1 6580 109 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 2 6581 45 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 3 5802 37 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 4 1141 27 CONCERTED CELL AND IN VIVO SCREEN FOR PANCREATIC DUCTAL ADENOCARCINOMA (PDA) CHEMOTHERAPEUTICS. PDA IS A MAJOR CAUSE OF US CANCER-RELATED DEATHS. ONCOGENIC KRAS PRESENTS IN 90% OF HUMAN PDAS. KRAS MUTATIONS OCCUR EARLY IN PRE-NEOPLASTIC LESIONS BUT ARE INSUFFICIENT TO CAUSE PDA. OTHER CONTRIBUTING FACTORS EARLY IN DISEASE PROGRESSION INCLUDE CHRONIC PANCREATITIS, ALTERATIONS IN EPIGENETIC REGULATORS, AND TUMOR SUPPRESSOR GENE MUTATION. GPCRS ACTIVATE HETEROTRIMERIC G-PROTEINS THAT STIMULATE INTRACELLULAR CALCIUM AND ONCOGENIC KRAS SIGNALING, THEREBY PROMOTING PANCREATITIS AND PROGRESSION TO PDA. BY CONTRAST, RGS PROTEINS INHIBIT GI/Q-COUPLED GPCRS TO NEGATIVELY REGULATE PDA PROGRESSION. RGS16::GFP IS EXPRESSED IN RESPONSE TO CAERULEIN-INDUCED ACINAR CELL DEDIFFERENTIATION, EARLY NEOPLASIA, AND THROUGHOUT PDA PROGRESSION. IN GENETICALLY ENGINEERED MOUSE MODELS OF PDA, RGS16::GFP IS USEFUL FOR PRE-CLINICAL RAPID IN VIVO VALIDATION OF NOVEL CHEMOTHERAPEUTICS TARGETING EARLY LESIONS IN PATIENTS FOLLOWING SUCCESSFUL RESECTION OR AT HIGH RISK FOR PROGRESSING TO PDA. CULTURED PRIMARY PDA CELLS EXPRESS RGS16::GFP IN RESPONSE TO CYTOTOXIC DRUGS. A HISTONE DEACETYLASE INHIBITOR, TSA, STIMULATED RGS16::GFP EXPRESSION IN PDA PRIMARY CELLS, POTENTIATED GEMCITABINE AND JQ1 CYTOTOXICITY IN CELL CULTURE, AND GEM + TSA + JQ1 INHIBITED TUMOR INITIATION AND PROGRESSION IN VIVO. HERE WE ESTABLISH THE USE OF RGS16::GFP EXPRESSION FOR TESTING DRUG COMBINATIONS IN CELL CULTURE AND VALIDATION OF BEST CANDIDATES IN OUR RAPID IN VIVO SCREEN. 2020 5 6795 21 [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 6 5114 37 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 7 2223 25 EPIGENETIC MODIFICATIONS IN SPINAL LIGAMENT AGING. SPINAL STENOSIS IS A COMMON DEGENERATIVE SPINE DISORDER IN THE AGED POPULATION AND THE SPINAL LIGAMENT AGING IS A MAIN CONTRIBUTOR TO THIS CHRONIC DISEASE. HOWEVER, THE UNDERLYING MECHANISMS OF SPINAL LIGAMENT AGING REMAIN UNCLEAR. EPIGENETICS IS THE STUDY OF HERITABLE AND REVERSIBLE CHANGES IN THE FUNCTION OF A GENE OR GENOME THAT OCCUR WITHOUT ANY ALTERATION IN THE PRIMARY DNA SEQUENCE. EPIGENETIC ALTERATIONS HAVE BEEN DEMONSTRATED TO PLAY CRUCIAL ROLES IN AGE-RELATED DISEASES AND CONDITIONS, AND THEY ARE RECENTLY STUDIED AS BIOMARKERS AND THERAPEUTIC TARGETS IN THE FIELD OF CANCER RESEARCH. THE MAIN EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION ALTERATION, HISTONE MODIFICATIONS AS WELL AS DYSREGULATED NONCODING RNA MODULATION, HAVE ALL BEEN IMPLICATED IN SPINAL LIGAMENT AGING DISEASES. DNA METHYLATION MODULATES THE EXPRESSION OF CRITICAL GENES INCLUDING WNT5A, GDNF, ACSM5, MIR-497 AND MIR-195 DURING SPINAL LIGAMENT DEGENERATION. HISTONE MODIFICATIONS WIDELY AFFECT GENE EXPRESSION AND OBVIOUS HISTONE MODIFICATION ABNORMALITIES HAVE BEEN FOUND IN SPINAL LIGAMENT AGING. MICRORNAS (MIRNAS), LONG NONCODING RNAS (LNCRNAS) AND CIRCULAR RNAS (CIRCRNAS) EXERT CRUCIAL REGULATING EFFECTS ON SPINAL LIGAMENT AGING CONDITIONS VIA TARGETING VARIOUS OSTEOGENIC OR FIBROGENIC DIFFERENTIATION RELATED GENES. TO OUR KNOWLEDGE, THERE IS NO SYSTEMATIC REVIEW YET TO SUMMARIZE THE INVOLVEMENT OF EPIGENETIC MECHANISMS OF SPINAL LIGAMENT AGING IN DEGENERATIVE SPINAL DISEASES. IN THIS STUDY, WE SYSTEMATICALLY DISCUSSED THE DIFFERENT EPIGENETIC MODIFICATIONS AND THEIR POTENTIAL FUNCTIONS IN SPINAL LIGAMENT AGING PROCESS. 2022 8 589 28 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 9 2784 26 EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. PULPITIS IS A COMPLICATED CHRONIC INFLAMMATORY PROCESS WHICH CAN BE IN A DYNAMIC BALANCE BETWEEN DAMAGE AND REPAIR. THE EXTRACELLULAR MATRIX PLAYS AN IMPORTANT REGULATORY ROLE IN WOUND HEALING AND TISSUE REPAIR. THE AIM OF THIS STUDY WAS TO EXPLORE THE ROLE OF THE EPIGENETIC MARK, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) ON THE DEGRADATION OF EXTRACELLULAR MATRIX DURING PULPITIS. QUANTITATIVE POLYMERASE CHAIN REACTION WAS USED TO ASSESS THE EXPRESSION OF MATRIX METALLOPROTEINASES (MMPS) AND TYPE I COLLAGEN IN HUMAN DENTAL PULP CELLS (HDPCS) UPON EZH2 AND EI1 (EZH2 INHIBITOR) STIMULATION. THE MECHANISM OF EZH2 AFFECTING EXTRACELLULAR MATRIX WAS EXPLORED THROUGH QUANTITATIVE POLYMERASE CHAIN REACTION AND WESTERN BLOT. A RAT MODEL OF DENTAL PULP INFLAMMATION WAS ESTABLISHED, AND THE EXPRESSION OF TYPE I COLLAGEN IN DENTAL PULP UNDER EZH2 STIMULATION WAS DETECTED BY IMMUNOHISTOCHEMICAL STAINING. EZH2 UPREGULATED THE EXPRESSION OF MMP-1, MMP-3, MMP-8, AND MMP-10 AND DECREASED THE PRODUCTION OF TYPE I COLLAGEN IN HDPCS, WHILE EI1 HAD THE OPPOSITE EFFECT. EZH2 ACTIVATED THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN HDPCS, THE INHIBITION OF WHICH REVERSED THE INDUCTION OF MMPS AND THE SUPPRESSION OF TYPE I COLLAGEN. EZH2 CAN DOWNREGULATE THE TYPE I COLLAGEN LEVELS IN AN EXPERIMENTAL MODEL OF DENTAL PULPITIS IN RATS. EZH2 PROMOTES EXTRACELLULAR MATRIX DEGRADATION VIA NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 SIGNALING PATHWAYS IN PULPITIS. EZH2 CAN DECREASE THE TYPE I COLLAGEN LEVELS IN VIVO AND IN VITRO. 2021 10 3204 35 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 11 2228 29 EPIGENETIC MODIFICATIONS OF HISTONES IN PERIODONTAL DISEASE. PERIODONTITIS IS A CHRONIC INFECTIOUS DISEASE DRIVEN BY DYSBIOSIS, AN IMBALANCE BETWEEN COMMENSAL BACTERIA AND THE HOST ORGANISM. PERIODONTITIS IS A LEADING CAUSE OF TOOTH LOSS IN ADULTS AND OCCURS IN ABOUT 50% OF THE US POPULATION. IN ADDITION TO THE CLINICAL CHALLENGES ASSOCIATED WITH TREATING PERIODONTITIS, THE PROGRESSION AND CHRONIC NATURE OF THIS DISEASE SERIOUSLY AFFECT HUMAN HEALTH. EMERGING EVIDENCE SUGGESTS THAT PERIODONTITIS IS ASSOCIATED WITH MECHANISMS BEYOND BACTERIA-INDUCED PROTEIN AND TISSUE DEGRADATION. HERE, WE HYPOTHESIZE THAT BACTERIA ARE ABLE TO INDUCE EPIGENETIC MODIFICATIONS IN ORAL EPITHELIAL CELLS MEDIATED BY HISTONE MODIFICATIONS. IN THIS STUDY, WE FOUND THAT DYSBIOSIS IN VIVO LED TO EPIGENETIC MODIFICATIONS, INCLUDING ACETYLATION OF HISTONES AND DOWNREGULATION OF DNA METHYLTRANSFERASE 1. IN ADDITION, IN VITRO EXPOSURE OF ORAL EPITHELIAL CELLS TO LIPOPOLYSACCHARIDES RESULTED IN HISTONE MODIFICATIONS, ACTIVATION OF TRANSCRIPTIONAL COACTIVATORS, SUCH AS P300/CBP, AND ACCUMULATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB). GIVEN THAT ORAL EPITHELIAL CELLS ARE THE FIRST LINE OF DEFENSE FOR THE PERIODONTIUM AGAINST BACTERIA, WE ALSO EVALUATED WHETHER ACTIVATION OF PATHOGEN RECOGNITION RECEPTORS INDUCED HISTONE MODIFICATIONS. WE FOUND THAT ACTIVATION OF THE TOLL-LIKE RECEPTORS 1, 2, AND 4 AND THE NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1 INDUCED HISTONE ACETYLATION IN ORAL EPITHELIAL CELLS. OUR FINDINGS CORROBORATE THE EMERGING CONCEPT THAT EPIGENETIC MODIFICATIONS PLAY A ROLE IN THE DEVELOPMENT OF PERIODONTITIS. 2016 12 5585 31 ROLE OF OXIDATIVE STRESS AND GENETIC POLYMORPHISM OF MATRIX METALLOPROTEINASE-2 AND TISSUE INHIBITOR OF METALLOPROTEINASE-2 IN COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), A COMPLAINT DESCRIBED BY PROGRESSIVE AND INADEQUATELY REVERSIBLE LIMITATION IN LUNGS WITH SYSTEMIC INFLAMMATION, IS LARGELY CURRENT IN INDIA. THERE'S NO REMEDY AVAILABLE SO FAR IT IS, THUS, IMPERATIVE TO UNDERSTAND THE UNDERPINNING PATHOGENESIS OF THE COMPLAINANT. A SET OF PROTEASES KNOWN AS MATRIX METALLOPROTEINASE (MMPS) ARE ESPECIALLY INVOLVED IN THE PROCESS OF ALVEOLAR DESTRUCTION AND MUCUS HYPERSECRETION. THERE ARE RESPONSIBLE FACTORS IN AN INHERITABLE POSITION TO CONTROL COPD LIKE MMPS AND TIMPS (TISSUE INHIBITOR OF METALLOPROTEINASES). MMPS DEGRADE EXTRACELLULAR MATRIX AND LEAD TO THE PATHOGENESIS OF COPD [1]. TIMPS PROTEINS THAT HELP TO INHIBIT THE MATRIX METALLOPROTEINASES. [2]. THIS REVIEW SUMMARIZES THE IMPLICIT PART OF CRUCIAL MMP-2 AND TIMP-2 IN COPD DISEASE. THOUGH THE CONCEPT SEEMS PROMISING, LIMITED KNOWLEDGE ABOUT THE EXACT FUNCTIONS OF A PARTICULAR MMP IN COPD AND THE COMPLICATIONS OF MMP IN SUBSTRATE AFFINITY MAKES THIS A GRUELING TASK. MMP2 AND TIMP2 BOTH ARE DIRECTLY OR INDIRECTLY REGULATED BY OXIDATIVE STRESS AND EPIGENETIC MECHANISM WHICH REGULATES THEIR EXPRESSIONS. COPD IS A SEDITIOUS RESPONSE TO FACTORS LIKE DUST, SMOKE, ETC., AND TRIGGERS EXTRA-PULMONARY GOODS WHICH CAUSE INFLAMMATION. [3]. THIS REVIEW EXPLAINS THE RELATIONSHIP BETWEEN MMP2 AND TIMP2 IN COPD PATIENTS WITH OXIDATIVE STRESS, ITS IMPACT ON COPD PATHOGENESIS, AND GENE EXPRESSION OF TIMP2 AND MMP2 WITH THEIR DOWNSTREAM EFFECTS. THIS ALSO GIVES SOME INSIGHTS INTO THERAPEUTIC INTERVENTIONS FOR TARGETING THESE ENZYMES. MMP2 AND TIMP2 BOTH PLAY A ROLE IN THE DEVELOPMENT OF COPD AND THEY NEED TO BE STUDIED WITH THE UTMOST FOCUS. 2023 13 4493 33 MORAXELLA CATARRHALIS INDUCES INFLAMMATORY RESPONSE OF BRONCHIAL EPITHELIAL CELLS VIA MAPK AND NF-KAPPAB ACTIVATION AND HISTONE DEACETYLASE ACTIVITY REDUCTION. MORAXELLA CATARRHALIS IS A MAJOR CAUSE OF INFECTIOUS EXACERBATIONS OF CHRONIC OBSTRUCTIVE LUNG DISEASE (COPD) AND MAY ALSO CONTRIBUTE TO THE PATHOGENESIS OF COPD. LITTLE IS KNOWN ABOUT M. CATARRHALIS-BRONCHIAL EPITHELIUM INTERACTION. WE INVESTIGATED ACTIVATION OF M. CATARRHALIS INFECTED BRONCHIAL EPITHELIAL CELLS AND CHARACTERIZED THE SIGNAL TRANSDUCTION PATHWAYS. MOREOVER, WE TESTED THE HYPOTHESIS THAT THE M. CATARRHALIS-INDUCED CYTOKINE EXPRESSION IS REGULATED BY ACETYLATION OF HISTONE RESIDUES AND CONTROLLED BY HISTONE DEACETYLASE ACTIVITY (HDAC). WE DEMONSTRATED THAT M. CATARRHALIS INDUCED A STRONG TIME- AND DOSE-DEPENDENT INFLAMMATORY RESPONSE IN THE BRONCHIAL EPITHELIAL CELL LINE (BEAS-2B), CHARACTERIZED BY THE RELEASE OF IL-8 AND GM-CSF. FOR THIS CYTOKINE LIBERATION ACTIVATION OF THE ERK AND P38 MITOGEN-ACTIVATED PROTEIN (MAP) KINASES AND TRANSCRIPTION FACTOR NF-KAPPAB WAS REQUIRED. FURTHERMORE, M. CATARRHALIS-INFECTED BRONCHIAL EPITHELIAL CELLS SHOWED AN ENHANCED ACETYLATION OF HISTONE H3 AND H4 GLOBALLY AND AT THE PROMOTER OF THE IL8 GENE. PREVENTING HISTONE DEACETYLATION BY THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A AUGMENTED THE M. CATARRHALIS-INDUCED IL-8 RESPONSE. AFTER EXPOSURE TO M. CATARRHALIS, WE FOUND A DECREASE IN GLOBAL HISTONE DEACETYLASE EXPRESSION AND ACTIVITY. OUR FINDINGS SUGGEST THAT M. CATARRHALIS-INDUCED ACTIVATION OF IL8 GENE TRANSCRIPTION WAS CAUSED BY INTERFERENCE WITH EPIGENETIC MECHANISMS REGULATING IL8 GENE ACCESSIBILITY. OUR FINDINGS PROVIDE INSIGHT INTO IMPORTANT MOLECULAR AND CELLULAR MECHANISMS OF M. CATARRHALIS-INDUCED ACTIVATION OF HUMAN BRONCHIAL EPITHELIUM. 2006 14 6332 20 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 15 3440 24 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 16 3678 25 INFLAMMATION AND REGENERATION IN THE DENTIN-PULP COMPLEX: A DOUBLE-EDGED SWORD. DENTAL TISSUE INFECTION AND DISEASE RESULT IN ACUTE AND CHRONIC ACTIVATION OF THE INNATE IMMUNE RESPONSE, WHICH IS MEDIATED BY MOLECULAR AND CELLULAR SIGNALING. DIFFERENT CELL TYPES WITHIN THE DENTIN-PULP COMPLEX ARE ABLE TO DETECT INVADING BACTERIA AT ALL STAGES OF THE INFECTION. INDEED, AT RELATIVELY EARLY DISEASE STAGES, ODONTOBLASTS WILL RESPOND TO BACTERIAL COMPONENTS, AND AS THE DISEASE PROGRESSES, CORE PULPAL CELLS INCLUDING FIBROBLASTS, STEMS CELLS, ENDOTHELIAL CELLS, AND IMMUNE CELLS WILL BECOME INVOLVED. PATTERN RECOGNITION RECEPTORS, SUCH AS TOLL-LIKE RECEPTORS EXPRESSED ON THESE CELL TYPES, ARE RESPONSIBLE FOR DETECTING BACTERIAL COMPONENTS, AND THEIR LIGAND BINDING LEADS TO THE ACTIVATION OF THE NUCLEAR FACTOR-KAPPA B AND P38 MITOGEN-ACTIVATED PROTEIN (MAP) KINASE INTRACELLULAR SIGNALING CASCADES. SUBSEQUENT NUCLEAR TRANSLOCATION OF THE TRANSCRIPTION FACTOR SUBUNITS FROM THESE PATHWAYS WILL LEAD TO PROINFLAMMATORY MEDIATOR EXPRESSION, INCLUDING INCREASES IN CYTOKINES AND CHEMOKINES, WHICH TRIGGER HOST CELLULAR DEFENSE MECHANISMS. THE COMPLEX MOLECULAR SIGNALING WILL RESULT IN THE RECRUITMENT OF IMMUNE SYSTEM CELLS TARGETED AT COMBATING THE INVADING MICROBES; HOWEVER, THE TRAFFICKING AND ANTIBACTERIAL ACTIVITY OF THESE CELLS CAN LEAD TO COLLATERAL TISSUE DAMAGE. RECENT EVIDENCE SUGGESTS THAT IF INFLAMMATION IS RESOLVED RELATIVELY LOW LEVELS OF PROINFLAMMATORY MEDIATORS MAY PROMOTE TISSUE REPAIR, WHEREAS IF CHRONIC INFLAMMATION ENSUES REPAIR MECHANISMS BECOME INHIBITED. THUS, THE EFFECTS OF MEDIATORS ARE TEMPORAL CONTEXT DEPENDENT. ALTHOUGH CONTAINMENT AND REMOVAL OF THE INFECTION ARE KEYS TO ENABLE DENTAL TISSUE REPAIR, IT IS FEASIBLE THAT THE DEVELOPMENT OF ANTI-INFLAMMATORY AND IMMUNOMODULATORY APPROACHES, BASED ON MOLECULAR, EPIGENETIC, AND PHOTOBIOMODULATORY TECHNOLOGIES, MAY ALSO BE BENEFICIAL FOR FUTURE ENDODONTIC TREATMENTS. 2014 17 5052 31 PHARMACOLOGICAL TARGETING OF HEME OXYGENASE-1 IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGING-ASSOCIATED DISEASE THAT CLINICALLY MANIFESTS AS JOINT PAIN, MOBILITY LIMITATIONS, AND COMPROMISED QUALITY OF LIFE. TODAY, OA TREATMENT IS LIMITED TO PAIN MANAGEMENT AND JOINT ARTHROPLASTY AT THE LATER STAGES OF DISEASE PROGRESSION. OA PATHOGENESIS IS PREDOMINANTLY MEDIATED BY OXIDATIVE DAMAGE TO JOINT CARTILAGE EXTRACELLULAR MATRIX AND LOCAL CELLS SUCH AS CHONDROCYTES, OSTEOCLASTS, OSTEOBLASTS, AND SYNOVIAL FIBROBLASTS. UNDER NORMAL CONDITIONS, CELLS PREVENT THE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) UNDER OXIDATIVELY STRESSFUL CONDITIONS THROUGH THEIR ADAPTIVE CYTOPROTECTIVE MECHANISMS. HEME OXYGENASE-1 (HO-1) IS AN IRON-DEPENDENT CYTOPROTECTIVE ENZYME THAT FUNCTIONS AS THE INDUCIBLE FORM OF HO. HO-1 AND ITS METABOLITES CARBON MONOXIDE AND BILIVERDIN CONTRIBUTE TOWARDS THE MAINTENANCE OF REDOX HOMEOSTASIS. HO-1 EXPRESSION IS PRIMARILY REGULATED AT THE TRANSCRIPTIONAL LEVEL THROUGH TRANSCRIPTIONAL FACTOR NUCLEAR FACTOR ERYTHROID 2 (NF-E2)-RELATED FACTOR 2 (NRF2), SPECIFICITY PROTEIN 1 (SP1), TRANSCRIPTIONAL REPRESSOR BTB-AND-CNC HOMOLOGY 1 (BACH1), AND EPIGENETIC REGULATION. SEVERAL STUDIES REPORT THAT HO-1 EXPRESSION CAN BE REGULATED USING VARIOUS ANTIOXIDATIVE FACTORS AND CHEMICAL COMPOUNDS, SUGGESTING THERAPEUTIC IMPLICATIONS IN OA PATHOGENESIS AS WELL AS IN THE WIDER CONTEXT OF JOINT DISEASE. HERE, WE REVIEW THE PROTECTIVE ROLE OF HO-1 IN OA WITH A FOCUS ON THE REGULATORY MECHANISMS THAT MEDIATE HO-1 ACTIVITY. 2021 18 1826 33 EFFECTS OF HISTONE DEACETYLASE INHIBITOR ON EXTRACELLULAR MATRIX PRODUCTION IN HUMAN NASAL POLYP ORGAN CULTURES. BACKGROUND: NASAL POLYPOSIS IS ASSOCIATED WITH A CHRONIC INFLAMMATORY CONDITION OF THE SINONASAL MUCOSA AND INVOLVES MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX (ECM) ACCUMULATION. EPIGENETIC MODULATION BY HISTONE DEACETYLASE (HDAC) INHIBITORS INCLUDING TRICHOSTATIN A (TSA) HAS BEEN REPORTED TO HAVE INHIBITORY EFFECTS ON MYOFIBROBLAST DIFFERENTIATION IN LUNG AND RENAL FIBROBLASTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE INHIBITORY EFFECT OF TSA ON MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION IN NASAL POLYP ORGAN CULTURES. METHODS: NASAL POLYP TISSUES FROM 18 PATIENTS WERE ACQUIRED DURING ENDOSCOPIC SINUS SURGERY. AFTER ORGAN CULTURE, NASAL POLYPS WERE STIMULATED WITH TGF-BETA1 AND THEN TREATED WITH TSA. ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), FIBRONECTIN, AND COLLAGEN TYPE I EXPRESSION LEVELS WERE EXAMINED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (PCR), REAL-TIME PCR, WESTERN BLOT, AND IMMUNOFLUORESCENT STAINING. HDAC2, HDAC4, AND ACETYLATED H4 EXPRESSION LEVELS WERE ASSAYED BY WESTERN BLOT. CYTOTOXICITY WAS ANALYZED BY THE TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE BIOTIN-DUTP NICK END LABELING ASSAY. RESULTS: THE EXPRESSION LEVELS OF ALPHA-SMA, FIBRONECTIN, AND COLLAGEN TYPE 1 WERE INCREASED IN NASAL POLYP AFTER TRANSFORMING GROWTH FACTOR (TGF) BETA1 TREATMENT. TSA-INHIBITED TGF-BETA1 INDUCED THESE GENE AND PROTEIN EXPRESSION LEVELS. FURTHERMORE, TSA SUPPRESSED PROTEIN EXPRESSION LEVELS OF HDAC2 AND HDAC4. HOWEVER, TSA INDUCED HYPERACETYLATION OF HISTONES H4. TREATMENT WITH TGF-BETA1 WITH OR WITHOUT TSA DID NOT HAVE CYTOTOXIC EFFECT. CONCLUSION: THESE FINDINGS PROVIDE NOVEL INSIGHTS INTO THE EPIGENETIC REGULATION IN MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION OF NASAL POLYP. TSA COULD BE A CANDIDATE OF A THERAPEUTIC AGENT FOR REVERSING THE TGF-BETA1-INDUCED ECM SYNTHESIS THAT LEADS TO NASAL POLYP DEVELOPMENT. 2013 19 2762 24 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 20 5507 23 RHEUMATOID ARTHRITIS PROGRESSION MEDIATED BY ACTIVATED SYNOVIAL FIBROBLASTS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DESTRUCTION. RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS (RASFS) ARE LEADING CELLS IN JOINT EROSION AND CONTRIBUTE ACTIVELY TO INFLAMMATION. RASFS SHOW AN ACTIVATED PHENOTYPE THAT IS INDEPENDENT OF THE INFLAMMATORY ENVIRONMENT AND REQUIRES THE COMBINATION OF SEVERAL FACTORS. ALTHOUGH NEW ASPECTS REGARDING RASF ACTIVATION VIA MATRIX DEGRADATION PRODUCTS, EPIGENETIC MODIFICATIONS, INFLAMMATORY FACTORS, TOLL-LIKE RECEPTOR (TLR) ACTIVATION AND OTHERS HAVE RECENTLY BEEN UNCOVERED, THE PRIMARY PATHOPHYSIOLOGICAL PROCESSES IN EARLY ARTHRITIS LEADING TO PERMANENT ACTIVATION ARE MOSTLY UNKNOWN. HERE, WE REVIEW NEW FINDINGS REGARDING RASF ACTIVATION AND THEIR ALTERED BEHAVIOR THAT CONTRIBUTE TO MATRIX DESTRUCTION AND INFLAMMATION AS WELL AS THEIR POTENTIAL TO SPREAD RA. 2010