1 5802 133 STIMULATION OF HUMAN PERIODONTAL LIGAMENT FIBROBLASTS USING PURIFIED DENTILISIN EXTRACTED FROM TREPONEMA DENTICOLA. PERIODONTAL DISEASE IS A CHRONIC MULTIFACTORIAL DISEASE TRIGGERED BY A COMPLEX OF BACTERIAL SPECIES. THESE INTERACT WITH HOST TISSUES TO CAUSE THE RELEASE OF A BROAD ARRAY OF PRO-INFLAMMATORY CYTOKINES, CHEMOKINES, AND TISSUE REMODELERS, SUCH AS MATRIX METALLOPROTEINASES (MMPS), WHICH LEAD TO THE DESTRUCTION OF PERIODONTAL TISSUES. PATIENTS WITH SEVERE FORMS OF PERIODONTITIS ARE LEFT WITH A PERSISTENT PRO-INFLAMMATORY TRANSCRIPTIONAL PROFILE THROUGHOUT THE PERIODONTIUM, EVEN AFTER CLINICAL INTERVENTION, LEADING TO THE DESTRUCTION OF TEETH-SUPPORTING TISSUES. THE ORAL SPIROCHETE, TREPONEMA DENTICOLA , IS CONSISTENTLY FOUND AT SIGNIFICANTLY ELEVATED LEVELS AT SITES WITH ADVANCED PERIODONTAL DISEASE. OF ALL T. DENTICOLA VIRULENCE FACTORS THAT HAVE BEEN DESCRIBED, ITS CHYMOTRYPSIN-LIKE PROTEASE COMPLEX, ALSO CALLED DENTILISIN, HAS DEMONSTRATED A MULTITUDE OF CYTOPATHIC EFFECTS CONSISTENT WITH PERIODONTAL DISEASE PATHOGENESIS, INCLUDING ALTERATIONS IN CELLULAR ADHESION ACTIVITY, DEGRADATION OF VARIOUS ENDOGENOUS EXTRACELLULAR MATRIX-SUBSTRATES, DEGRADATION OF HOST CHEMOKINES AND CYTOKINES, AND ECTOPIC ACTIVATION OF HOST MMPS. THUS, THE FOLLOWING MODEL OF T. DENTICOLA -HUMAN PERIODONTAL LIGAMENT CELL INTERACTIONS MAY PROVIDE NEW KNOWLEDGE ABOUT THE MECHANISMS THAT DRIVE THE CHRONICITY OF PERIODONTAL DISEASE AT THE PROTEIN, TRANSCRIPTIONAL, AND EPIGENETIC LEVELS, WHICH COULD AFFORD NEW PUTATIVE THERAPEUTIC TARGETS. THIS PROTOCOL WAS VALIDATED IN: PLOS PATHOG (2021), DOI: 10.1371/JOURNAL.PPAT.1009311. 2022 2 6332 30 THE ROLE OF CYTOMEGALOVIRUS INFECTION IN THE PATHOGENESIS OF PERIODONTAL DISEASES. THE MAIN CHARACTERISTIC OFPERIODONTAL DISEASE IS CHRONIC INFLAMMATION THAT LEADS TO PROGRESSIVE DESTRUCTION OF THE CONNECTIVE TISSUES AND BONE WITH SUBSEQUENT TOOTH MOBILITY AND FINALLY TOOTH LOSS. TRADITIONALLY, THE PATHOGENESIS OF PERIODONTITIS WAS BASED ON THE INFECTION CAUSED BY BACTERIA THAT COLONIZE TOOTH SURFACE AND GINGIVAL SULCUS. ACCUMULATED EVIDENCE SHOW THAT HOST RESPONSE FACTORS SUCH AS INFLAMMATORY REACTION AND ACTIVATION OF THE INNATE IMMUNE SYSTEM ARE CRITICAL TO THE PATHOGENESIS OF PERIODONTAL DISEASE. PERIODONTAL DISEASE HAS BEEN WIDELY RECOGNIZED AS A CHRONIC DISEASE BUT THE NATURE OF CHRONICITY REMAINS UNCLEAR. THE QUESTION IS WHETHER PERIODONTAL DISEASE IS A CONTINUOUS PROCESS OR CONSISTS OF EPISODES OF EXACERBATIONS AND REMISSIONS. MAYBE CYTOMEGALOVIRUS INFECTION OF THE PERIODONTIUM, DEPENDING ON THE LATENT OR ACTIVE PHASE OF INFECTION, CAN PARTLY EXPLAIN THE EPISODIC PROGRESSIVE NATURE OF PERIODONTAL DISEASE. CYTOMEGALOVIRUS INFECTION IMPAIRS PERIODONTAL DEFENSE AND PERMITS OVERGROWTH OF PERIODONTOPATHOGENIC BACTERIA. OWING TO ADVANCES IN NEW TECHNOLOGIES, EXPERIMENTAL EVIDENCE SHOW THE INFLUENCE AND INTERRELATEDNESS OF GENOMIC, EPIGENETIC, PROTEOMIC AND METABOLIC FACTORS IN THE PATHOGENESIS OF PERIODONTAL DISEASE. DATA ON THE PATHOGENESIS OF PERIODONTAL DISEASE ARE REVIEWED. 2011 3 5114 34 PORPHYROMONAS GINGIVALIS LIPOPOLYSACCHARIDE STIMULATION IN HUMAN PERIODONTAL LIGAMENT STEM CELLS: ROLE OF EPIGENETIC MODIFICATIONS TO THE INFLAMMATION. PERIODONTITIS IS A CHRONIC ORAL INFLAMMATORY DISEASE PRODUCED BY BACTERIA. GINGIVAL RETRACTION AND BONE AND CONNECTIVE TISSUES RESORPTION ARE THE HALLMARKS OF THIS DISEASE. CHRONIC PERIODONTITIS MAY CONTRIBUTE TO THE RISK OF ONSET OR PROGRESSION OF NEUROINFLAMMATORY PATHOLOGICAL CONDITIONS, SUCH AS ALZHEIMER'S DISEASE. THE MAIN GOAL OF THE PRESENT STUDY WAS TO INVESTIGATE IF THE ROLE OF EPIGENETIC MODULATIONS IS INVOLVED IN PERIODONTITIS USING HUMAN PERIODONTAL LIGAMENT STEM CELLS (HPDLSCS) AS AN IN VITRO MODEL SYSTEM. HPDLSCS WERE TREATED WITH LIPOPOLYSACCHARIDE OF PORPHYROMONAS GINGIVALIS AND THE EXPRESSION OF PROTEINS ASSOCIATED WITH DNA METHYLATION AND HISTONE ACETYLATION, SUCH AS DNMT1 AND P300, RESPECTIVELY, AND INFLAMMATORY TRANSCRIPTION FACTOR NF-KB, WERE EXAMINED. IMMUNOFLUORESCENCE, WESTERN BLOT AND NEXT GENERATION SEQUENCING RESULTS DEMONSTRATED THAT P. GINGIVALIS LIPOPOLYSACCHARIDE SIGNIFICANTLY REDUCED DNA METHYLASE DNMT1, WHILE IT MARKEDLY UPREGULATED THE LEVEL OF HISTONE ACETYLTRANSFERASE P300 AND NF-KB IN HPDLSCS. OUR RESULTS SHOWED THAT P. GINGIVALIS LIPOPOLYSACCHARIDE MARKEDLY REGULATE THE GENES INVOLVED IN EPIGENETIC MECHANISM, WHICH MAY RESULT IN INFLAMMATION INDUCTION. WE PROPOSE THAT P. GINGIVALIS LIPOPOLYSACCHARIDE-TREATED HPDLSCS COULD BE A POTENTIAL IN VITRO MODEL SYSTEM TO STUDY EPIGENETICS MODULATIONS ASSOCIATED WITH PERIODONTITIS, WHICH MIGHT BE HELPFUL TO IDENTIFY NOVEL BIOMARKERS LINKED TO THIS ORAL INFLAMMATORY DISEASE. 2017 4 5375 16 RECENT ADVANCES ON POSSIBLE ASSOCIATION BETWEEN THE PERIODONTAL INFECTION OF PORPHYROMONAS GINGIVALIS AND CENTRAL NERVOUS SYSTEM INJURY. CHRONIC PERIODONTITIS CAUSED BY PORPHYROMONAS GINGIVALIS (P. GINGIVALIS) INFECTION GENERALLY LASTS FOR A LIFETIME. THE LONG-TERM EXISTENCE AND DEVELOPMENT OF P. GINGIVALIS INFECTION GRADUALLY AGGRAVATE THE ACCUMULATION OF INFLAMMATORY SIGNALS AND TOXIC SUBSTANCES IN THE BODY. RECENT EVIDENCE HAS REVEALED THAT P. GINGIVALIS INFECTION MAY BE RELEVANT TO SOME CENTRAL NERVOUS SYSTEM (CNS) DISEASES. THE CURRENT WORK COLLECTS INFORMATION AND TRIES TO EXPLORE THE POSSIBLE RELATIONSHIP BETWEEN P. GINGIVALIS INFECTION AND CNS DISEASES, INCLUDING THE INTERACTION OR PATHWAYS BETWEEN PERIPHERAL INFECTION AND CNS INJURY, AND THE UNDERLYING NEUROTOXIC MECHANISMS. 2021 5 5002 29 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 6 6795 18 [EFFECT OF HISTONE ACETYLATION ON OSTEOGENIC DIFFERENTIATION OF PERIODONTAL LIGAMENT STEM CELLS DERIVED FROM PERIODONTITIS TISSUE]. EPIGENETICS IS DEFINED AS A CHANGE IN GENE EXPRESSION WITHOUT THE ALTERATION OF THE GENETIC SEQUENCE. SUCH A CHANGE WOULD BE INHERITED BY OFFSPRING. HISTONE ACETYLATION IS A TYPE OF EPIGENETICS. EXISTING STUDIES PROPOSED THAT CHRONIC PERIODONTITIS IS RELATED TO EPIGENETIC MODIFICATION. IN THIS REVIEW, WE SUMMARISED THE INFLUENCE OF CHRONIC PERIODONTITIS ON PERIODONTAL LIGAMENT STEM CELLS BY HISTONE ACETYLATION. 2019 7 3705 28 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 8 6581 38 TREPONEMA DENTICOLA UPREGULATES MMP-2 ACTIVATION IN PERIODONTAL LIGAMENT CELLS: INTERPLAY BETWEEN EPIGENETICS AND PERIODONTAL INFECTION. OBJECTIVE: PERIODONTAL PATHOGENS INITIATE CHRONIC DYSREGULATION OF INFLAMMATION AND TISSUE HOMEOSTASIS THAT CHARACTERIZE PERIODONTAL DISEASE. TO BETTER UNDERSTAND ORAL MICROBE-HOST TISSUE INTERACTIONS, WE INVESTIGATED EXPRESSION AND ACTIVATION OF MMP-2 IN PERIODONTAL LIGAMENT CELLS FOLLOWING TREPONEMA DENTICOLA CHALLENGE. DESIGN: CULTURED PDL CELLS WERE CHALLENGED WITH T. DENTICOLA, AND BACTERIAL ADHERENCE, INTERNALIZATION AND SURVIVAL WERE ASSAYED BY IMMUNOFLUORESCENCE MICROSCOPY AND ANTIBIOTIC PROTECTION ASSAYS, RESPECTIVELY. MMP-2 ACTIVATION WAS DETECTED BY ZYMOGRAPHY. MMP-2, MT1/MMP AND TIMP-2 EXPRESSION FOLLOWING T. DENTICOLA CHALLENGE WAS DETERMINED BY QRT-PCR. PROMOTER METHYLATION OF MMP-2 AND MT1/MMP WAS SCREENED BY METHYLATION-SENSITIVE RESTRICTION ANALYSIS AND BY BISULFITE DNA SEQUENCING. RESULTS: T. DENTICOLA ADHERED TO AND WAS INTERNALIZED BY PDL CELLS BUT DID NOT SURVIVE INTRACELLULARLY BEYOND 24H. IMPORTANTLY, WHILE DENTILISIN ACTIVITY IN PDL CULTURE SUPERNATANTS GRADUALLY DECREASED FOLLOWING T. DENTICOLA CHALLENGE, MMP-2 ACTIVATION PERSISTED FOR UP TO 5 DAYS, SUGGESTING INVOLVEMENT OF OTHER REGULATORY MECHANISMS. TRANSCRIPTION AND EXPRESSION OF MT1/MMP AND TIMP-2 INCREASED IN RESPONSE TO T. DENTICOLA CHALLENGE. HOWEVER, CONSISTENT WITH PREVIOUSLY REPORTED CONSTITUTIVE PRO-MMP-2 EXPRESSION IN PDL CELLS, THE MMP-2 PROMOTER WAS HYPOMETHYLATED, INDEPENDENT OF T. DENTICOLA CHALLENGE. CONCLUSIONS: MMP-2 PROMOTER HYPOMETHYLATION IS CONSISTENT WITH CONSTITUTIVE PRO-MMP-2 EXPRESSION IN PDL CELLS. THIS, COUPLED WITH T. DENTICOLA-MEDIATED UPREGULATION OF MMP-2-RELATED GENES AND CHRONIC ACTIVATION OF PRO-MMP-2, MIMICS KEY IN VIVO MECHANISMS OF PERIODONTAL DISEASE CHRONICITY, IN PARTICULAR MMP-2-DEPENDENT MATRIX DEGRADATION AND BONE RESORPTION. ADHERENCE AND/OR INTERNALIZATION OF T. DENTICOLA MAY CONTRIBUTE TO THESE PROCESSES BY ONE OR MORE REGULATORY MECHANISMS, INCLUDING CONTACT-DEPENDENT SIGNAL TRANSDUCTION OR OTHER EPIGENETIC MECHANISMS. 2014 9 3440 28 HYPERMETHYLATION AND LOW TRANSCRIPTION OF TLR2 GENE IN CHRONIC PERIODONTITIS. PERIODONTITIS IS AN INFLAMMATORY DISORDER CHARACTERIZED BY INTERACTIONS BETWEEN PERIODONTAL PATHOGENS AND HOST'S IMMUNE RESPONSE. EPIGENETIC MAY CONTRIBUTE TO DISEASE DEVELOPMENT AND OUTCOME BY INFLUENCING THE EXPRESSION OF GENES INVOLVED IN THE IMMUNE RESPONSE. IT HAS BEEN SHOWN THAT TOLL-LIKE RECEPTORS (TLR) PLAY AN IMPORTANT ROLE IN THE RESPONSE TO PERIODONTOPATHIC BACTERIA. THE AIM OF STUDY WAS TO EVALUATE THE METHYLATION STATUS AND THE EXPRESSION OF TLR2 GENE IN GINGIVAL SAMPLES FROM INDIVIDUALS WITH AND WITHOUT PERIODONTITIS. DNA WAS ANALYZED USING THE METHYL PROFILER DNA METHYLATION QPCR ASSAY. DNA METHYLATION AND TRANSCRIPT LEVELS WERE EVALUATED BY REAL-TIME POLYMERASE CHAIN REACTION. THE PERIODONTITIS GROUP SHOWED A HYPERMETHYLATED PROFILE AND A LOW EXPRESSION OF GENE. POSITIVE CORRELATION BETWEEN THE TLR2 METHYLATION FREQUENCY AND PROBING DEPTH WAS OBSERVED. THIS STUDY GIVES THE FIRST EVIDENCE OF METHYLATION FREQUENCY IN INFLAMED PERIODONTAL TISSUES AND OF THE POSSIBLE PARTICIPATION OF METHYLATION IN THE DEVELOPMENT OF PERIODONTITIS. 2013 10 2110 30 EPIGENETIC FINDINGS IN PERIODONTITIS IN UK TWINS: A CROSS-SECTIONAL STUDY. BACKGROUND: GENETIC AND ENVIRONMENTAL RISK FACTORS CONTRIBUTE TO PERIODONTAL DISEASE, BUT THE UNDERLYING SUSCEPTIBILITY PATHWAYS ARE NOT FULLY UNDERSTOOD. EPIGENETIC MECHANISMS ARE MALLEABLE REGULATORS OF GENE FUNCTION THAT CAN CHANGE IN RESPONSE TO GENETIC AND ENVIRONMENTAL STIMULI, THEREBY PROVIDING A POTENTIAL MECHANISM FOR MEDIATING RISK EFFECTS IN PERIODONTITIS. THE AIM OF THIS STUDY IS TO IDENTIFY EPIGENETIC CHANGES ACROSS TISSUES THAT ARE ASSOCIATED WITH PERIODONTAL DISEASE. METHODS: SELF-REPORTED GINGIVAL BLEEDING AND HISTORY OF GUM DISEASE, OR TOOTH MOBILITY, WERE USED AS INDICATORS OF PERIODONTAL DISEASE. DNA METHYLATION PROFILES WERE GENERATED USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP IN WHOLE BLOOD, BUCCAL, AND ADIPOSE TISSUE SAMPLES FROM PREDOMINANTLY OLDER FEMALE TWINS (MEAN AGE 58) FROM THE TWINSUK COHORT. EPIGENOME-WIDE ASSOCIATION SCANS (EWAS) OF GINGIVAL BLEEDING AND TOOTH MOBILITY WERE CONDUCTED IN WHOLE BLOOD IN 528 AND 492 TWINS, RESPECTIVELY. SUBSEQUENTLY, TARGETED CANDIDATE GENE ANALYSIS AT 28 GENOMIC REGIONS WAS CARRIED OUT TESTING FOR PHENOTYPE-METHYLATION ASSOCIATIONS IN 41 (TOOTH MOBILITY) AND 43 (GINGIVAL BLEEDING) BUCCAL, AND 501 (TOOTH MOBILITY) AND 556 (GINGIVAL BLEEDING) ADIPOSE DNA SAMPLES. RESULTS: EPIGENOME-WIDE ANALYSES IN BLOOD IDENTIFIED ONE CPG-SITE (CG21245277 IN ZNF804A) ASSOCIATED WITH GINGIVAL BLEEDING (FDR = 0.03, NOMINAL P VALUE = 7.17E-8) AND 58 SITES ASSOCIATED WITH TOOTH MOBILITY (FDR < 0.05) WITH THE TOP SIGNALS IN IQCE AND XKR6. EPIGENETIC VARIATION AT 28 CANDIDATE REGIONS (247 CPG-SITES) FOR CHRONIC PERIODONTITIS SHOWED AN ENRICHMENT FOR ASSOCIATION WITH PERIODONTAL TRAITS, AND SIGNALS IN EIGHT GENES (VDR, IL6ST, TMCO6, IL1RN, CD44, IL1B, WHAMM, AND CXCL1) WERE SIGNIFICANT IN BOTH TRAITS. THE METHYLATION-PHENOTYPE ASSOCIATION SIGNALS VALIDATED IN BUCCAL SAMPLES, AND A SUBSET (25%) ALSO VALIDATED IN ADIPOSE TISSUE. CONCLUSIONS: EPIGENOME-WIDE ANALYSES IN ADULT FEMALE TWINS IDENTIFIED SPECIFIC DNA METHYLATION CHANGES LINKED TO SELF-REPORTED PERIODONTAL DISEASE. FUTURE WORK WILL EXPLORE THE ENVIRONMENTAL BASIS AND FUNCTIONAL IMPACT OF THESE RESULTS TO INFER POTENTIAL FOR STRATEGIC PERSONALIZED TREATMENTS AND PREVENTION OF CHRONIC PERIODONTITIS. 2019 11 6580 37 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 12 333 26 ALTERATION OF PTGS2 PROMOTER METHYLATION IN CHRONIC PERIODONTITIS. LEVELS OF PROSTAGLANDIN E(2) AND THE PROSTAGLANDIN-ENDOPEROXIDE SYNTHASE-2 (PTGS2, OR COX-2) INCREASE IN ACTIVELY PROGRESSING PERIODONTAL LESIONS, BUT DECREASE IN CHRONIC DISEASE. WE HYPOTHESIZED THAT CHRONIC INFLAMMATION IS ASSOCIATED WITH ALTERED DNA METHYLATION LEVELS WITHIN THE PTGS2 PROMOTER, WITH EFFECTS ON COX-2 MRNA EXPRESSION. PTGS2 PROMOTER METHYLATION LEVELS FROM PERIODONTALLY INFLAMED GINGIVAL BIOPSIES SHOWED A 5.06-FOLD INCREASE AS COMPARED WITH NON-INFLAMED SAMPLES (P = 0.03), AND THE ODDS OF METHYLATION IN A CPG SITE IN THE INFLAMED GINGIVAL GROUP IS 4.46 TIMES HIGHER THAN IN THE SAME SITE IN THE NON-INFLAMED GROUP (P = 0.016). THE LEVEL OF METHYLATION AT -458 BP WAS INVERSELY ASSOCIATED WITH TRANSCRIPTIONAL LEVELS OF PTGS2 (RT-PCR) (P = 0.01). ANALYSIS OF THE DATA SUGGESTS THAT, IN CHRONICALLY INFLAMED TISSUES, THERE IS A HYPERMETHYLATION PATTERN OF THE PTGS2 PROMOTER IN ASSOCIATION WITH A LOWER LEVEL OF PTGS2 TRANSCRIPTION, CONSISTENT WITH A DAMPENING OF COX-2 EXPRESSION IN CHRONIC PERIODONTITIS. THESE FINDINGS SUGGEST THAT THE CHRONIC PERSISTENCE OF THE BIOFILM AND INFLAMMATION MAY BE ASSOCIATED WITH EPIGENETIC CHANGES IN LOCAL TISSUES AT THE BIOFILM-GINGIVAL INTERFACE. 2010 13 589 31 BET BROMODOMAIN INHIBITORS SUPPRESS INFLAMMATORY ACTIVATION OF GINGIVAL FIBROBLASTS AND EPITHELIAL CELLS FROM PERIODONTITIS PATIENTS. BET BROMODOMAIN PROTEINS ARE IMPORTANT EPIGENETIC REGULATORS OF GENE EXPRESSION THAT BIND ACETYLATED HISTONE TAILS AND REGULATE THE FORMATION OF ACETYLATION-DEPENDENT CHROMATIN COMPLEXES. BET INHIBITORS SUPPRESS INFLAMMATORY RESPONSES IN MULTIPLE CELL TYPES AND ANIMAL MODELS, AND PROTECT AGAINST BONE LOSS IN EXPERIMENTAL PERIODONTITIS IN MICE. HERE, WE ANALYZED THE ROLE OF BET PROTEINS IN INFLAMMATORY ACTIVATION OF GINGIVAL FIBROBLASTS (GFS) AND GINGIVAL EPITHELIAL CELLS (GECS). WE SHOW THAT THE BET INHIBITORS I-BET151 AND JQ1 SIGNIFICANTLY REDUCED EXPRESSION AND/OR PRODUCTION OF DISTINCT, BUT OVERLAPPING, PROFILES OF CYTOKINE-INDUCIBLE MEDIATORS OF INFLAMMATION AND BONE RESORPTION IN GFS FROM HEALTHY DONORS (IL6, IL8, IL1B, CCL2, CCL5, COX2, AND MMP3) AND THE GEC LINE TIGK (IL6, IL8, IL1B, CXCL10, MMP9) WITHOUT AFFECTING CELL VIABILITY. ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASE AND NUCLEAR FACTOR-KAPPAB PATHWAYS WAS UNAFFECTED BY I-BET151, AS WAS THE HISTONE ACETYLATION STATUS, AND NEW PROTEIN SYNTHESIS WAS NOT REQUIRED FOR THE ANTI-INFLAMMATORY EFFECTS OF BET INHIBITION. I-BET151 AND JQ1 ALSO SUPPRESSED EXPRESSION OF INFLAMMATORY CYTOKINES, CHEMOKINES, AND OSTEOCLASTOGENIC MEDIATORS IN GFS AND TIGKS INFECTED WITH THE KEY PERIODONTAL PATHOGEN PORPHYROMONAS GINGIVALIS. NOTABLY, P. GINGIVALIS INTERNALIZATION AND INTRACELLULAR SURVIVAL IN GFS AND TIGKS REMAINED UNAFFECTED BY BET INHIBITORS. FINALLY, INHIBITION OF BET PROTEINS SIGNIFICANTLY REDUCED P. GINGIVALIS-INDUCED INFLAMMATORY MEDIATOR EXPRESSION IN GECS AND GFS FROM PATIENTS WITH PERIODONTITIS. OUR RESULTS DEMONSTRATE THAT BET INHIBITORS MAY BLOCK THE EXCESSIVE INFLAMMATORY MEDIATOR PRODUCTION BY RESIDENT CELLS OF THE GINGIVAL TISSUE AND IDENTIFY THE BET FAMILY OF EPIGENETIC READER PROTEINS AS A POTENTIAL THERAPEUTIC TARGET IN THE TREATMENT OF PERIODONTAL DISEASE. 2019 14 2558 39 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 15 3235 31 HEMIN AVAILABILITY INDUCES COORDINATED DNA METHYLATION AND GENE EXPRESSION CHANGES IN PORPHYROMONAS GINGIVALIS. PERIODONTAL DISEASE IS A CHRONIC INFLAMMATORY DISEASE IN WHICH THE ORAL PATHOGEN PORPHYROMONAS GINGIVALIS PLAYS AN IMPORTANT ROLE. PORPHYROMONAS GINGIVALIS EXPRESSES VIRULENCE DETERMINANTS IN RESPONSE TO HIGHER HEMIN CONCENTRATIONS, BUT THE UNDERLYING REGULATORY PROCESSES REMAIN UNCLEAR. BACTERIAL DNA METHYLATION HAS THE POTENTIAL TO FULFIL THIS MECHANISTIC ROLE. WE CHARACTERIZED THE METHYLOME OF P. GINGIVALIS, AND COMPARED ITS VARIATION TO TRANSCRIPTOME CHANGES IN RESPONSE TO HEMIN AVAILABILITY. PORPHYROMONAS GINGIVALIS W50 WAS GROWN IN CHEMOSTAT CONTINUOUS CULTURE WITH EXCESS OR LIMITED HEMIN, PRIOR TO WHOLE-METHYLOME AND TRANSCRIPTOME PROFILING USING NANOPORE AND ILLUMINA RNA-SEQ. DNA METHYLATION WAS QUANTIFIED FOR DAM/DCM MOTIFS AND ALL-CONTEXT N6-METHYLADENINE (6MA) AND 5-METHYLCYTOSINE (5MC). OF ALL 1,992 GENES ANALYZED, 161 AND 268 WERE RESPECTIVELY OVER- AND UNDER-EXPRESSED WITH EXCESS HEMIN. NOTABLY, WE DETECTED DIFFERENTIAL DNA METHYLATION SIGNATURES FOR THE DAM "GATC" MOTIF AND BOTH ALL-CONTEXT 6MA AND 5MC IN RESPONSE TO HEMIN AVAILABILITY. JOINT ANALYSES IDENTIFIED A SUBSET OF COORDINATED CHANGES IN GENE EXPRESSION, 6MA, AND 5MC METHYLATION THAT TARGET GENES INVOLVED IN LACTATE UTILIZATION AND ABC TRANSPORTERS. THE RESULTS IDENTIFY ALTERED METHYLATION AND EXPRESSION RESPONSES TO HEMIN AVAILABILITY IN P. GINGIVALIS, WITH INSIGHTS INTO MECHANISMS REGULATING ITS VIRULENCE IN PERIODONTAL DISEASE. IMPORTANCE DNA METHYLATION HAS IMPORTANT ROLES IN BACTERIA, INCLUDING IN THE REGULATION OF TRANSCRIPTION. PORPHYROMONAS GINGIVALIS, AN ORAL PATHOGEN IN PERIODONTITIS, EXHIBITS WELL-ESTABLISHED GENE EXPRESSION CHANGES IN RESPONSE TO HEMIN AVAILABILITY. HOWEVER, THE REGULATORY PROCESSES UNDERLYING THESE EFFECTS REMAIN UNKNOWN. WE PROFILED THE NOVEL P. GINGIVALIS EPIGENOME, AND ASSESSED EPIGENETIC AND TRANSCRIPTOME VARIATION UNDER LIMITED AND EXCESS HEMIN CONDITIONS. AS EXPECTED, MULTIPLE GENE EXPRESSION CHANGES WERE DETECTED IN RESPONSE TO LIMITED AND EXCESS HEMIN THAT REFLECT HEALTH AND DISEASE, RESPECTIVELY. NOTABLY, WE ALSO DETECTED DIFFERENTIAL DNA METHYLATION SIGNATURES FOR THE DAM "GATC" MOTIF AND BOTH ALL-CONTEXT 6MA AND 5MC IN RESPONSE TO HEMIN. JOINT ANALYSES IDENTIFIED COORDINATED CHANGES IN GENE EXPRESSION, 6MA, AND 5MC METHYLATION THAT TARGET GENES INVOLVED IN LACTATE UTILIZATION AND ABC TRANSPORTERS. THE RESULTS IDENTIFY NOVEL REGULATORY PROCESSES UNDERLYING THE MECHANISM OF HEMIN REGULATED GENE EXPRESSION IN P. GINGIVALIS, WITH PHENOTYPIC IMPACTS ON ITS VIRULENCE IN PERIODONTAL DISEASE. 2023 16 3783 28 INTERFERON-GAMMA PROMOTER HYPOMETHYLATION AND INCREASED EXPRESSION IN CHRONIC PERIODONTITIS. AIM: THE GOAL OF THIS INVESTIGATION WAS TO DETERMINE WHETHER EPIGENETIC MODIFICATIONS IN THE IFNG PROMOTER ARE ASSOCIATED WITH AN INCREASE OF IFNG TRANSCRIPTION IN DIFFERENT STAGES OF PERIODONTAL DISEASES. MATERIALS AND METHODS: DNA WAS EXTRACTED FROM GINGIVAL BIOPSY SAMPLES COLLECTED FROM 47 TOTAL SITES FROM 47 DIFFERENT SUBJECTS: 23 PERIODONTALLY HEALTHY SITES, 12 EXPERIMENTALLY INDUCED GINGIVITIS SITES AND 12 CHRONIC PERIODONTITIS SITES. LEVELS OF DNA METHYLATION WITHIN THE IFNG PROMOTER CONTAINING SIX CPG DINUCLEOTIDES WERE DETERMINED USING PYROSEQUENCING TECHNOLOGY. INTERFERON GAMMA MRNA EXPRESSION WAS ANALYSED BY QUANTITATIVE POLYMERASE CHAIN REACTIONS USING ISOLATED RNA FROM PART OF THE BIOLOGICAL SAMPLES MENTIONED ABOVE. RESULTS: THE METHYLATION LEVEL OF ALL SIX ANALYSED CPG SITES WITHIN THE IFNG PROMOTER REGION IN THE PERIODONTITIS BIOPSIES 52% [INTERQUARTILE RANGE, IQR (43.8%, 63%)] WAS SIGNIFICANTLY LOWER THAN PERIODONTALLY HEALTHY SAMPLES 62% [IQR (51.3%, 74%)], P=0.007 AND GINGIVITIS BIOPSIES 63% [IQR (55%, 74%)], P=0.02. THE TRANSCRIPTIONAL LEVEL OF IFNG IN PERIODONTITIS BIOPSIES WAS 1.96-FOLD AND SIGNIFICANTLY HIGHER THAN TISSUES WITH PERIODONTAL HEALTH (P=0.04). ALTHOUGH THE MRNA LEVEL FROM EXPERIMENTAL GINGIVITIS SAMPLES EXHIBITED AN 8.5-FOLD INCREASE AS COMPARED WITH PERIODONTALLY HEALTHY SAMPLES, NO SIGNIFICANT METHYLATION DIFFERENCE WAS OBSERVED IN EXPERIMENTAL GINGIVITIS SAMPLE. CONCLUSIONS: A HYPOMETHYLATION PROFILE WITHIN IFNG PROMOTER REGION IS RELATED TO AN INCREASE OF IFNG TRANSCRIPTION PRESENT IN THE CHRONIC PERIODONTITIS BIOPSIES, WHILE SUCH AN INCREASE OF IFNG IN EXPERIMENTALLY INDUCED GINGIVITIS SEEMS INDEPENDENT OF PROMOTER METHYLATION ALTERATION. 2010 17 2762 23 EXPRESSION OF TET2 ENZYME INDICATES ENHANCED EPIGENETIC MODIFICATION OF CELLS IN PERIODONTITIS. DNA METHYLATION IS AN IMPORTANT EPIGENETIC MECHANISM INVOLVED IN THE REGULATION OF GENE EXPRESSION, AND A REDUCTION IN DNA METHYLATION INFLUENCES CELL-CYCLE PROGRESSION AND CELL DIFFERENTIATION IN INFLAMMATORY CELLS. THE AIM OF THE PRESENT STUDY WAS TO ANALYZE THE DNA-METHYLATION PATTERN AT LOCAL AND GLOBAL/SYSTEMIC LEVELS IN PATIENTS WITH PERIODONTITIS AND GINGIVITIS. TWENTY-ONE SUBJECTS WITH GENERALIZED, SEVERE PERIODONTITIS AND 17 SUBJECTS WITH GINGIVAL INFLAMMATION BUT NO ATTACHMENT LOSS WERE RECRUITED. GINGIVAL BIOPSIES AND PERIPHERAL BLOOD SAMPLES WERE COLLECTED AND PREPARED FOR IMMUNOHISTOCHEMICAL ANALYSIS OF 5-METHYLCYTOSINE (5MC), 5-HYDROXYMETHYLCYTOSINE (5HMC), TEN-ELEVEN TRANSLOCATION 2 (TET2), AND DNA METHYLTRANSFERASE 1 (DNMT1). WHILST A SIMILAR PATTERN FOR 5MC AND 5HMC DNA METHYLATION WAS FOUND IN BOTH TYPES OF LESIONS, A SIGNIFICANTLY LARGER PROPORTION OF TET2-POSITIVE CELLS WAS FOUND IN PERIODONTITIS LESIONS THAN IN GINGIVITIS LESIONS. QUANTITATIVE REAL-TIME PCR ANALYSIS SHOWED NO DIFFERENCES BETWEEN GINGIVITIS AND PERIODONTITIS LESIONS REGARDING EXPRESSION OF TET2 AND ISOCITRATE DEHYDROGENASE (IDH) GENES, WHILE THE GLOBAL LEVEL OF 5HMC WAS SIGNIFICANTLY HIGHER IN BLOOD THAN IN TISSUE IN PATIENTS WITH PERIODONTITIS. IT IS SUGGESTED THAT EPIGENETIC CHANGES ARE MORE COMMON IN PERIODONTITIS LESIONS THAN IN GINGIVITIS LESIONS AND THAT SUCH CHANGES ARE TISSUE SPECIFIC. 2016 18 2024 29 EPIGENETIC CHANGES CAUSED BY DIABETES AND THEIR POTENTIAL ROLE IN THE DEVELOPMENT OF PERIODONTITIS. AIMS/INTRODUCTION: PERIODONTAL DISEASE, A CHRONIC INFLAMMATION INDUCED BY BACTERIA, IS CLOSELY LINKED WITH DIABETES MELLITUS. MANY COMPLICATIONS ASSOCIATED WITH DIABETES ARE RELATED TO EPIGENETIC CHANGES. HOWEVER, THE EXACT EPIGENETIC CHANGES WHEREBY DIABETES AFFECTS PERIODONTAL DISEASE REMAIN LARGELY UNKNOWN. THUS, WE SOUGHT TO INVESTIGATE THE ROLE OF DIABETES-DEPENDENT EPIGENETIC CHANGES OF GINGIVAL TISSUE IN THE SUSCEPTIBILITY TO PERIODONTAL DISEASE. MATERIALS AND METHODS: WE STUDIED THE EFFECT OF STREPTOZOTOCIN-INDUCED DIABETES IN MINIPIGS ON GINGIVAL MORPHOLOGICAL AND EPIGENETIC TISSUE CHANGES. ACCORDINGLY, WE RANDOMLY DIVIDED SIX MINIPIGS INTO TWO GROUPS: STREPTOZOTOCIN-INDUCED DIABETES GROUP, N = 3; AND NON-DIABETES HEALTHY CONTROL GROUP, N = 3. AFTER 85 DAYS, ALL ANIMALS WERE KILLED, AND GINGIVAL TISSUE WAS COLLECTED FOR HISTOLOGY, DEOXYRIBONUCLEIC ACID METHYLATION ANALYSIS AND IMMUNOHISTOCHEMISTRY. RESULTS: A DIABETES MELLITUS MODEL WAS SUCCESSFULLY CREATED, AS EVIDENCED BY SIGNIFICANTLY INCREASED BLOOD GLUCOSE LEVELS, REDUCTION OF PANCREATIC INSULIN-PRODUCING BETA-CELLS AND HISTOPATHOLOGICAL CHANGES IN THE KIDNEYS. THE GINGIVAL TISSUES IN THE DIABETES GROUP PRESENTED ACANTHOSIS OF BOTH GINGIVAL SQUAMOUS EPITHELIUM AND SULCULAR/JUNCTIONAL EPITHELIUM, AND A SIGNIFICANT REDUCTION IN THE NUMBER AND LENGTH OF RETE PEGS. DEOXYRIBONUCLEIC ACID METHYLATION ANALYSIS SHOWED A TOTAL OF 1,163 AFFECTED GENES, OF WHICH 599 AND 564 WERE SIGNIFICANTLY HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY. IMMUNOHISTOCHEMISTRY STAINING SHOWED THAT THE HYPOMETHYLATED GENES - TUMOR NECROSIS FACTOR-ALPHA AND INTERLEUKIN-6 - WERE POSITIVELY EXPRESSED UNDER THE JUNCTIONAL EPITHELIUM AREA IN THE DIABETES GROUP. CONCLUSIONS: DIABETES MELLITUS INDUCES MORPHOLOGICAL AND EPIGENETIC CHANGES IN PERIODONTAL TISSUE, WHICH MIGHT CONTRIBUTE TO THE INCREASED SUSCEPTIBILITY OF PERIODONTAL DISEASES IN PATIENTS WITH DIABETES. 2021 19 194 30 ACETYLSHIKONIN SUPPRESSES INVASION OF PORPHYROMONAS GINGIVALIS?INFECTED YD10B ORAL CANCER CELLS BY MODULATING THE INTERLEUKIN-8/MATRIX METALLOPROTEINASE AXIS. THE DEVELOPMENT OF PHARMACEUTICAL AGENTS POSSESSING ANTI?INVASIVE AND ANTI?METASTATIC ABILITIES, AS WELL AS APOPTOTIC ACTIVITY, IS IMPORTANT IN DECREASING THE INCIDENCE AND RECURRENCE OF ORAL CANCER. CANCER CELLS ARE KNOWN TO ACQUIRE INVASIVENESS NOT ONLY THROUGH EPIGENETIC CHANGES, BUT ALSO FROM INFLAMMATORY STIMULI WITHIN THE TUMOR MICROENVIRONMENT. ACCORDINGLY, THE IDENTIFICATION OF AGENTS THAT CAN SUPPRESS THE INFLAMMATION?PROMOTED INVASIVENESS OF CANCER CELLS MAY BE IMPORTANT IN TREATING CANCER AND IMPROVING THE PROGNOSIS OF PATIENTS WITH CANCER. ACETYLSHIKONIN, A FLAVONOID WITH ANTI?INFLAMMATORY ACTIVITY, INHIBITS PROLIFERATION AND INDUCES APOPTOSIS OF ORAL CANCER CELLS. IN THE PRESENT STUDY, THE ANTI?INVASIVE EFFECT OF ACETYLSHIKONIN ON YD10B ORAL CANCER CELLS INFECTED WITH PORPHYROMONAS GINGIVALIS, A MAJOR PATHOGEN OF CHRONIC PERIODONTITIS, AND THE MECHANISMS INVOLVED WERE INVESTIGATED. FIRSTLY, WE EXAMINED WHETHER P. GINGIVALIS INFECTION INCREASED THE INVASIVENESS OF YD10B CELLS. RESULTS SUGGESTED THAT YD10B ORAL CANCER CELLS BECOME MORE AGGRESSIVE WHEN THEY ARE INFECTED WITH P. GINGIVALIS. SECONDLY, ACETYLSHIKONIN SIGNIFICANTLY INHIBITED THE INVASION OF P. GINGIVALIS?INFECTED YD10B CELLS BY SUPPRESSING IL?8 RELEASE AND IL?8?DEPENDENT MMP RELEASE. THESE DATA SUGGEST THAT ACETYLSHIKONIN MAY BE A USEFUL PREVENTIVE AND THERAPEUTIC CANDIDATE FOR ORAL CANCER THAT IS CHRONICALLY INFECTED WITH PERIODONTAL PATHOGENS. 2018 20 1997 18 EPIGENETIC AND INFLAMMATORY EVENTS IN EXPERIMENTAL PERIODONTITIS FOLLOWING SYSTEMIC MICROBIAL CHALLENGE. AIM: THE PURPOSE OF THIS STUDY WAS TO DETERMINE INFLAMMATORY AND EPIGENETIC FEATURES FOLLOWING INDUCTION OF ORAL AND GUT DYSBIOSIS IN EXPERIMENTAL PERIODONTITIS IN ORDER TO EXAMINE THE INTERPLAY BETWEEN ORAL AND SYSTEMIC INFECTION. MATERIALS AND METHODS: PERIODONTITIS WAS INDUCED IN 6- TO 8-WEEK-OLD C57BL/6 MICE BY (A) LIGATURE PLACEMENT (LIG GROUP) (ORAL CHALLENGE); (B) P. GINGIVALIS GAVAGE (PG GROUP) (SYSTEMIC CHALLENGE); AND (C) THE COMBINATION OF THE TWO MODELS ORAL AND SYSTEMIC CHALLENGE (PG + LIG). THE DURATION OF THE EXPERIMENT WAS 60 DAYS, AND THE ANIMALS WERE THEN SACRIFICED FOR ANALYSES. ALVEOLAR BONE LOSS WAS ASSESSED, AND A MULTIPLEX IMMUNOASSAY WAS PERFORMED. MAXILLAE AND GUT TISSUES WERE IMMUNOSTAINED FOR DNMT3B (DE NOVO METHYLATION MARKER), B AND T LYMPHOCYTE ATTENUATOR (BTLA) AND IL-18R1 (INFLAMMATION MARKERS). RESULTS: PG AND PG + LIG GROUPS EXHIBITED HIGHER BONE LOSS WHEN COMPARED TO SHAM. BAFF, VEGF, RANKL, RANTES AND IP-10 WERE SIGNIFICANTLY HIGHER WITH PG GAVAGE. LIKEWISE, DNMT3B WAS OVEREXPRESSED IN BOTH GUT AND MAXILLA AFTER THE PG ADMINISTRATION. THE SAME PATTERN WAS OBSERVED FOR BTLA AND IL-18R1 IN GUT TISSUES. CONCLUSIONS: THE SYSTEMIC MICROBIAL CHALLENGE EITHER ALONE OR IN COMBINATION WITH LOCAL CHALLENGE LEADS TO DISTINCT PATTERNS OF INFLAMMATORY AND EPIGENETIC FEATURES WHEN COMPARED TO SIMPLY LOCALLY INDUCED EXPERIMENTAL PERIODONTITIS. 2019