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 2 194 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 3 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 4 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 5 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 6 4416 30 MOLECULAR AND CELLULAR PATHWAYS CONTRIBUTING TO JOINT DAMAGE IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS IS A CHRONIC AUTOIMMUNE SYNDROME ASSOCIATED WITH SEVERAL GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS AFFECTING THE ARTICULAR JOINTS CONTRIBUTING TO CARTILAGE AND BONE DAMAGE. ALTHOUGH ETIOLOGY OF THIS DISEASE IS NOT CLEAR, SEVERAL IMMUNE PATHWAYS, INVOLVING IMMUNE (T CELLS, B CELLS, DENDRITIC CELLS, MACROPHAGES, AND NEUTROPHILS) AND NONIMMUNE (FIBROBLASTS AND CHONDROCYTES) CELLS, PARTICIPATE IN THE SECRETION OF MANY PROINFLAMMATORY CYTOKINES, CHEMOKINES, PROTEASES (MMPS, ADAMTS), AND OTHER MATRIX LYSING ENZYMES THAT COULD DISTURB THE IMMUNE BALANCE LEADING TO CARTILAGE AND BONE DAMAGE. THE PRESENCE OF AUTOANTIBODIES PRECEDING THE CLINICAL ONSET OF ARTHRITIS AND THE INDUCTION OF BONE EROSION EARLY IN THE DISEASE COURSE CLEARLY SUGGEST THAT INITIATION EVENTS DAMAGING THE CARTILAGE AND BONE START VERY EARLY DURING THE AUTOIMMUNE PHASE OF THE ARTHRITIS DEVELOPMENT. DURING THIS PROCESS, SEVERAL SIGNALING MOLECULES (RANKL-RANK, NF-KAPPAB, MAPK, NFATC1, AND SRC KINASE) ARE ACTIVATED IN THE OSTEOCLASTS, CELLS RESPONSIBLE FOR BONE RESORPTION. HENCE, COMPREHENSIVE KNOWLEDGE ON PATHOGENESIS IS A PREREQUISITE FOR PREVENTION AND DEVELOPMENT OF TARGETED CLINICAL TREATMENT FOR RA PATIENTS THAT CAN RESTORE THE IMMUNE BALANCE IMPROVING CLINICAL THERAPY. 2020 7 2533 39 EPIGENETICS IN AUTOIMMUNE CONNECTIVE TISSUE DISEASES. BACKGROUND. AUTOIMMUNE CONNECTIVE TISSUE DISEASES (ACTDS) ENCOMPASS A HETEROGENEOUS GROUP OF CHRONIC IMMUNE-MEDIATED INFLAMMATORY DISORDERS, PRIMARILY AFFECTING CONNECTIVE TISSUES AND CLINICALLY CHARACTERIZED BY VARIABLE MULTISYSTEM MANIFESTATIONS, FREQUENTLY OVERLAPPING. ENVIRONMENTAL FACTORS ARE THOUGHT TO PROMOTE ACTD DEVELOPMENT IN GENETIC PREDISPOSING/ENDOCRINE PERMISSIVE BACKGROUND THROUGH THE INDUCTION OF EPIGENETIC MODIFICATIONS, CONSISTING OF STABLE, HERITABLE, BUT POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION, OCCURRING WITHOUT ALTERATIONS OF THE DNA SEQUENCE. ACTUALLY, EPIGENETIC MECHANISMS (SUCH AS HISTONE MODIFICATIONS, DNA METHYLATION, NUCLEOSOME POSITIONING, AND RNA INTERFERENCE) LINK GENOTYPE UPSTREAM AND PHENOTYPE DOWNSTREAM, AND, IF PERSISTENTLY ABERRANT, MAY CAUSE A VARIETY OF HUMAN DISEASES, INCLUDING ACTDS. WE AIMED TO REVIEW THE RECENT ADVANCES IN THE KNOWLEDGE OF THE ACTD EPIGENETIC ALTERATIONS. METHODS: A DETAILED SEARCH OF THE AVAILABLE LITERATURE WAS PERFORMED IN THE PUBMED (U.S. NATIONAL LIBRARY OF MEDICINE) DATABASE. RESULTS: GROWING EVIDENCE UNDERLINES THE RELEVANT ROLE OF EPIGENETIC DEFECTS IN THE ACTD PATHOGENESIS, AND SPECIFIC EPIGENETIC PATTERNS CAN REPRESENT DISEASE BIOMARKERS. IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA), EPIGENETIC VARIATIONS INTERACT DETERMINING THE TYPICAL "AGGRESSIVE" PHENOTYPE DISPLAYED BY RA SYNOVIAL FIBROBLASTS. EPIGENETIC MODIFICATIONS ARE INVOLVED IN THE PROFIBROTIC PROCESS THAT CHARACTERIZES SYSTEMIC SCLEROSIS. IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME, COMPLEX EPIGENETIC CHANGES ALTERING GENE EXPRESSION HAVE BEEN DEMONSTRATED. CONCLUSIONS: COMPREHENSIVE STUDIES WILL CONTRIBUTE TO FURTHER DEFINE THE ABERRANT EPIGENETIC MECHANISMS INVOLVED IN THE ACTDS ETIOPATHOGENESIS. MOREOVER, BEING EPIGENETIC CHANGES POTENTIALLY REVERSIBLE, THE IDENTIFICATION OF ACTDS EPIGENETIC BIOMARKERS WILL ALLOW THE DEVELOPMENT OF THERAPEUTIC STRATEGIES ADDRESSED TO TARGET DYSREGULATED GENES AND CORRECT ABERRANT EPIGENOMIC ALTERATIONS. 2014 8 6906 29 [THE ROLE OF GLYCANS IN CANCER DEVELOPMENT AND PROGRESSION. CLINICAL APPLICATIONS]. CHANGES IN GLYCOSYLATION PATTERN OF CELL SURFACE, BODY FLUIDS AND EXTRACELLULAR MATRIX GLYCOCONJUGATES IS A CHARACTERISTIC FEATURE OF TUMOR CELL MALIGNANCY. THESE CHANGES ARE THE RESULT OF MUTATIONS OF TUMOR-ASSOCIATED GENES AS WELL AS EPIGENETIC CHANGES IN THE TUMOR ENVIRONMENT, INCLUDING NUTRIENT INFLUX, HYPOXIA, CYTOKINE EXPRESSION AND STIMULATION OF CHRONIC INFLAMMATION. THE UNIQUE SET OF CELL SURFACE GLYCOANTIGENS ON NEOPLASTIC CELLS IS RECOGNIZED BY ENDOGENOUS LECTINS LOCATED IN THE EXTRACELLULAR MATRIX, VASCULAR ENDOTHELIUM, ON LEUKOCYTES OR PLATELETS, AND HAS AN IMPACT ON DISRUPTING BASIC CELLULAR PROCESSES, SUCH AS INTERCELLULAR RECOGNITION, CELL-CELL ADHESION OR CELL-ECM INTERACTION. THESE CHANGES HAVE A CRITICAL IMPACT ON THE MIGRATION, INVASIVE AND METASTATIC POTENTIAL OF NEOPLASTIC CELLS AND MODULATE THE IMMUNE RESPONSE. THIS UNIQUE PATTERN OF SUGAR ANTIGENS ON THE CANCER CELLS CAN BE A VAULABLE MARKER TO IDENTIFY THEM, DETERMINE THE STAGE OF THE DISEASE AS WELL AS BE A TARGET OF ANTI-CANCER THERAPY. 2021 9 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 10 4414 31 MOLECULAR AND CELLULAR MECHANISMS OF PROPOLIS AND ITS POLYPHENOLIC COMPOUNDS AGAINST CANCER. IN RECENT YEARS, INTEREST IN NATURAL PRODUCTS SUCH AS ALTERNATIVE SOURCES OF PHARMACEUTICALS FOR NUMEROUS CHRONIC DISEASES, INCLUDING TUMORS, HAS BEEN RENEWED. PROPOLIS, A NATURAL PRODUCT COLLECTED BY HONEYBEES, AND POLYPHENOLIC/FLAVONOID PROPOLIS-RELATED COMPONENTS MODULATE ALL STEPS OF THE CANCER PROGRESSION PROCESS. ANTICANCER ACTIVITY OF PROPOLIS AND ITS COMPOUNDS RELIES ON VARIOUS MECHANISMS: CELL-CYCLE ARREST AND ATTENUATION OF CANCER CELLS PROLIFERATION, REDUCTION IN THE NUMBER OF CANCER STEM CELLS, INDUCTION OF APOPTOSIS, MODULATION OF ONCOGENE SIGNALING PATHWAYS, INHIBITION OF MATRIX METALLOPROTEINASES, PREVENTION OF METASTASIS, ANTI-ANGIOGENESIS, ANTI-INFLAMMATORY EFFECTS ACCOMPANIED BY THE MODULATION OF THE TUMOR MICROENVIRONMENT (BY MODIFYING MACROPHAGE ACTIVATION AND POLARIZATION), EPIGENETIC REGULATION, ANTIVIRAL AND BACTERICIDAL ACTIVITIES, MODULATION OF GUT MICROBIOTA, AND ATTENUATION OF CHEMOTHERAPY-INDUCED DELETERIOUS SIDE EFFECTS. INGREDIENTS FROM PROPOLIS ALSO "SENSITIZE" CANCER CELLS TO CHEMOTHERAPEUTIC AGENTS, LIKELY BY BLOCKING THE ACTIVATION OF THE TRANSCRIPTION FACTOR NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB). IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE RELATED TO THE THE EFFECTS OF FLAVONOIDS AND OTHER POLYPHENOLIC COMPOUNDS FROM PROPOLIS ON TUMOR GROWTH AND METASTASIZING ABILITY, AND DISCUSS POSSIBLE MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE MODULATION OF INFLAMMATORY PATHWAYS AND CELLULAR PROCESSES THAT AFFECT SURVIVAL, PROLIFERATION, INVASION, ANGIOGENESIS, AND METASTASIS OF THE TUMOR. 2022 11 2308 25 EPIGENETIC REGULATION OF CHEMOKINE (CC-MOTIF) LIGAND 2 IN INFLAMMATORY DISEASES. APPROPRIATE RESPONSES TO INFLAMMATION ARE CONDUCIVE TO PATHOGEN ELIMINATION AND TISSUE REPAIR, WHILE UNCONTROLLED INFLAMMATORY REACTIONS ARE LIKELY TO RESULT IN THE DAMAGE OF TISSUES. CHEMOKINE (CC-MOTIF) LIGAND 2 (CCL2) IS THE MAIN CHEMOKINE AND ACTIVATOR OF MONOCYTES, MACROPHAGES, AND NEUTROPHILS. CCL2 PLAYED A KEY ROLE IN AMPLIFYING AND ACCELERATING THE INFLAMMATORY CASCADE AND IS CLOSELY RELATED TO CHRONIC NON-CONTROLLABLE INFLAMMATION (CIRRHOSIS, NEUROPATHIC PAIN, INSULIN RESISTANCE, ATHEROSCLEROSIS, DEFORMING ARTHRITIS, ISCHEMIC INJURY, CANCER, ETC.). THE CRUCIAL REGULATORY ROLES OF CCL2 MAY PROVIDE POTENTIAL TARGETS FOR THE TREATMENT OF INFLAMMATORY DISEASES. THEREFORE, WE PRESENTED A REVIEW OF THE REGULATORY MECHANISMS OF CCL2. GENE EXPRESSION IS LARGELY AFFECTED BY THE STATE OF CHROMATIN. DIFFERENT EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, POST-TRANSLATIONAL MODIFICATION OF HISTONES, HISTONE VARIANTS, ATP-DEPENDENT CHROMATIN REMODELLING, AND NON-CODING RNA, COULD AFFECT THE 'OPEN' OR 'CLOSED' STATE OF DNA, AND THEN SIGNIFICANTLY AFFECT THE EXPRESSION OF TARGET GENES. SINCE MOST EPIGENETIC MODIFICATIONS ARE PROVEN TO BE REVERSIBLE, TARGETING THE EPIGENETIC MECHANISMS OF CCL2 IS EXPECTED TO BE A PROMISING THERAPEUTIC STRATEGY FOR INFLAMMATORY DISEASES. THIS REVIEW FOCUSES ON THE EPIGENETIC REGULATION OF CCL2 IN INFLAMMATORY DISEASES. 2023 12 4558 28 MUTATIONS IN THE NF-KAPPAB SIGNALING PATHWAY: IMPLICATIONS FOR HUMAN DISEASE. THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) SIGNALING PATHWAY IS A MULTI-COMPONENT PATHWAY THAT REGULATES THE EXPRESSION OF HUNDREDS OF GENES THAT ARE INVOLVED IN DIVERSE AND KEY CELLULAR AND ORGANISMAL PROCESSES, INCLUDING CELL PROLIFERATION, CELL SURVIVAL, THE CELLULAR STRESS RESPONSE, INNATE IMMUNITY AND INFLAMMATION. NOT SURPRISINGLY, MIS-REGULATION OF THE NF-KAPPAB PATHWAY, EITHER BY MUTATION OR EPIGENETIC MECHANISMS, IS INVOLVED IN MANY HUMAN AND ANIMAL DISEASES, ESPECIALLY ONES ASSOCIATED WITH CHRONIC INFLAMMATION, IMMUNODEFICIENCY OR CANCER. THIS REVIEW DESCRIBES HUMAN DISEASES IN WHICH MUTATIONS IN THE COMPONENTS OF THE CORE NF-KAPPAB SIGNALING PATHWAY HAVE BEEN IMPLICATED AND DISCUSSES THE MOLECULAR MECHANISMS BY WHICH THESE ALTERATIONS IN NF-KAPPAB SIGNALING ARE LIKELY TO CONTRIBUTE TO THE DISEASE PATHOLOGY. THESE MUTATIONS CAN BE GERMLINE OR SOMATIC AND INCLUDE GENE AMPLIFICATION (E.G., REL), POINT MUTATIONS AND DELETIONS (REL, NFKB2, IKBA, CYLD, NEMO) AND CHROMOSOMAL TRANSLOCATIONS (BCL-3). IN ADDITION, HUMAN GENETIC DISEASES ARE BRIEFLY DESCRIBED WHEREIN MUTATIONS AFFECT PROTEIN MODIFIERS OR TRANSDUCERS OF NF-KAPPAB SIGNALING OR DISRUPT NF-KAPPAB-BINDING SITES IN PROMOTERS/ENHANCERS. 2006 13 5476 30 RESTORING T CELL TOLERANCE, EXPLORING THE POTENTIAL OF HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF JUVENILE IDIOPATHIC ARTHRITIS. JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS CHARACTERIZED BY A LOSS OF IMMUNE TOLERANCE. HERE, THE BALANCE BETWEEN THE ACTIVITY OF EFFECTOR T (TEFF) CELLS AND REGULATORY T (TREG) CELLS IS DISTURBED RESULTING IN CHRONIC INFLAMMATION IN THE JOINTS. PRESENTLY, THERAPEUTIC STRATEGIES ARE PREDOMINANTLY AIMED AT SUPPRESSING IMMUNE ACTIVATION AND PRO-INFLAMMATORY EFFECTOR MECHANISMS, IGNORING THE OPPORTUNITY TO ALSO PROMOTE TOLERANCE BY BOOSTING THE REGULATORY SIDE OF THE IMMUNE BALANCE. HISTONE DEACETYLASES (HDACS) CAN DEACETYLATE BOTH HISTONE AND NON-HISTONE PROTEINS AND HAVE BEEN DEMONSTRATED TO MODULATE EPIGENETIC REGULATION AS WELL AS CELLULAR SIGNALING IN VARIOUS CELL TYPES. IMPORTANTLY, HDACS ARE POTENT REGULATORS OF BOTH TEFF CELL AND TREG CELL FUNCTION AND CAN THUS BE REGARDED AS ATTRACTIVE THERAPEUTIC TARGETS IN CHRONIC INFLAMMATORY ARTHRITIS. HDAC INHIBITORS (HDACI) HAVE PROVEN THERAPEUTIC POTENTIAL IN THE CANCER FIELD, AND ARE PRESENTLY BEING EXPLORED FOR THEIR POTENTIAL IN THE TREATMENT OF AUTOIMMUNE DISEASES. SPECIFIC HDACI HAVE ALREADY BEEN DEMONSTRATED TO REDUCE THE SECRETION OF PRO-INFLAMMATORY CYTOKINES BY TEFF CELLS, AND PROMOTE TREG NUMBERS AND SUPPRESSIVE CAPACITY IN VITRO AND IN VIVO. IN THIS REVIEW, WE OUTLINE THE ROLE OF THE DIFFERENT CLASSES OF HDACS IN BOTH TEFF CELL AND TREG CELL FUNCTION. FURTHERMORE, WE WILL REVIEW THE EFFECT OF DIFFERENT HDACI ON T CELL TOLERANCE AND EXPLORE THEIR POTENTIAL AS A THERAPEUTIC STRATEGY FOR THE TREATMENT OF OLIGOARTICULAR AND POLYARTICULAR JIA. 2019 14 6057 24 THE DARK SIDE OF REGULATORY T CELLS IN PSORIASIS. PSORIASIS IS A HEREDITARY DISEASE ELICITED BY CHRONIC ACTIVATION OF CUTANEOUS T CELLS. DELINEATING THE MECHANISTIC INTERPLAY OF THE CELL SUBSETS INVOLVED IS KEY TO DEVELOPING THE NEXT GENERATION OF EFFECTIVE TREATMENTS. IN THIS ISSUE, BOVENSCHEN ET AL. REPORT THAT REGULATORY T CELLS MAINTAIN A FINE BALANCE BETWEEN THE TRANSCRIPTION FACTORS FOXP3 AND RORGAMMAT. IN PATIENTS WITH PSORIASIS, TREGS READILY TURN INTO IL-17-EXPRESSING CELLS, THUS POTENTIALLY PERPETUATING THE INFLAMMATORY PROCESS THAT CHARACTERIZES THE DISEASE. RESULTS DEMONSTRATING THAT THE HISTONE/PROTEIN DEACETYLATION INHIBITOR TRICHOSTATIN A CAN BLOCK THIS CONVERSION SUGGEST THAT AN EPIGENETIC MODIFICATION MAY UNDERLIE REGULATORY T-CELL PLASTICITY. 2011 15 3525 28 IL-1BETA, IL-8, AND MATRIX METALLOPROTEINASES-1, -2, AND -10 ARE ENRICHED UPON MONOCYTE-BREAST CANCER CELL COCULTIVATION IN A MATRIGEL-BASED THREE-DIMENSIONAL SYSTEM. BREAST CANCER REMAINS THE FIRST CANCER-RELATED CAUSE OF DEATH IN WOMEN WORLDWIDE, PARTICULARLY IN DEVELOPING COUNTRIES IN WHICH MOST CASES ARE DIAGNOSED IN LATE STAGES. ALTHOUGH MOST CANCER STUDIES ARE BASED IN THE GENETIC OR EPIGENETIC CHANGES OF THE TUMOR CELLS, IMMUNE CELLS WITHIN THE TUMOR STROMA OFTEN COOPERATE WITH CANCER PROGRESSION. PARTICULARLY, MONOCYTES ARE ATTRACTED TO THE TUMOR PRIMARY SITE IN WHICH THEY ARE DIFFERENTIATED INTO TUMOR-ASSOCIATED MACROPHAGES THAT FACILITATE TUMOR CELL INVASION AND METASTASIS. IN THIS STUDY, WE USED THREE-DIMENSIONAL CULTURES TO FORM ACINI-LIKE STRUCTURES TO ANALYZE THE INFLAMMATORY SECRETION PROFILE OF TUMOR CELLS INDIVIDUALLY OR IN CO-CULTURE WITH MONOCYTES. BREAST CANCER CELL LINES AND PRIMARY ISOLATES FROM EIGHT MEXICAN PATIENTS WITH BREAST CANCER WERE USED. WE FOUND HIGH LEVELS OF RANTES/CCL5, MCP-1/CCL2, AND G-CSF IN THE BREAST CANCER INDIVIDUAL CULTURES, SUPPORTING AN IMPORTANT RECRUITMENT CAPACITY OF MONOCYTES, BUT ALSO OF NEUTROPHILS. THE CO-CULTURES OF THE TUMOR CELLS AND MONOCYTES WERE SIGNIFICANTLY ENRICHED WITH THE POTENT PRO-INFLAMMATORY CYTOKINES INTERLEUKIN (IL)-1BETA AND IL-8, KNOWN TO SUPPORT MALIGNANT PROGRESSION. WE ALSO FOUND THAT THE INTERACTION OF TUMOR CELLS WITH MONOCYTES PROMOTED HIGH LEVELS OF MATRIX METALLOPROTEINASES (MMP)-1, MMP-2, AND MMP-10. OUR STUDY SUPPORTS THAT A KEY EVENT FOR MALIGNANT PROGRESSION IS THE RECRUITMENT OF DIFFERENT IMMUNE CELL POPULATIONS, WHICH HELP TO SUSTAIN AND ENHANCE A CHRONIC INFLAMMATORY MICROENVIRONMENT THAT HIGHLY FAVORS TUMOR MALIGNANCY. 2017 16 2340 32 EPIGENETIC REGULATION OF LEUKOCYTE INFLAMMATORY MEDIATOR PRODUCTION DICTATES STAPHYLOCOCCUS AUREUS CRANIOTOMY INFECTION OUTCOME. STAPHYLOCOCCUS AUREUS IS A COMMON CAUSE OF SURGICAL-SITE INFECTIONS, INCLUDING THOSE ARISING AFTER CRANIOTOMY, WHICH IS PERFORMED TO ACCESS THE BRAIN FOR THE TREATMENT OF TUMORS, EPILEPSY, OR HEMORRHAGE. CRANIOTOMY INFECTION IS CHARACTERIZED BY COMPLEX SPATIAL AND TEMPORAL DYNAMICS OF LEUKOCYTE RECRUITMENT AND MICROGLIAL ACTIVATION. WE RECENTLY IDENTIFIED UNIQUE TRANSCRIPTIONAL PROFILES OF THESE IMMUNE POPULATIONS DURING S. AUREUS CRANIOTOMY INFECTION. EPIGENETIC PROCESSES ALLOW RAPID AND REVERSIBLE CONTROL OVER GENE TRANSCRIPTION; HOWEVER, LITTLE IS KNOWN ABOUT HOW EPIGENETIC PATHWAYS INFLUENCE IMMUNITY TO LIVE S. AUREUS. AN EPIGENETIC COMPOUND LIBRARY SCREEN IDENTIFIED BROMODOMAIN AND EXTRATERMINAL DOMAIN-CONTAINING (BET) PROTEINS AND HISTONE DEACETYLASES (HDACS) AS CRITICAL FOR REGULATING TNF, IL-6, IL-10, AND CCL2 PRODUCTION BY PRIMARY MOUSE MICROGLIA, MACROPHAGES, NEUTROPHILS, AND GRANULOCYTIC MYELOID-DERIVED SUPPRESSOR CELLS IN RESPONSE TO LIVE S. AUREUS. CLASS I HDACS (C1HDACS) WERE INCREASED IN THESE CELL TYPES IN VITRO AND IN VIVO DURING ACUTE DISEASE IN A MOUSE MODEL OF S. AUREUS CRANIOTOMY INFECTION. HOWEVER, SUBSTANTIAL REDUCTIONS IN C1HDACS WERE OBSERVED DURING CHRONIC INFECTION, HIGHLIGHTING TEMPORAL REGULATION AND THE IMPORTANCE OF THE TISSUE MICROENVIRONMENT FOR DICTATING C1HDAC EXPRESSION. MICROPARTICLE DELIVERY OF HDAC AND BET INHIBITORS IN VIVO CAUSED WIDESPREAD DECREASES IN INFLAMMATORY MEDIATOR PRODUCTION, WHICH SIGNIFICANTLY INCREASED BACTERIAL BURDEN IN THE BRAIN, GALEA, AND BONE FLAP. THESE FINDINGS IDENTIFY HISTONE ACETYLATION AS AN IMPORTANT MECHANISM FOR REGULATING CYTOKINE AND CHEMOKINE PRODUCTION ACROSS DIVERSE IMMUNE CELL LINEAGES THAT IS CRITICAL FOR BACTERIAL CONTAINMENT. ACCORDINGLY, ABERRANT EPIGENETIC REGULATION MAY BE IMPORTANT FOR PROMOTING S. AUREUS PERSISTENCE DURING CRANIOTOMY INFECTION. 2023 17 6869 32 [PATHOGENESIS OF RHEUMATOID ARTHRITIS]. RHEUMATOID ARTHRITIS (RA) IS AN AUTOIMMUNE SYSTEMIC DISEASE THAT PRIMARILY AFFECTS JOINTS. ETIOLOGY AND THE PATHOGENESIS OF RA ARE COMPLEX, INVOLVING MANY TYPES OF CELLS, AMONG OTHERS MACROPHAGES, T AND B CELLS, FIBRO- BLASTS, CHONDROCYTES AND DENDRITIC CELLS. DESPITE WELL DOCUMENTED ROLE OF MANY GENES AND EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT AND EVOLUTION OF THE DISEASE, IN MOST RA PATIENTS THERE IS NO CLEAR PREDISPOSING FACTOR PRESENT. ENVIRONMENTAL FACTORS INVOLVED IN RA PATHOGENESIS ARE CIGARETTE SMOKE, INDUSTRIAL POLLUTANTS LIKE SILICA CRYSTALS, DISTURBANCES OF INTESTINAL, LUNG, AND ORAL MICROBIOTA AND SOME SPECIFIC BACTERIAL AND VIRAL INFECTIOUS AGENTS AND THEIR COMPONENTS. IN THE INITIAL DISEASE STAGE THERE ARE QUALITATIVE AND QUANTITATIVE DISTURBANCES OFPEPTIDE CITRULINATION AS WELL AS OTHER PROTEIN MODIFICATIONS, FOLLOWED BY ANTIGEN PRESENTING CELL (APC) (MACROPHAGES AND DENDRITIC CELLS) AND FIBROBLAST LIKE SYNOVIOCYTES (FLS) ACTIVATION. SOME MICROBES FOSTER THIS PROCESSES BY APC AND FLS DIRECT AND INDIRECT ACTIVATION. IN THE SECOND STAGE APC'S ELICIT SPECIFIC HUMORAL B CELL RE- SPONSE RESULTING IN SPECIFIC ANTIBODIES PRODUCTION AND T CELL AUTOREACTIVITY. INHERITED AND ACQUIRED DEFECTS IN T AND B CELL RESPONSES CAUSED BY REPEATED ACTIVATION OF INNATE IMMUNITY AS WELL AS LOSS OF TOLERANCE, ELICIT CHRONIC AUTOIMMUNE INFLAMMATION, PRIMARILY OF SYNOVIAL MEMBRANES, AND DEVELOPMENT OF CELLULAR PANUS. PATHOLOGIC ACTIVATION OF THE OSTEOCLASTS AND RELEASE OF THE IMMUNE SYSTEM EFFECTOR MOLECULES AND THE PROTEOLYTIC ENZYMES DAMAGE THE CARTILAGE, BONE AND TENDONS COMPOSITION AND STRUCTURE. PERSISTENT INFLAMMATION THROUGH ITS COMPLEX MECHANISMS RESULTS IN MANY SYSTEMIC AND EXTRAARTICULAR RA MANIFESTATIONS OF ALMOST ALL ORGAN SYSTEMS, RESULTING IN SEVERE COMPLICATIONS AND COMORBIDITIES SUCH AS RHEUMATOID LUNG, CARDITIS, VASCULITIS, CAHEXIA, ANEMIA, ACCELERATED ATHEROSCLEROSIS, MYOCARDIAL AND CEREBROVASCULAR VASCULAR DISEASE, LYMPHOMA, OSTEOPOROSIS, DEPRESSION ETC. ACCUMULATED COMPLICATIONS AND COMORBIDITIES FINALLY RESULT IN HANDICAP, SOCIAL DYSFUNCTION AND PREMATURE DEATH. 2014 18 4164 31 MEDIATORS OF CAPILLARY-TO-VENULE CONVERSION IN THE CHRONIC INFLAMMATORY SKIN DISEASE PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EPIDERMAL HYPERPLASIA AND HYPERKERATOSIS, IMMUNE CELL INFILTRATION AND VASCULAR REMODELING. DESPITE THE EMERGING RECOGNITION OF VASCULAR NORMALIZATION AS A POTENTIAL STRATEGY FOR MANAGING PSORIASIS, AN IN-DEPTH DELINEATION OF THE REMODELED DERMAL VASCULATURE HAS BEEN MISSING. IN THIS STUDY, WE EXPLOITED 5' SINGLE-CELL RNA SEQUENCING TO INVESTIGATE THE TRANSCRIPTOMIC ALTERATIONS IN DIFFERENT SUBPOPULATIONS OF BLOOD VASCULAR AND LYMPHATIC ENDOTHELIAL CELLS DIRECTLY ISOLATED FROM PSORIATIC AND HEALTHY HUMAN SKIN. INDIVIDUAL SUBTYPES OF ENDOTHELIAL CELLS UNDERWENT SPECIFIC MOLECULAR REPATTERNING ASSOCIATED WITH CELL ADHESION AND EXTRACELLULAR MATRIX ORGANIZATION. BLOOD CAPILLARIES, IN PARTICULAR, SHOWED UPREGULATION OF THE MELANOMA CELL ADHESION MOLECULE AS WELL AS ITS BINDING PARTNERS AND ADOPTED POSTCAPILLARY VENULE?LIKE CHARACTERISTICS DURING CHRONIC INFLAMMATION THAT ARE MORE PERMISSIVE TO LEUKOCYTE TRANSMIGRATION. WE ALSO IDENTIFIED PSORIASIS-SPECIFIC INTERACTIONS BETWEEN CIS-REGULATORY ENHANCERS AND PROMOTERS FOR EACH ENDOTHELIAL CELL SUBTYPE, REVEALING THE DYSREGULATED GENE REGULATORY NETWORKS IN PSORIASIS. TOGETHER, OUR RESULTS PROVIDE MORE INSIGHTS INTO THE SPECIFIC TRANSCRIPTIONAL RESPONSES AND EPIGENETIC SIGNATURES OF ENDOTHELIAL CELLS LINING DIFFERENT VESSEL COMPARTMENTS IN CHRONIC SKIN INFLAMMATION. 2022 19 4096 28 MATRIX METALLOPROTEINASES, NEURAL EXTRACELLULAR MATRIX, AND CENTRAL NERVOUS SYSTEM PATHOLOGY. THE FUNCTIONALITY AND STABILITY OF THE CENTRAL NERVOUS SYSTEM (CNS) PABULUM, CALLED NEURAL EXTRACELLULAR MATRIX (NECM), IS PARAMOUNT FOR THE MAINTENANCE OF A HEALTHY NETWORK. THE LOOSENING OR THE DAMAGE OF THE SCAFFOLD DISRUPTS SYNAPTIC TRANSMISSION WITH THE CONSEQUENT IMBALANCE OF THE NEUROTRANSMITTERS, REACTIVE CELLS INVASION, ASTROCYTOSIS, NEW MATRIX DEPOSITION, DIGESTION OF THE PREVIOUS STRUCTURE AND ULTIMATELY, MALADAPTIVE PLASTICITY WITH THE LOSS OF NEURONAL VIABILITY. NECM IS CONSTANTLY AFFECTED BY CNS DISORDERS, PARTICULARLY IN CHRONIC MODIFYING SUCH AS NEURODEGENERATIVE DISEASE, OR IN ACUTE/SUBACUTE WITH CHRONIC SEQUELAE, LIKE CEREBROVASCULAR AND INFLAMMATORY PATHOLOGY. MATRIX METALLOPROTEINASES (MMPS) ARE THE MAIN INTERFERING AGENT OF NECM, GUIDING THE BALANCE OF DEGRADATION AND NEW DEPOSITION OF PROTEINS SUCH AS PROTEOGLYCANS AND GLYCOPROTEINS, OR GLYCOSAMINOGLYCANS, SUCH AS HYALURONIC ACID. ACTIVATION OF THESE ENZYMES IS MODULATED BY THEIR PHYSIOLOGIC INHIBITORS, THE TISSUE INHIBITORS OF MMPS OR VIA OTHER PROTEASES INHIBITORS, AS WELL AS GENETIC OR EPIGENETIC UP- OR DOWNREGULATION THROUGH MOLECULAR INTERACTION OR RECEPTOR ACTIVATION. THE APPROPRIATE UNDERSTANDING OF THE PATHWAYS UNDERLYING NECM MODIFICATIONS IN CNS PATHOLOGY IS PROBABLY ONE OF THE PIVOTAL FUTURE DIRECTIONS TO IDENTIFY THE HEALTHY BRAIN NETWORK AND SUBSEQUENTLY DESIGN NEW THERAPIES TO INTERFERE WITH THE PROGRESSION OF THE CNS DISEASE AND EVENTUALLY FIND APPROPRIATE THERAPIES. 2017 20 4507 30 MRTF: BASIC BIOLOGY AND ROLE IN KIDNEY DISEASE. A LESSER KNOWN BUT CRUCIALLY IMPORTANT DOWNSTREAM EFFECT OF RHO FAMILY GTPASES IS THE REGULATION OF GENE EXPRESSION. THIS MAJOR ROLE IS MEDIATED VIA THE CYTOSKELETON, THE ORGANIZATION OF WHICH DICTATES THE NUCLEOCYTOPLASMIC SHUTTLING OF A SET OF TRANSCRIPTION FACTORS. CENTRAL AMONG THESE IS MYOCARDIN-RELATED TRANSCRIPTION FACTOR (MRTF), WHICH UPON ACTIN POLYMERIZATION TRANSLOCATES TO THE NUCLEUS AND BINDS TO ITS COGNATE PARTNER, SERUM RESPONSE FACTOR (SRF). THE MRTF/SRF COMPLEX THEN DRIVES A LARGE COHORT OF GENES INVOLVED IN CYTOSKELETON REMODELING, CONTRACTILITY, EXTRACELLULAR MATRIX ORGANIZATION AND MANY OTHER PROCESSES. ACCORDINGLY, MRTF, ACTIVATED BY A VARIETY OF MECHANICAL AND CHEMICAL STIMULI, AFFECTS A PLETHORA OF FUNCTIONS WITH PHYSIOLOGICAL AND PATHOLOGICAL RELEVANCE. THESE INCLUDE CELL MOTILITY, DEVELOPMENT, METABOLISM AND THUS METASTASIS FORMATION, INFLAMMATORY RESPONSES AND-PREDOMINANTLY-ORGAN FIBROSIS. THE AIM OF THIS REVIEW IS TWOFOLD: TO PROVIDE AN UP-TO-DATE SUMMARY ABOUT THE BASIC BIOLOGY AND REGULATION OF THIS VERSATILE TRANSCRIPTIONAL COACTIVATOR; AND TO HIGHLIGHT ITS PRINCIPAL INVOLVEMENT IN THE PATHOBIOLOGY OF KIDNEY DISEASE. ACTING THROUGH BOTH DIRECT TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS, MRTF PLAYS A KEY (YET NOT FULLY APPRECIATED) ROLE IN THE INDUCTION OF A PROFIBROTIC EPITHELIAL PHENOTYPE (PEP) AS WELL AS IN FIBROBLAST-MYOFIBROBLAST TRANSITION, PRIME PATHOMECHANISMS IN CHRONIC KIDNEY DISEASE AND RENAL FIBROSIS. 2021