND SODIUM/GLUCOSE CO-TRANSPORTER (SGLT)2 INHIBITORS THAT CONFER BENEFITS ON CARDIOVASCULAR OUTCOMES, TOGETHER WITH NOVEL EXPERIMENTAL APPROACHES, HIGHLIGHT A NEW AND EXCITING ERA IN DIABETES RESEARCH, WHICH IS LIKELY TO RESULT IN MAJOR CLINICAL IMPACT. 2017 7 523 28 ASSOCIATIONS BETWEEN PERIODONTITIS AND SYSTEMIC INFLAMMATORY DISEASES: RESPONSE TO TREATMENT. THERE IS A SIGNIFICANT PREVALENCE OF SUBJECTS WITH PERIODONTITIS PRESENTING WITH OTHER INFLAMMATORY CONDITIONS SUCH AS CORONARY HEART DISEASE, INSULIN RESISTANCE AND ARTHRITIS. THIS PATTERN OF DISEASE PRESENTATION UNDERSCORES THE IMPORTANCE OF INFLAMMATORY LOADING FROM CHRONIC DISEASES, IN DRIVING THEIR PATHOGENESES IN A MULTIDIRECTIONAL MANNER. PRO-INFLAMMATORY CYTOKINES AND OTHER AGENTS PLAY AN IMPORTANT ROLE IN THIS PROCESS; FOR EXAMPLE, A SINGLE NUCLEOTIDE POLYMORPHISM OF THE TNF-ALPHA GENE IS ASSOCIATED WITH SIGNIFICANT PERIODONTAL ATTACHMENT LOSS IN PATIENTS WITH CORONARY HEART DISEASE. CHANGES IN GENE EXPRESSION ASSOCIATED WITH INFLAMMATION AND LIPID METABOLISM IN RESPONSE TO ORAL INFECTION WITH THE PERIODONTAL PATHOGEN PORPHYROMONAS GINGIVALIS (PG) HAVE BEEN DEMONSTRATED IN MOUSE MODELS, INDEPENDENT OF THE DEMONSTRATION OF ATHEROSCLEROTIC LESIONS. INSULIN RESISTANCE IS CONSIDERED TO BE A CHRONIC LOW-GRADE INFLAMMATORY CONDITION, ASSOCIATED WITH ALTERED GLUCOSE TOLERANCE, HYPERTRIGLYCERIDEMIA, CENTRAL OBESITY AND CORONARY HEART DISEASE. IT IS ACCOMPANIED BY ELEVATED LEVELS OF IL-1, IL-6 AND TNF-ALPHA ALSO RELEVANT TO THE PROGRESSION OF PERIODONTITIS. THERE IS EVIDENCE THAT UNCONTROLLED PERIODONTAL DISEASE CONTRIBUTES TO MAINTENANCE OF SYSTEMIC DISEASES, INCLUDING RHEUMATOID ARTHRITIS (RA), WITH INCREASED RISK OF PERIODONTITIS IN SUBJECTS WITH RA. THE PERIODONTAL PATHOGEN PG IS SIGNIFICANT IN CONTRIBUTING TO CITRULLINATION OF PROTEINS RESULTING IN IMMUNE DYSREGULATION AND AUTOIMMUNE RESPONSES, SEEN IN RA. HOWEVER, THEY ARE BOTH MULTIFACTORIAL CHRONIC DISEASES WITH COMPLEX ETIOPATHOGENESES THAT AFFECT THEIR PRESENTATION. CONSISTENT BUT WEAK ASSOCIATIONS ARE SEEN FOR SURROGATE MARKERS OF PERIODONTITIS SUCH AS TOOTH LOSS, WITH MULTIPLE SYSTEMIC CONDITIONS. EFFECTIVE TREATMENT OF PERIODONTITIS WOULD BE IMPORTANT IN REDUCING SYSTEMIC INFLAMMATORY LOADING FROM CHRONIC LOCAL INFLAMMATION AND IN ACHIEVING SYSTEMIC HEALTH. LACK OF A CONSISTENT CAUSE AND EFFECT RELATIONSHIP IN ALL SUBJECTS WOULD BE INFLUENCED BY GENETIC, EPIGENETIC AND OTHER SUBJECT VARIABLES, ALTHOUGH THERE ARE CLEAR MECHANISMS THAT LINK THE ASSOCIATIONS. THIS ARTICLE INCLUDES AN APPRAISAL OF PATENTS AND THEIR APPLICATIONS. 2013 8 3705 23 INFLUENCE OF EPIGENETICS ON PERIODONTITIS AND PERI-IMPLANTITIS PATHOGENESIS. PERIODONTITIS IS A DISEASE CHARACTERIZED BY TOOTH-ASSOCIATED MICROBIAL BIOFILMS THAT DRIVE CHRONIC INFLAMMATION AND DESTRUCTION OF PERIODONTAL-SUPPORTING TISSUES. IN SOME INDIVIDUALS, DISEASE PROGRESSION CAN LEAD TO TOOTH LOSS. A SIMILAR CONDITION CAN OCCUR AROUND DENTAL IMPLANTS IN THE FORM OF PERI-IMPLANTITIS. THE IMMUNE RESPONSE TO BACTERIAL CHALLENGES IS NOT ONLY INFLUENCED BY GENETIC FACTORS, BUT ALSO BY ENVIRONMENTAL FACTORS. EPIGENETICS INVOLVES THE STUDY OF GENE FUNCTION INDEPENDENT OF CHANGES TO THE DNA SEQUENCE AND ITS ASSOCIATED PROTEINS, AND REPRESENTS A CRITICAL LINK BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS HAVE BEEN SHOWN TO CONTRIBUTE TO THE PROGRESSION OF SEVERAL DISEASES, INCLUDING CHRONIC INFLAMMATORY DISEASES LIKE PERIODONTITIS AND PERI-IMPLANTITIS. THIS REVIEW AIMS TO PRESENT THE LATEST FINDINGS ON EPIGENETIC INFLUENCES ON PERIODONTITIS AND TO DISCUSS POTENTIAL MECHANISMS THAT MAY INFLUENCE PERI-IMPLANTITIS, GIVEN THE PAUCITY OF INFORMATION CURRENTLY AVAILABLE. 2022 9 4050 23 MALADAPTIVE TRAINED IMMUNITY AND CLONAL HEMATOPOIESIS AS POTENTIAL MECHANISTIC LINKS BETWEEN PERIODONTITIS AND INFLAMMATORY COMORBIDITIES. PERIODONTITIS IS BIDIRECTIONALLY ASSOCIATED WITH SYSTEMIC INFLAMMATORY DISORDERS. THE PREVALENCE AND SEVERITY OF THIS ORAL DISEASE AND LINKED COMORBIDITIES INCREASES WITH AGING. HERE, WE REVIEW TWO NEWLY EMERGED CONCEPTS, TRAINED INNATE IMMUNITY (TII) AND CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP), WHICH TOGETHER SUPPORT A POTENTIAL HYPOTHESIS ON HOW PERIODONTITIS AFFECTS AND IS AFFECTED BY COMORBIDITIES AND WHY THE SUSCEPTIBILITY TO PERIODONTITIS AND COMORBIDITIES INCREASES WITH AGING. GIVEN THAT CHRONIC DISEASES ARE LARGELY TRIGGERED BY THE ACTION OF INFLAMMATORY IMMUNE CELLS, MODULATION OF THEIR BONE MARROW PRECURSORS, THE HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS), MAY AFFECT MULTIPLE DISORDERS THAT EMERGE AS COMORBIDITIES. SUCH ALTERATIONS IN HSPCS CAN BE MEDIATED BY TII AND/OR CHIP, TWO NON-MUTUALLY EXCLUSIVE PROCESSES SHARING A BIAS FOR ENHANCED MYELOPOIESIS AND PRODUCTION OF INNATE IMMUNE CELLS WITH HEIGHTENED PROINFLAMMATORY POTENTIAL. TII IS A STATE OF ELEVATED IMMUNE RESPONSIVENESS BASED ON INNATE IMMUNE (EPIGENETIC) MEMORY. SYSTEMIC INFLAMMATION CAN INITIATE TII IN THE BONE MARROW VIA SUSTAINED REWIRING OF HSPCS, WHICH THEREBY DISPLAY A SKEWING TOWARD THE MYELOID LINEAGE, RESULTING IN GENERATION OF HYPER-REACTIVE OR "TRAINED" MYELOID CELLS. CHIP ARISES FROM AGING-RELATED SOMATIC MUTATIONS IN HSPCS, WHICH CONFER A SURVIVAL AND PROLIFERATION ADVANTAGE TO THE MUTANT HSPCS AND GIVE RISE TO AN OUTSIZED FRACTION OF HYPER-INFLAMMATORY MUTANT MYELOID CELLS IN THE CIRCULATION AND TISSUES. THIS REVIEW DISCUSSES EMERGING EVIDENCE THAT SUPPORTS THE NOTION THAT TII AND CHIP MAY UNDERLIE A CAUSAL AND AGE-RELATED ASSOCIATION BETWEEN PERIODONTITIS AND COMORBIDITIES. A HOLISTIC MECHANISTIC UNDERSTANDING OF THE PERIODONTITIS-SYSTEMIC DISEASE CONNECTION MAY OFFER NOVEL DIAGNOSTIC AND THERAPEUTIC TARGETS FOR TREATING INFLAMMATORY COMORBIDITIES. 2022 10 5800 21 STEPWISE PATHOGENIC EVOLUTION OF MYCOBACTERIUM ABSCESSUS. ALTHOUGH ALMOST ALL MYCOBACTERIAL SPECIES ARE SAPROPHYTIC ENVIRONMENTAL ORGANISMS, A FEW, SUCH AS MYCOBACTERIUM TUBERCULOSIS, HAVE EVOLVED TO CAUSE TRANSMISSIBLE HUMAN INFECTION. BY ANALYZING THE RECENT EMERGENCE AND SPREAD OF THE ENVIRONMENTAL ORGANISM M. ABSCESSUS THROUGH THE GLOBAL CYSTIC FIBROSIS POPULATION, WE HAVE DEFINED KEY, GENERALIZABLE STEPS INVOLVED IN THE PATHOGENIC EVOLUTION OF MYCOBACTERIA. WE SHOW THAT EPIGENETIC MODIFIERS, ACQUIRED THROUGH HORIZONTAL GENE TRANSFER, CAUSE SALTATIONAL INCREASES IN THE PATHOGENIC POTENTIAL OF SPECIFIC ENVIRONMENTAL CLONES. ALLOPATRIC PARALLEL EVOLUTION DURING CHRONIC LUNG INFECTION THEN PROMOTES RAPID INCREASES IN VIRULENCE THROUGH MUTATIONS IN A DISCRETE GENE NETWORK; THESE MUTATIONS ENHANCE GROWTH WITHIN MACROPHAGES BUT IMPAIR FOMITE SURVIVAL. AS A CONSEQUENCE, WE OBSERVE CONSTRAINED PATHOGENIC EVOLUTION WHILE PERSON-TO-PERSON TRANSMISSION REMAINS INDIRECT, BUT POSTULATE ACCELERATED PATHOGENIC ADAPTATION ONCE DIRECT TRANSMISSION IS POSSIBLE, AS OBSERVED FOR M. TUBERCULOSIS OUR FINDINGS INDICATE HOW KEY INTERVENTIONS, SUCH AS EARLY TREATMENT AND CROSS-INFECTION CONTROL, MIGHT RESTRICT THE SPREAD OF EXISTING MYCOBACTERIAL PATHOGENS AND PREVENT NEW, EMERGENT ONES. 2021 11 3470 39 HYPOXIA-INDUCIBLE KDM3A ADDICTION IN MULTIPLE MYELOMA. IN MULTIPLE MYELOMA (MM), THE BONE MARROW (BM) MICROENVIRONMENT MAY CONTAIN A MYELOMA CELL FRACTION THAT HAS ACQUIRED TREATMENT RESISTANCE BY UNDERGOING AN EPIGENETIC GENE EXPRESSION CHANGE. HYPOXIC STRESS IS AN IMPORTANT FACTOR IN THE BM MICROENVIRONMENT. RECENTLY, WE DEMONSTRATED THAT MIR-210 WAS UPREGULATED IN HYPOXIA AND DOWNREGULATED IRF4, WHICH IS KNOWN AS AN ESSENTIAL FACTOR IN MYELOMA ONCOGENESIS IN NORMOXIA. IN THE STUDY, WE DEMONSTRATED THAT MYELOMA CELLS STILL SHOWED A STRONG ANTIAPOPTOTIC PHENOTYPE DESPITE IRF4 DOWNREGULATION, SUGGESTING THAT ANOTHER ANTIAPOPTOTIC FACTOR MIGHT BE INVOLVED UNDER HYPOXIC STRESS. TO DETERMINE THE FACTOR OR FACTORS, WE CONDUCTED GENE EXPRESSION ANALYSIS ON MYELOMA CELLS (PRIMARY SAMPLES AND CELL LINES) THAT WERE EXPOSED TO CHRONIC HYPOXIA AND OBSERVED UPREGULATION OF GLYCOLYTIC GENES AND GENES ENCODING H3K9 DEMETHYLASES IN MYELOMA CELLS WITH HYPOXIA. AMONG THESE, KDM3A WAS MOST SIGNIFICANTLY UPREGULATED IN ALL EXAMINED CELLS, AND ITS KNOCKDOWN INDUCED APOPTOSIS OF MYELOMA CELLS IN CHRONIC HYPOXIA. EXPRESSION OF KDM3A WAS DEPENDENT ON HIF-1ALPHA, WHICH IS A TRANSCRIPTION FACTOR SPECIFICALLY UPREGULATED IN HYPOXIA. WE FURTHER DEMONSTRATED THAT AN ESSENTIAL TARGET OF KDM3A WAS A NONCODING GENE, MALAT1, WHOSE UPREGULATION CONTRIBUTED TO ACQUISITION OF AN ANTIAPOPTOTIC PHENOTYPE BY ACCUMULATION OF HIF-1ALPHA, LEADING TO UPREGULATION OF GLYCOLYTIC GENES UNDER HYPOXIA. THIS PROCESS WAS INDEPENDENT FROM IRF4. THESE RESULTS LED US TO CONCLUDE THAT THE HYPOXIA-INDUCIBLE HIF-1ALPHA-KDM3A-MALAT1 AXIS ALSO CONTRIBUTES TO ACQUISITION OF THE ANTIAPOPTOTIC PHENOTYPE VIA UPREGULATION OF GLYCOLYSIS-PROMOTING GENES. THUS, THIS AXIS IS A PROMISING THERAPEUTIC TARGET AGAINST MYELOMA CELLS IN THE BM MICROENVIRONMENT. 2018 12 5477 33 RESTORING THE FUNCTIONAL IMMUNOGENICITY OF CHRONIC LYMPHOCYTIC LEUKEMIA USING EPIGENETIC MODIFIERS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS A MALIGNANCY ARISING FROM IMMUNE CELLS (B-LYMPHOCYTES) ENDOWED WITH INTRINSIC ANTIGEN-PRESENTING CAPABILITIES. SUCH A FUNCTION HOWEVER IS LOST DURING MALIGNANT TRANSFORMATION AND CLL CELLS ARE WELL KNOWN FOR THEIR INABILITY TO PROCESS AND PRESENT ANTIGENS TO THE T-CELL ARM OF THE IMMUNE SYSTEM. INSTEAD, MALIGNANT CLL CELLS ELICIT A VAST ARRAY OF IMMUNE REGULATORY MECHANISMS CONDUCIVE TO T-CELL DYSFUNCTION AND IMMUNOSUPPRESSION. PREVIOUSLY, WE HAVE SHOWN THAT TREATMENT OF CLL CELLS WITH THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE UNLEASHED TARGET ANTIGEN EXPRESSION. HERE WE SHOW FOR THE FIRST TIME THAT COMBINING TWO EPIGENETIC MODIFIERS, 5-AZA-2'-DEOXYCYTIDINE AND THE HISTONE DEACETYLASE INHIBITOR LAQ824 EFFECTIVELY RESTORES THE IMMUNOGENICITY OF CLL CELL LINES AS WELL AS PRIMARY CELLS OBTAINED FROM CLL PATIENTS. INDEED, SUCH A COMBINATION INDUCES THE EXPRESSION OF NOVEL AND HIGHLY ANTIGENIC CANCER-TESTIS ANTIGENS (CTAS) AND COSTIMULATORY MOLECULES. THESE CHANGES FACILITATE THE FORMATION OF ROBUST SUPRAMOLECULAR ACTIVATION COMPLEXES (SMAC) BETWEEN CLL CELLS AND RESPONDER T-CELLS LEADING TO INTRACELLULAR SIGNALING, LYTIC GRANULE MOBILIZATION, AND POLARIZATION OF FUNCTIONAL AND RELEVANT T-CELL RESPONSES. THIS CASCADE OF T-CELL ACTIVATING EVENTS TRIGGERED BY CLL CELLS WITH RESTORED APC FUNCTION, POINTS TO COMBINED EPIGENETIC MODIFIER TREATMENT AS A POTENTIAL IMMUNOTHERAPEUTIC STRATEGY FOR CLL PATIENTS. 2011 13 1642 24 DOES INFLAMMATION AFFECT OUTCOMES IN DIALYSIS PATIENTS? CHRONIC, LOW-GRADE INFLAMMATION IS A COMMON COMORBID CONDITION IN CHRONIC KIDNEY DISEASE (CKD), AND PARTICULARLY IN CHRONIC DIALYSIS PATIENTS. IN THIS REVIEW, WE CONSIDER THE QUESTION OF WHETHER INFLAMMATION AFFECTS OUTCOMES IN DIALYSIS PATIENTS. LEVELS OF PROINFLAMMATORY CYTOKINES, AS WELL AS C-REACTIVE PROTEIN, ARE ELEVATED IN CHRONIC DIALYSIS PATIENTS. MULTIPLE FACTORS LIKELY CONTRIBUTE TO CHRONIC INFLAMMATORY ACTIVATION IN KIDNEY DISEASE PATIENTS INCLUDING THE UREMIC MILIEU, LIFESTYLE AND EPIGENETIC INFLUENCES, INFECTIOUS AND THROMBOTIC EVENTS, THE DIALYSIS PROCESS, AND DYSBIOSIS. INCREASED INFLAMMATORY MARKERS IN BOTH CKD AND CHRONIC DIALYSIS PATIENTS ARE ASSOCIATED WITH ADVERSE CLINICAL OUTCOMES INCLUDING ALL-CAUSE MORTALITY, CARDIOVASCULAR EVENTS, KIDNEY DISEASE PROGRESSION, PROTEIN ENERGY WASTING AND DIMINISHED MOTOR FUNCTION, COGNITIVE IMPAIRMENT, AS WELL AS OTHER ADVERSE CONSEQUENCES INCLUDING CKD-MINERAL AND BONE DISORDER, ANEMIA, AND INSULIN RESISTANCE. STRATEGIES THAT HAVE BEEN SHOWN TO REDUCE CHRONIC SYSTEMIC INFLAMMATION IN CKD AND CHRONIC DIALYSIS PATIENTS INCLUDE BOTH PHARMACOLOGICAL AND NONPHARMACOLOGICAL INTERVENTIONS. HOWEVER, DESPITE EVIDENCE THAT SYSTEMIC INFLAMMATORY MARKERS CAN BE LOWERED IN KIDNEY DISEASE PATIENTS TREATED WITH VARIOUS STRATEGIES, EVIDENCE THAT THIS IMPROVES CLINICAL OUTCOMES IS LARGELY UNAVAILABLE AND REPRESENTS AN IMPORTANT FUTURE RESEARCH DIRECTION. OVERALL, THERE IS STRONG OBSERVATIONAL EVIDENCE THAT INFLAMMATION IS HIGH IN CHRONIC DIALYSIS PATIENTS AND THAT THIS IS INDEPENDENTLY ASSOCIATED WITH NUMEROUS ADVERSE CLINICAL OUTCOMES. TARGETING INFLAMMATION REPRESENTS A POTENTIALLY NOVEL AND ATTRACTIVE STRATEGY IF IT CAN INDEED IMPROVE ADVERSE OUTCOMES COMMON IN THIS POPULATION. 2018 14 5002 22 PERIODONTITIS AND PERIODONTOPATHIC BACTERIA AS RISK FACTORS FOR RHEUMATOID ARTHRITIS: A REVIEW OF THE LAST 10 YEARS. RHEUMATOID ARTHRITIS (RA) IS CHARACTERIZED BY CHRONIC INFLAMMATORY DESTRUCTION OF JOINT TISSUE AND IS CAUSED BY AN ABNORMAL AUTOIMMUNE RESPONSE TRIGGERED BY INTERACTIONS BETWEEN GENETICS, ENVIRONMENTAL FACTORS, AND EPIGENETIC AND POSTTRANSLATIONAL MODIFICATIONS. RA HAS BEEN SUGGESTED TO BE INTERRELATED WITH PERIODONTITIS, A SERIOUS FORM OR STAGE OF CHRONIC INFLAMMATORY PERIODONTAL DISEASE ASSOCIATED WITH PERIODONTOPATHIC BACTERIAL INFECTIONS, GENETIC PREDISPOSITION, ENVIRONMENTAL FACTORS, AND EPIGENETIC INFLUENCES. OVER THE LAST DECADE, A NUMBER OF ANIMAL AND CLINICAL STUDIES HAVE BEEN CONDUCTED TO ASSESS WHETHER OR NOT PERIODONTITIS AND ASSOCIATED PERIODONTOPATHIC BACTERIA CONSTITUTE RISK FACTORS FOR RA. THE PRESENT REVIEW INTRODUCES RECENT ACCUMULATING EVIDENCE TO SUPPORT THE ASSOCIATIONS OF PERIODONTITIS AND PERIODONTOPATHIC BACTERIA WITH THE RISK OF RA OR THE OUTCOME OF RA PHARMACOLOGICAL TREATMENT WITH DISEASE-MODIFYING ANTIRHEUMATIC DRUGS. IN ADDITION, THE RESULTS FROM INTERVENTION STUDIES HAVE SUGGESTED AN IMPROVEMENT IN RA CLINICAL PARAMETERS AFTER NONSURGICAL PERIODONTAL TREATMENT. FURTHERMORE, THE POTENTIAL CAUSAL MECHANISMS UNDERLYING THE LINK BETWEEN PERIODONTITIS AND PERIODONTOPATHIC BACTERIA AND RA ARE SUMMARIZED. 2023 15 5912 27 TARGETED THERAPIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM DISORDER CHARACTERISED BY LOSS OF TOLERANCE TO ENDOGENOUS NUCLEAR ANTIGENS AND AUTOANTIBODY FORMATION. RECENT INSIGHT INTO THE IMMUNOPATHOGENESIS OF LUPUS HAS PROVIDED THE FOUNDATION FOR A NOVEL CLASS OF AGENTS WHICH TARGET SPECIFIC, DYSREGULATED COMPONENTS OF THE IMMUNE SYSTEM. EFFORTS HAVE FOCUSED PREDOMINANTLY ON B-CELL DEPLETING THERAPIES, OF WHICH BELIMUMAB WAS THE FIRST TO DEMONSTRATE SUCCESS IN PHASE III STUDIES AND THUS RECEIVE MARKETING AUTHORISATION. OFF-LABEL PRESCRIBING OF RITUXIMAB IN REFRACTORY CASES IS COMMON AND SUPPORTED BY UNCONTROLLED STUDIES, WHICH SUGGEST A FAVOURABLE RISK:BENEFIT PROFILE. HOWEVER, TWO PLACEBO-CONTROLLED TRIALS FAILED TO SHOW BENEFIT, POSSIBLY BECAUSE OF INAPPROPRIATE PATIENT SELECTION AND OTHER ASPECTS OF TRIAL METHODOLOGY. INHIBITION OF DYSREGULATED CO-STIMULATORY SIGNALS AND CYTOKINES ARE OTHER THERAPEUTIC STRATEGIES CURRENTLY UNDER INVESTIGATION. SOME CANDIDATE DRUGS FAILED TO MEET PRIMARY ENDPOINTS IN EARLY-PHASE CLINICAL TRIALS, YET DEMONSTRATED CLINICAL BENEFIT WHEN ALTERNATIVE ASSESSMENT CRITERIA WERE APPLIED OR SPECIFIC PATIENT SUB-GROUPS ANALYSED. WELL-DESIGNED STUDIES OF GREATER SIZE AND DURATION ARE NEEDED TO CLARIFY THE THERAPEUTIC UTILITY OF THESE AGENTS. FUTURE IMMUNOMODULATORY STRATEGIES TARGETING INTERFERON-ALPHA, T CELLS, OXIDATIVE STRESS AND EPIGENETIC ABNORMALITIES MAY REDUCE MULTISYSTEM DISEASE ACTIVITY AND PROLONG SURVIVAL IN THIS COMPLEX AND HETEROGENEIC DISEASE. 2013 16 1068 35 CLL INTRACLONAL FRACTIONS EXHIBIT ESTABLISHED AND RECENTLY ACQUIRED PATTERNS OF DNA METHYLATION. INTRACLONAL SUBPOPULATIONS OF CIRCULATING CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS WITH DIFFERENT PROLIFERATIVE HISTORIES AND RECIPROCAL SURFACE EXPRESSION OF CXCR4 AND CD5 HAVE BEEN OBSERVED IN THE PERIPHERAL BLOOD OF CLL PATIENTS AND NAMED PROLIFERATIVE (PF), INTERMEDIATE (IF), AND RESTING (RF) CELLULAR FRACTIONS. HERE, WE FOUND THAT THESE INTRACLONAL CIRCULATING FRACTIONS SHARE PERSISTENT DNA METHYLATION SIGNATURES LARGELY ASSOCIATED WITH THE MUTATION STATUS OF THE IMMUNOGLOBULIN HEAVY CHAIN LOCUS (IGHV) AND THEIR ORIGINS FROM DISTINCT STAGES OF DIFFERENTIATION OF ANTIGEN-EXPERIENCED B CELLS. INCREASED LEUKEMIC BIRTH RATE, HOWEVER, SHOWED A VERY LIMITED IMPACT ON DNA METHYLATION OF CIRCULATING CLL FRACTIONS INDEPENDENT OF IGHV MUTATION STATUS. ADDITIONALLY, DNA METHYLATION HETEROGENEITY INCREASED AS LEUKEMIC CELLS ADVANCED FROM PF TO RF IN THE PERIPHERAL BLOOD. THIS FREQUENTLY CO-OCCURRED WITH HETEROCHROMATIN HYPOMETHYLATION AND HYPERMETHYLATION OF POLYCOMB-REPRESSED REGIONS IN THE PF, SUGGESTING ACCUMULATION OF LONGEVITY-ASSOCIATED EPIGENETIC FEATURES IN RECENTLY BORN CELLS. ON THE OTHER HAND, TRANSCRIPTIONAL DIFFERENCES BETWEEN PAIRED INTRACLONAL FRACTIONS CONFIRMED THEIR PROLIFERATIVE EXPERIENCE AND FURTHER SUPPORTED A LINEAR ADVANCEMENT FROM PF TO RF IN THE PERIPHERAL BLOOD. SEVERAL OF THESE DIFFERENTIALLY EXPRESSED GENES SHOWED UNIQUE ASSOCIATIONS WITH CLINICAL OUTCOME NOT EVIDENT IN THE BULK CLONE, SUPPORTING THE PATHOLOGICAL AND THERAPEUTIC RELEVANCE OF STUDYING INTRACLONAL CLL FRACTIONS. WE CONCLUDE THAT INDEPENDENT METHYLATION AND TRANSCRIPTIONAL LANDSCAPES REFLECT BOTH PREEXISTING CELL-OF-ORIGIN FINGERPRINTS AND MORE RECENTLY ACQUIRED HALLMARKS ASSOCIATED WITH THE LIFE CYCLE OF CIRCULATING CLL CELLS. 2020 17 2558 25 EPIGENETICS IN SUSCEPTIBILITY, PROGRESSION, AND DIAGNOSIS OF PERIODONTITIS. PERIODONTITIS IS CHARACTERIZED BY IRREVERSIBLE DESTRUCTION OF PERIODONTAL TISSUE. AT PRESENT, THE ACCEPTED ETIOLOGY OF PERIODONTITIS IS BASED ON A THREE-FACTOR THEORY INCLUDING PATHOGENIC BACTERIA, HOST FACTORS, AND ACQUIRED FACTORS. PERIODONTITIS DEVELOPMENT USUALLY TAKES A DECADE OR LONGER AND IS THEREFORE CALLED CHRONIC PERIODONTITIS (CP). TO SEARCH FOR GENETIC FACTORS ASSOCIATED WITH CP, SEVERAL GENOME-WIDE ASSOCIATION STUDY (GWAS) ANALYSES WERE CONDUCTED; HOWEVER, POLYMORPHISMS ASSOCIATED WITH CP HAVE NOT BEEN IDENTIFIED. EPIGENETICS, ON THE OTHER HAND, INVOLVES ACQUIRED TRANSCRIPTIONAL REGULATORY MECHANISMS DUE TO REVERSIBLY ALTERED CHROMATIN ACCESSIBILITY. EPIGENETIC STATUS IS A CONDITION SPECIFIC TO EACH TISSUE AND CELL, MOSTLY DETERMINED BY THE RESPONSES OF HOST CELLS TO STIMULATIONS BY LOCAL FACTORS, LIKE BACTERIAL INFLAMMATION, AND SYSTEMIC FACTORS SUCH AS NUTRITION STATUS, METABOLIC DISEASES, AND HEALTH CONDITIONS. SIGNIFICANTLY, EPIGENETIC STATUS HAS BEEN LINKED WITH THE ONSET AND PROGRESSION OF SEVERAL ACQUIRED DISEASES. THUS, EPIGENETIC FACTORS IN PERIODONTAL TISSUES ARE ATTRACTIVE TARGETS FOR PERIODONTITIS DIAGNOSIS AND TREATMENTS. IN THIS REVIEW, WE INTRODUCE ACCUMULATING EVIDENCE TO REVEAL THE EPIGENETIC BACKGROUND EFFECTS RELATED TO PERIODONTITIS CAUSED BY GENETIC FACTORS, SYSTEMIC DISEASES, AND LOCAL ENVIRONMENTAL FACTORS, SUCH AS SMOKING, AND CLARIFY THE UNDERLYING MECHANISMS BY WHICH EPIGENETIC ALTERATION INFLUENCES THE SUSCEPTIBILITY OF PERIODONTITIS. 2022 18 3734 30 INNATE IMMUNE MEMORY IN MONOCYTES AND MACROPHAGES: THE POTENTIAL THERAPEUTIC STRATEGIES FOR ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A COMPLEX METABOLIC DISEASE CHARACTERIZED BY THE DYSFUNCTION OF LIPID METABOLISM AND CHRONIC INFLAMMATION IN THE INTIMAL SPACE OF THE VESSEL. AS THE MOST ABUNDANT INNATE IMMUNE CELLS, MONOCYTE-DERIVED MACROPHAGES PLAY A PIVOTAL ROLE IN THE INFLAMMATORY RESPONSE, CHOLESTEROL METABOLISM, AND FOAM CELL FORMATION. IN RECENT DECADES, IT HAS BEEN DEMONSTRATED THAT MONOCYTES AND MACROPHAGES CAN ESTABLISH INNATE IMMUNE MEMORY (ALSO TERMED TRAINED IMMUNITY) VIA ENDOGENOUS AND EXOGENOUS ATHEROGENIC STIMULI AND EXHIBIT A LONG-LASTING PROINFLAMMATORY PHENOTYPE. THE IMPORTANT CELLULAR METABOLISM PROCESSES, INCLUDING GLYCOLYSIS, OXIDATIVE PHOSPHORYLATION (OXPHOS), THE TRICARBOXYLIC ACID (TCA) CYCLE, FATTY ACID SYNTHESIS, AND CHOLESTEROL SYNTHESIS, ARE REPROGRAMMED. TRAINED MONOCYTES/MACROPHAGES WITH INNATE IMMUNE MEMORY CAN BE PERSISTENTLY HYPERACTIVATED AND CAN UNDERGO EXTENSIVE EPIGENETIC REWIRING, WHICH CONTRIBUTES TO THE PATHOPHYSIOLOGICAL DEVELOPMENT OF ATHEROSCLEROSIS VIA INCREASED PROINFLAMMATORY CYTOKINE PRODUCTION AND LIPID ACCUMULATION. HERE, WE PROVIDE AN OVERVIEW OF THE REGULATION OF CELLULAR METABOLIC PROCESSES AND EPIGENETIC MODIFICATIONS OF INNATE IMMUNE MEMORY IN MONOCYTES/MACROPHAGES AS WELL AS THE POTENTIAL ENDOGENOUS AND EXOGENOUS STIMULATIONS INVOLVED IN THE PROGRESSION OF ATHEROSCLEROSIS THAT HAVE BEEN REPORTED RECENTLY. THESE ELUCIDATIONS MIGHT BE BENEFICIAL FOR FURTHER UNDERSTANDING INNATE IMMUNE MEMORY AND THE DEVELOPMENT OF THERAPEUTIC STRATEGIES FOR INFLAMMATORY DISEASES AND ATHEROSCLEROSIS. 2022 19 4415 24 MOLECULAR AND CELLULAR MECHANISMS THAT INDUCE ARTERIAL CALCIFICATION BY INDOXYL SULFATE AND P-CRESYL SULFATE. THE PROTEIN-BOUND UREMIC TOXINS, INDOXYL SULFATE (IS) AND P-CRESYL SULFATE (PCS), ARE CONSIDERED TO BE HARMFUL VASCULAR TOXINS. ARTERIAL MEDIA CALCIFICATION, OR THE DEPOSITION OF CALCIUM PHOSPHATE CRYSTALS IN THE ARTERIES, CONTRIBUTES SIGNIFICANTLY TO CARDIOVASCULAR COMPLICATIONS, INCLUDING LEFT VENTRICULAR HYPERTROPHY, HYPERTENSION, AND IMPAIRED CORONARY PERFUSION IN THE ELDERLY AND PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) AND DIABETES. RECENTLY, WE REPORTED THAT BOTH IS AND PCS TRIGGER MODERATE TO SEVERE CALCIFICATION IN THE AORTA AND PERIPHERAL VESSELS OF CKD RATS. THIS REVIEW DESCRIBES THE MOLECULAR AND CELLULAR MECHANISMS BY WHICH THESE UREMIC TOXINS INDUCE ARTERIAL MEDIA CALCIFICATION. A COMPLEX INTERPLAY BETWEEN INFLAMMATION, COAGULATION, AND LIPID METABOLISM PATHWAYS, INFLUENCED BY EPIGENETIC FACTORS, IS CRUCIAL IN IS/PCS-INDUCED ARTERIAL MEDIA CALCIFICATION. HIGH LEVELS OF GLUCOSE ARE LINKED TO THESE EVENTS, SUGGESTING THAT A GOOD BALANCE BETWEEN GLUCOSE AND LIPID LEVELS MIGHT BE IMPORTANT. ON THE CELLULAR LEVEL, EFFECTS ON ENDOTHELIAL CELLS, WHICH ACT AS THE PRIMARY SENSORS OF CIRCULATING PATHOLOGICAL TRIGGERS, MIGHT BE AS IMPORTANT AS THOSE ON VASCULAR SMOOTH MUSCLE CELLS. ENDOTHELIAL DYSFUNCTION, PROVOKED BY IS AND PCS TRIGGERED OXIDATIVE STRESS, MAY BE CONSIDERED A KEY EVENT IN THE ONSET AND DEVELOPMENT OF ARTERIAL MEDIA CALCIFICATION. IN THIS REVIEW A NUMBER OF IMPORTANT OUTSTANDING QUESTIONS SUCH AS THE ROLE OF MIRNA'S, PHENOTYPIC SWITCHING OF BOTH ENDOTHELIAL AND VASCULAR SMOOTH MUSCLE CELLS AND NEW TYPES OF PROGRAMMED CELL DEATH IN ARTERIAL MEDIA CALCIFICATION RELATED TO PROTEIN-BOUND UREMIC TOXINS ARE PUT FORWARD AND DISCUSSED. 2020 20 3064 37 GENOME-WIDE DNA METHYLATION ENCODES CARDIAC TRANSCRIPTIONAL REPROGRAMMING IN HUMAN ISCHEMIC HEART FAILURE. ISCHEMIC CARDIOMYOPATHY (ICM) IS THE CLINICAL ENDPOINT OF CORONARY HEART DISEASE AND A LEADING CAUSE OF HEART FAILURE. DESPITE GROWING DEMANDS TO DEVELOP PERSONALIZED APPROACHES TO TREAT ICM, PROGRESS IS LIMITED BY INADEQUATE KNOWLEDGE OF ITS PATHOGENESIS. SINCE EPIGENETICS HAS BEEN IMPLICATED IN THE DEVELOPMENT OF OTHER CHRONIC DISEASES, THE CURRENT STUDY WAS DESIGNED TO DETERMINE WHETHER TRANSCRIPTIONAL AND/OR EPIGENETIC CHANGES ARE SUFFICIENT TO DISTINGUISH ICM FROM OTHER ETIOLOGIES OF HEART FAILURE. SPECIFICALLY, WE HYPOTHESIZE THAT GENOME-WIDE DNA METHYLATION ENCODES TRANSCRIPTIONAL REPROGRAMMING IN ICM. RNA-SEQUENCING ANALYSIS WAS PERFORMED ON HUMAN ISCHEMIC LEFT VENTRICULAR TISSUE OBTAINED FROM PATIENTS WITH END-STAGE HEART FAILURE, WHICH ENRICHED KNOWN TARGETS OF THE POLYCOMB METHYLTRANSFERASE EZH2 COMPARED TO NON-ISCHEMIC HEARTS. COMBINED RNA SEQUENCING AND GENOME-WIDE DNA METHYLATION ANALYSIS REVEALED A ROBUST GENE EXPRESSION PATTERN CONSISTENT WITH SUPPRESSION OF OXIDATIVE METABOLISM, INDUCED ANAEROBIC GLYCOLYSIS, AND ALTERED CELLULAR REMODELING. LASTLY, KLF15 WAS IDENTIFIED AS A PUTATIVE UPSTREAM REGULATOR OF METABOLIC GENE EXPRESSION THAT WAS ITSELF REGULATED BY EZH2 IN A SET DOMAIN-DEPENDENT MANNER. OUR OBSERVATIONS THEREFORE DEFINE A NOVEL ROLE OF DNA METHYLATION IN THE METABOLIC REPROGRAMMING OF ICM. FURTHERMORE, WE IDENTIFY EZH2 AS AN EPIGENETIC REGULATOR OF KLF15 ALONG WITH DNA HYPERMETHYLATION, AND WE PROPOSE A NOVEL MECHANISM THROUGH WHICH CORONARY HEART DISEASE REPROGRAMS THE EXPRESSION OF BOTH INTERMEDIATE ENZYMES AND UPSTREAM REGULATORS OF CARDIAC METABOLISM SUCH AS KLF15. 2019