1  3204 144 HDAC3 REGULATES GINGIVAL FIBROBLAST INFLAMMATORY RESPONSES IN PERIODONTITIS. HISTONE DEACETYLASES (HDACS) ARE IMPORTANT REGULATORS OF GENE EXPRESSION THAT ARE ABERRANTLY REGULATED IN SEVERAL INFLAMMATORY AND INFECTIOUS DISEASES. HDAC INHIBITORS (HDACI) SUPPRESS INFLAMMATORY ACTIVATION OF VARIOUS CELL TYPES THROUGH EPIGENETIC AND NON-EPIGENETIC MECHANISMS, AND AMELIORATE PATHOLOGY IN A MOUSE MODEL OF PERIODONTITIS. ACTIVATION OF GINGIVAL FIBROBLASTS (GFS) SIGNIFICANTLY CONTRIBUTES TO THE DEVELOPMENT OF PERIODONTITIS AND THE ANAEROBIC BACTERIUM PORPHYROMONAS GINGIVALIS PLAYS A KEY ROLE IN DRIVING CHRONIC INFLAMMATION. HERE, WE ANALYZED THE ROLE OF HDACS IN INFLAMMATORY RESPONSES OF GFS. PAN-HDACI SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) AND/OR ITF2357 (GIVINOSTAT) SIGNIFICANTLY REDUCED TNFALPHA- AND P. GINGIVALIS-INDUCIBLE EXPRESSION AND/OR PRODUCTION OF A CLUSTER OF INFLAMMATORY MEDIATORS IN HEALTHY DONOR GFS (IL1B, CCL2, CCL5, CXCL10, COX2, AND MMP3) WITHOUT AFFECTING CELL VIABILITY. SELECTIVE INHIBITION OF HDAC3/6, BUT NOT SPECIFIC HDAC1, HDAC6, OR HDAC8 INHIBITION, REPRODUCED THE SUPPRESSIVE EFFECTS OF PAN-HDACI ON THE INFLAMMATORY GENE EXPRESSION PROFILE INDUCED BY TNFALPHA AND P. GINGIVALIS, SUGGESTING A CRITICAL ROLE FOR HDAC3 IN GF INFLAMMATORY ACTIVATION. CONSISTENTLY, SILENCING OF HDAC3 EXPRESSION WITH SIRNA LARGELY RECAPITULATED THE EFFECTS OF HDAC3/6I ON MRNA LEVELS OF INFLAMMATORY MEDIATORS IN P. GINGIVALIS-INFECTED GFS. IN CONTRAST, P. GINGIVALIS INTERNALIZATION AND INTRACELLULAR SURVIVAL IN GFS REMAINED UNAFFECTED BY HDACI. ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASES AND NFKAPPAB SIGNALING WAS UNAFFECTED BY GLOBAL OR HDAC3/6-SELECTIVE HDACI, AND NEW PROTEIN SYNTHESIS WAS NOT REQUIRED FOR GENE SUPPRESSION BY HDACI. FINALLY, PAN-HDACI AND HDAC3/6I SUPPRESSED P. GINGIVALIS-INDUCED EXPRESSION OF IL1B, CCL2, CCL5, CXCL10, MMP1, AND MMP3 IN GFS FROM PATIENTS WITH PERIODONTITIS. OUR RESULTS IDENTIFY HDAC3 AS AN IMPORTANT REGULATOR OF INFLAMMATORY GENE EXPRESSION IN GFS AND SUGGEST THAT THERAPEUTIC TARGETING OF HDAC ACTIVITY, IN PARTICULAR HDAC3, MAY BE CLINICALLY BENEFICIAL IN SUPPRESSING INFLAMMATION IN PERIODONTAL DISEASE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2   589  73 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
3  5375  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4  3235  37 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	

5  5114  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6  2241  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  3785  21 INTERGENERATIONAL EFFECTS OF PRE-PREGNANCY CHRONIC LIPOPOLYSACCHARIDE FROM PORPHYROMONAS GINGIVALIS ON THE LEARNING, MEMORY AND SEIZURE SUSCEPTIBILITY OF OFFSPRING. OBJECTIVE: THE AIM OF THIS STUDY WAS TO INVESTIGATE THE EFFECTS OF PRE-PREGNANCY CHRONIC EXPOSURE TO PORPHYROMONAS GINGIVALIS LPS (PG LPS) ON THE LEARNING, MEMORY, AND SEIZURE SUSCEPTIBILITY OF THE OFFSPRING. DESIGN: TO ACHIEVE PERIODONTITIS, PG LPS (5 MUG/KG) WAS INJECTED INTO THE GINGIVAL OF FIVE FEMALE RATS EVERY 48 H FOR THREE WEEKS. FIVE CONTROL FEMALE RATS RECEIVED SALINE (0.9 %) AND FIVE FEMALE WERE KEPT INTACT. THE CONCENTRATIONS OF TNF-ALPHA AND IL-6 WERE MEASURED IN THE BLOOD SAMPLES. ONE WEEK AFTER THE FINAL INJECTION, FEMALES WERE MATED WITH INTACT MALES. FOLLOWING BIRTH AND WEANING, TWO MALE AND TWO FEMALE OFFSPRING WERE RANDOMLY SELECTED FROM EACH MOTHER, AND NEW GROUPS OF MALE AND FEMALE OFFSPRING WERE DEFINED FOR BEHAVIORAL ASSESSMENTS. MORRIS WATER MAZE WAS USED TO EVALUATE SPATIAL MEMORY, SHUTTLE BOX WAS USED TO INVESTIGATE AVOIDANCE MEMORY AND A PENTYLENETETRAZOLE-INDUCED SEIZURE WAS USED TO EVALUATE SEIZURE SUSCEPTIBILITY IN THE OFFSPRING. RESULTS: SPATIAL LEARNING AND AVOIDANCE MEMORY SIGNIFICANTLY DECREASED IN BOTH MALE AND FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE RATS, COMPARED TO THE CONTROL OFFSPRING. LATENCY TO REACH SEIZURE STAGES 1 AND 2 SIGNIFICANTLY INCREASED IN THE MALE OFFSPRING, BUT NOT THE FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE, COMPARED TO THE CONTROL OFFSPRING. HOWEVER, NO SIGNIFICANT DIFFERENCE WAS FOUND IN LATENCY TO REACH STAGES 3-5. CONCLUSION: PRE-PREGNANCY EXPOSURE TO PG LPS COULD AFFECT SOME BEHAVIORAL FUNCTIONS IN BOTH MALE AND FEMALE OFFSPRING INTERGENERATIONALLY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8   194  41 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9  6589  37 TUMOR NECROSIS FACTOR-ALPHA GENE PROMOTER METHYLATION IN JAPANESE ADULTS WITH CHRONIC PERIODONTITIS AND RHEUMATOID ARTHRITIS. BACKGROUND AND OBJECTIVE: OVER-EXPRESSION OF TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) PLAYS A PATHOLOGICAL ROLE IN CHRONIC PERIODONTITIS (CP) AND RHEUMATOID ARTHRITIS (RA), WHICH MIGHT BE REGULATED BY THE EPIGENETIC MECHANISM. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE WHETHER THERE IS A UNIQUE METHYLATION PROFILE OF THE TNF-ALPHA GENE PROMOTER IN BLOOD CELLS OF INDIVIDUALS WITH CP AND RA. MATERIAL AND METHODS: THE STUDY PARTICIPANTS CONSISTED OF 30 JAPANESE ADULTS WITH RA (RA GROUP), 30 RACE-MATCHED ADULTS WITH CP ONLY (CP GROUP) AND 30 RACE-MATCHED HEALTHY CONTROLS (H GROUP). GENOMIC DNA ISOLATED FROM PERIPHERAL BLOOD WAS MODIFIED BY SODIUM BISULFITE AND ANALYZED, BY DIRECT SEQUENCING, TO INVESTIGATE DNA METHYLATION OF THE TNF-ALPHA GENE PROMOTER REGION. THE LEVEL OF TNF-ALPHA PRODUCED IN MONONUCLEAR CELLS STIMULATED WITH PORPHYROMONAS GINGIVALIS LIPOPOLYSACCHARIDE WAS DETERMINED USING ELISA. RESULTS: TWELVE CYTOSINE-GUANINE DINUCLEOTIDE (CPG) MOTIFS WERE IDENTIFIED IN THE TNF-ALPHA PROMOTER FRAGMENT FROM -343 TO +57 BP. THE CP GROUP SHOWED A SIGNIFICANTLY HIGHER METHYLATION RATE AND FREQUENCY AT -72 BP THAN THE H GROUP (P < 0.01). THE RA GROUP EXHIBITED SIGNIFICANTLY HIGHER METHYLATION RATES AT SEVEN CPG MOTIFS (-302, -163, -119, -72, -49, -38 AND +10 BP), AND SIGNIFICANTLY HIGHER METHYLATION FREQUENCIES AT SIX CPG MOTIFS (-163, -119, -72, -49, -38 AND +10 BP), THAN THE H GROUP (P < 0.01 FOR ALL COMPARISONS). THE LEVELS OF TNF-ALPHA PRODUCED WERE SIGNIFICANTLY DIFFERENT BETWEEN INDIVIDUALS WITH AND WITHOUT METHYLATION AT -163 BP (P = 0.03). CONCLUSION: THESE RESULTS SUGGEST THAT THE HYPERMETHYLATED STATUS OF CPG MOTIFS IN THE TNF-ALPHA GENE PROMOTER IN BLOOD CELLS MAY BE UNIQUE TO JAPANESE ADULTS WITH CP AND RA.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  6580  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11   655  38 BLOCKADE OF IMMUNE-CHECKPOINT B7-H4 AND LYSINE DEMETHYLASE 5B IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA CONFERS PROTECTIVE IMMUNITY AGAINST P. GINGIVALIS INFECTION. PATHOGENS ARE CAPABLE OF HIJACKING IMMUNE DEFENSE MECHANISMS, THEREBY CREATING A TOLEROGENIC ENVIRONMENT FOR HYPERMUTATED MALIGNANT CELLS THAT ARISE WITHIN THE SITE OF INFECTION. IMMUNE CHECKPOINT-ORIENTED IMMUNOTHERAPIES HAVE SHOWN CONSIDERABLE PROMISE. EQUALLY IMPORTANT, THE EPIGENETIC REPROGRAMMING OF AN IMMUNE-EVASIVE PHENOTYPE THAT ACTIVATES THE IMMUNE SYSTEM IN A SYNERGISTIC MANNER CAN IMPROVE IMMUNOTHERAPY OUTCOMES. THESE ADVANCES HAVE LED TO COMBINATIONS OF EPIGENETIC- AND IMMUNE-BASED THERAPEUTICS. WE PREVIOUSLY DEMONSTRATED THAT PORPHYROMONAS GINGIVALIS ISOLATED FROM ESOPHAGEAL SQUAMOUS CELL CARCINOMA (ESCC) LESIONS REPRESENTS A MAJOR PATHOGEN ASSOCIATED WITH THIS DEADLY DISEASE. IN THIS STUDY, WE EXAMINED THE MECHANISMS ASSOCIATED WITH HOST IMMUNITY DURING P. GINGIVALIS INFECTION AND DEMONSTRATED THAT EXPERIMENTALLY INFECTED ESCC RESPONDS BY INCREASING THE EXPRESSION OF B7-H4 AND LYSINE DEMETHYLASE 5B, WHICH ALLOWED SUBSEQUENT IN VIVO ANALYSIS OF THE IMMUNOTHERAPEUTIC EFFECTS OF ANTI-B7-H4 AND HISTONE DEMETHYLASE INHIBITORS IN MODELS OF CHRONIC INFECTION AND IMMUNITY AGAINST XENOGRAFTED HUMAN TUMORS. USING THREE DIFFERENT PRECLINICAL MOUSE MODELS RECEIVING COMBINED THERAPY, WE SHOWED THAT MICE MOUNTED STRONG RESISTANCE AGAINST P. GINGIVALIS INFECTION AND TUMOR CHALLENGE. THIS MAY HAVE OCCURRED VIA GENERATION OF A T CELL-MEDIATED RESPONSE IN THE MICROENVIRONMENT AND FORMATION OF IMMUNE MEMORY. IN ESCC SUBJECTS, COEXPRESSION OF B7-H4 AND KDM5B CORRELATED MORE SIGNIFICANTLY WITH BACTERIAL LOAD THAN WITH THE EXPRESSION OF EITHER MOLECULE ALONE. THESE RESULTS HIGHLIGHT THE UNIQUE ABILITY OF P. GINGIVALIS TO EVADE IMMUNITY AND DEFINE POTENTIAL TARGETS THAT CAN BE EXPLOITED THERAPEUTICALLY TO IMPROVE THE CONTROL OF P. GINGIVALIS INFECTION AND THE DEVELOPMENT OF ASSOCIATED NEOPLASIA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
12  2374  40 EPIGENETIC REGULATION OF TNFA EXPRESSION IN PERIODONTAL DISEASE. BACKGROUND: TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) PLAYS A CENTRAL ROLE IN THE MOLECULAR PATHOGENESIS OF PERIODONTAL DISEASE. HOWEVER, THE EPIGENETIC REGULATION ATTRIBUTABLE TO MICROBIAL AND INFLAMMATORY SIGNALS AT THE BIOFILM-GINGIVAL INTERFACE ARE POORLY UNDERSTOOD. IN THIS STUDY, THE DNA METHYLATION ALTERATION WITHIN THE TNFA PROMOTER IN HUMAN GINGIVAL BIOPSIES FROM DIFFERENT STAGES OF PERIODONTAL DISEASE IS INVESTIGATED AND THE REGULATORY MECHANISM OF TNFA TRANSCRIPTION BY DNA METHYLATION IS EXPLORED. METHODS: GINGIVAL BIOPSIES WERE OBTAINED FROM 17 PATIENTS WITH CHRONIC PERIODONTITIS (CP) AND 18 PERIODONTALLY HEALTHY INDIVIDUALS. ANOTHER 11 INDIVIDUALS PARTICIPATED IN AN EXPERIMENTALLY INDUCED GINGIVITIS STUDY, AND GINGIVAL BIOPSIES WERE COLLECTED AT THE BASELINE, INDUCTION, AND RESOLUTION PHASE. TO CONFIRM THAT TNFA PROMOTER METHYLATION MODULATED TNFA TRANSCRIPTION, THP.1 CELLS WERE TREATED WITH A DNA METHYLTRANSFERASE INHIBITOR, 5-AZA-2-DEOXYCYTIDINE (5-AZA-2DC), AND AN RAW294.7 CELL LINE TRANSFECTED WITH A TNFA PROMOTER-SPECIFIC LUCIFERASE REPORTER SYSTEM WITH OR WITHOUT METHYLATION WAS USED. RESULTS: IN GINGIVAL BIOPSIES FROM INDIVIDUALS WITH SEVERE CP, TWO INDIVIDUAL CYTOSINE-GUANINE DINUCLEOTIDES (CPG SITES) WITHIN THE TNFA PROMOTER (AT -163 AND -161 BP) DISPLAYED INCREASED METHYLATION IN CP SAMPLES COMPARED TO THOSE WITH GINGIVAL HEALTH (16.1% +/- 5.1% VERSUS 11.0% +/- 4.6%, P = 0.02 AND 19.8% +/- 4.1% VERSUS 15.4% +/- 3.6%, P = 0.04, RESPECTIVELY). THE METHYLATION LEVEL AT -163 BP WAS INVERSELY ASSOCIATED WITH THE TRANSCRIPTION LEVEL OF TNFA (P = 0.018). HOWEVER, NO SIGNIFICANT DIFFERENCE IN THE TNFA PROMOTER METHYLATION PATTERN WAS OBSERVED IN SAMPLES BIOPSIED DURING THE INDUCTION OR RESOLUTION PHASE OF EXPERIMENTALLY INDUCED GINGIVITIS, WHICH REPRESENTED A REVERSIBLE PERIODONTAL LESION. THP.1 CELLS TREATED WITH 5-AZA-2DC DEMONSTRATED A TIME-DEPENDENT INCREASE IN TNFA MESSENGER LEVEL. IT WAS ALSO FOUND THAT THE LUCIFERASE ACTIVITY DECREASED 2.6-FOLD IN A CONSTRUCT CONTAINING AN IN VITRO METHYLATED TNFA PROMOTER WHEN COMPARED TO THE UNMETHYLATED INSERT (P = 0.03). CONCLUSION: ALTHOUGH THE BIOPSY SAMPLES REPRESENTED A MIXED CELL POPULATION, THE CHANGE IN PROMOTER METHYLATION STATUS IN CHRONIC PERIODONTAL DISEASE SUGGESTED THAT DNA METHYLATION MAY BE AN IMPORTANT REGULATORY MECHANISM IN CONTROLLING TNFA TRANSCRIPTIONAL EXPRESSION IN PERIODONTAL DISEASE.	2013	
                                                                                                                                                                                      
13  1997  20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  6581  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15  5802  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16  6795  19 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17  3440  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  2766  36 EXPRESSION, POLYMORPHISM AND METHYLATION PATTERN OF INTERLEUKIN-6 IN PERIODONTAL TISSUES. PERIODONTITIS IS CONSIDERED AN INFLAMMATORY DISORDER OF BACTERIAL ETIOLOGY THAT RESULTS IN PERIODONTAL TISSUE DESTRUCTION, AS A RESULT OF COMPLEX INTERACTIONS BETWEEN PERIODONTAL PATHOGENS, HOST AND IMMUNE RESPONSE. GENETIC AND EPIGENETIC MECHANISMS MAY MODULATE THE INDIVIDUAL RESPONSE SINCE IT IS ABLE TO INFLUENCE THE GENE EXPRESSION. THE AIM OF THIS STUDY WAS TO EVALUATE THE IMPACT OF -174 G/C POLYMORPHISM AND THE METHYLATION STATUS OF THE PROMOTER REGION OF IL-6 GENE ON THE EXPRESSION OF IL-6 IN GINGIVAL SAMPLES FROM INDIVIDUALS WITH CHRONIC PERIODONTITIS. GINGIVAL BIOPSIES WERE COLLECTED FROM 21 PATIENTS WITH CHRONIC PERIODONTITIS AND 21 CONTROLS. HISTOLOGIC SECTIONS STAINED BY HEMATOXYLIN-EOSIN WERE USED FOR HISTOPATHOLOGICAL EVALUATION. THE IL-6 GENE EXPRESSION WAS ASSESSED BY QUANTITATIVE REAL-TIME PCR. THE POLYMORPHISM IL-6 -174 C/G WAS STUDIED BY POLYMERASE CHAIN REACTION (PCR) AMPLIFICATION AND RESTRICTION ENDONUCLEASE DIGESTION (HSPII). METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION WAS USED TO VERIFY THE DNA METHYLATION PATTERN. THE NUMBER OF INFLAMMATORY CELLS IN TISSUE FRAGMENTS FROM INDIVIDUALS WITH CHRONIC PERIODONTITIS WAS HIGHER THAN IN THE CONTROL GROUP AND THE INFLAMMATORY INFILTRATE WAS PREDOMINANTLY MONONUCLEAR. THE EXPRESSION OF IL-6 WAS HIGHER IN THE GROUP WITH PERIODONTITIS. IN POLYMORPHISM ASSAY, NO STATISTICAL DIFFERENCE IN THE DISTRIBUTION OF GENOTYPES AND ALLELES IN BOTH GROUPS WERE OBSERVED. THE MOST OF SAMPLES WERE PARTIALLY METHYLATED. NO DIFFERENCE WAS OBSERVED IN METHYLATION PATTERN FROM TWO DIFFERENT REGIONS OF THE IL-6 GENE AMONG GROUPS. THE HIGH EXPRESSION OF IL-6 IS AN IMPORTANT FACTOR RELATED TO CHRONIC PERIODONTITIS, BUT WAS NOT ASSOCIATED WITH METHYLATION STATUS OR THE -174 (G/C) GENETIC POLYMORPHISM, SUGGESTING THAT OTHER MECHANISMS ARE INVOLVED IN THIS GENE TRANSCRIPTION REGULATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  6111  25 THE EPIGENETIC ARCHITECTURE AT GENE PROMOTERS DETERMINES CELL TYPE-SPECIFIC LPS TOLERANCE. SYNOVIAL FIBROBLASTS (SF) DRIVE INFLAMMATION AND JOINT DESTRUCTION IN CHRONIC ARTHRITIS. HERE WE SHOW THAT SF POSSESS A DISTINCT TYPE OF LPS TOLERANCE COMPARED TO MACROPHAGES AND OTHER TYPES OF FIBROBLASTS. IN SF AND DERMAL FIBROBLASTS, GENES THAT WERE NON-TOLERIZABLE AFTER REPEATED LPS STIMULATION INCLUDED PRO-INFLAMMATORY CYTOKINES, CHEMOKINES AND MATRIX METALLOPROTEINASES, WHEREAS ANTI-VIRAL GENES WERE TOLERIZABLE. IN MACROPHAGES, ALL MEASURED GENES WERE TOLERIZABLE, WHEREAS IN GINGIVAL AND FORESKIN FIBROBLASTS THESE GENES WERE NON-TOLERIZABLE. REPEATED STIMULATION OF SF WITH LPS RESULTED IN LOSS OF ACTIVATING HISTONE MARKS ONLY IN PROMOTERS OF TOLERIZABLE GENES. THE EPIGENETIC LANDSCAPE AT PROMOTERS OF TOLERIZABLE GENES WAS SIMILAR IN UNSTIMULATED SF AND MONOCYTES, WHEREAS THE BASAL CONFIGURATION OF HISTONE MARKS PROFOUNDLY DIFFERED IN GENES THAT WERE NON-TOLERIZABLE IN SF ONLY. OUR DATA SUGGEST THAT THE EPIGENETIC CONFIGURATION AT GENE PROMOTERS REGULATES CELL-SPECIFIC LPS-INDUCED RESPONSES AND PRIMES SF TO SUSTAIN THEIR INFLAMMATORY RESPONSE IN CHRONIC ARTHRITIS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  2762  30 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