1 1853 169 ELEVATED METHIONINE FLUX DRIVES PYROPTOSIS EVASION IN PERSISTER CANCER CELLS. INDUCTION OF CELL DEATH REPRESENTS A PRIMARY GOAL OF MOST ANTICANCER TREATMENTS. DESPITE THE EFFICACY OF SUCH APPROACHES, A SMALL POPULATION OF "PERSISTERS" DEVELOP EVASION STRATEGIES TO THERAPY-INDUCED CELL DEATH. WHILE PREVIOUS STUDIES HAVE IDENTIFIED MECHANISMS OF RESISTANCE TO APOPTOSIS, THE MECHANISMS BY WHICH PERSISTERS DAMPEN OTHER FORMS OF CELL DEATH, SUCH AS PYROPTOSIS, REMAIN TO BE ELUCIDATED. PYROPTOSIS IS A FORM OF INFLAMMATORY CELL DEATH THAT INVOLVES FORMATION OF MEMBRANE PORES, ION GRADIENT IMBALANCE, WATER INFLOW, AND MEMBRANE RUPTURE. HEREIN, WE INVESTIGATE MECHANISMS BY WHICH CANCER PERSISTERS RESIST PYROPTOSIS, SURVIVE, THEN PROLIFERATE IN THE PRESENCE OF TYROSINE KINASE INHIBITORS (TKI). LUNG, PROSTATE, AND ESOPHAGEAL CANCER PERSISTER CELLS REMAINING AFTER TREATMENTS EXHIBITED SEVERAL HALLMARKS INDICATIVE OF PYROPTOSIS RESISTANCE. THE INFLAMMATORY ATTRIBUTES OF PERSISTERS INCLUDED CHRONIC ACTIVATION OF INFLAMMASOME, STING, AND TYPE I INTERFERONS. COMPREHENSIVE METABOLOMIC CHARACTERIZATION UNCOVERED THAT TKI-INDUCED PYROPTOTIC PERSISTERS DISPLAY HIGH METHIONINE CONSUMPTION AND EXCESSIVE TAURINE PRODUCTION. ELEVATED METHIONINE FLUX OR EXOGENOUS TAURINE PRESERVED PLASMA MEMBRANE INTEGRITY VIA OSMOLYTE-MEDIATED EFFECTS. INCREASED DEPENDENCY ON METHIONINE FLUX DECREASED THE LEVEL OF ONE CARBON METABOLISM INTERMEDIATE S-(5'-ADENOSYL)-L-HOMOCYSTEINE, A DETERMINANT OF CELL METHYLATION CAPACITY. THE CONSEQUENT INCREASE IN METHYLATION POTENTIAL INDUCED DNA HYPERMETHYLATION OF GENES REGULATING METAL ION BALANCE AND INTRINSIC IMMUNE RESPONSE. THIS ENABLED THWARTING TKI RESISTANCE BY USING THE HYPOMETHYLATING AGENT DECITABINE. IN SUMMARY, THE EVOLUTION OF RESISTANCE TO PYROPTOSIS CAN OCCUR VIA A STEPWISE PROCESS OF PHYSICAL ACCLIMATION AND EPIGENETIC CHANGES WITHOUT EXISTING OR RECURRENT MUTATIONS. SIGNIFICANCE: METHIONINE ENABLES CANCER CELLS TO PERSIST BY EVADING PYROPTOTIC OSMOTIC LYSIS, WHICH LEADS TO GENOME-WIDE HYPERMETHYLATION THAT ALLOWS PERSISTERS TO GAIN PROLIFERATIVE ADVANTAGES. 2023 2 4769 39 NUCLEAR MORPHOMETRY, NUCLEOMICS AND PROSTATE CANCER PROGRESSION. PROSTATE CANCER (PCA) RESULTS FROM A MULTISTEP PROCESS. THIS PROCESS INCLUDES INITIATION, WHICH OCCURS THROUGH VARIOUS AGING EVENTS AND MULTIPLE INSULTS (SUCH AS CHRONIC INFECTION, INFLAMMATION AND GENETIC INSTABILITY THROUGH REACTIVE OXYGEN SPECIES CAUSING DNA DOUBLE-STRAND BREAKS), FOLLOWED BY A MULTISTEP PROCESS OF PROGRESSION. THESE STEPS INCLUDE SEVERAL GENETIC AND EPIGENETIC ALTERATIONS, AS WELL AS ALTERATIONS TO THE CHROMATIN STRUCTURE, WHICH OCCUR IN RESPONSE TO THE CARCINOGENIC STRESS-RELATED EVENTS THAT SUSTAIN PROLIFERATIVE SIGNALING. EVENTS SUCH AS EVADING GROWTH SUPPRESSORS, RESISTING CELL DEATH, ENABLING REPLICATIVE IMMORTALITY, INDUCING ANGIOGENESIS, AND ACTIVATING INVASION AND METASTASIS ARE READILY OBSERVED. IN ADDITION, IN CONJUNCTION WITH THESE CRITICAL DRIVERS OF CARCINOGENESIS, OTHER FACTORS RELATED TO THE ETIOPATHOGENESIS OF PCA, INVOLVING ENERGY METABOLISM AND EVASION OF THE IMMUNE SURVEILLANCE SYSTEM, APPEAR TO BE INVOLVED. IN ADDITION, WHEN CANCER SPREAD AND METASTASIS OCCUR, THE 'TUMOR MICROENVIRONMENT' IN THE BONE OF PCA PATIENTS MAY PROVIDE A WAY TO SUSTAIN DORMANCY OR SENESCENCE AND EVENTUALLY ESTABLISH A 'SEED AND SOIL' SITE WHERE PCA PROLIFERATION AND GROWTH MAY OCCUR OVER TIME. WHEN PCA IS INITIATED AND PROGRESSION ENSUES, SIGNIFICANT ALTERATIONS IN NUCLEAR SIZE, SHAPE AND HETEROCHROMATIN (DNA TRANSCRIPTION) ORGANIZATION ARE FOUND, AND KEY NUCLEAR TRANSCRIPTIONAL AND STRUCTURAL PROTEINS, AS WELL AS MULTIPLE NUCLEAR BODIES CAN LEAD TO PRECANCEROUS AND MALIGNANT CHANGES. THESE SERIES OF CELLULAR AND TISSUE-RELATED MALIGNANCY-ASSOCIATED EVENTS CAN BE QUANTIFIED TO ASSESS DISEASE PROGRESSION AND MANAGEMENT. 2012 3 2823 31 FLAVONOIDS AS EPIGENETIC MODULATORS FOR PROSTATE CANCER PREVENTION. PROSTATE CANCER (PCA) IS A MULTIFACTORIAL DISEASE WITH AN UNCLEAR ETIOLOGY. DUE TO ITS HIGH PREVALENCE, LONG LATENCY, AND SLOW PROGRESSION, PCA IS AN IDEAL TARGET FOR CHEMOPREVENTION STRATEGIES. MANY RESEARCH STUDIES HAVE HIGHLIGHTED THE POSITIVE EFFECTS OF NATURAL FLAVONOIDS ON CHRONIC DISEASES, INCLUDING PCA. DIFFERENT CLASSES OF DIETARY FLAVONOIDS EXHIBIT ANTI-OXIDATIVE, ANTI-INFLAMMATORY, ANTI-MUTAGENIC, ANTI-AGING, CARDIOPROTECTIVE, ANTI-VIRAL/BACTERIAL AND ANTI-CARCINOGENIC PROPERTIES. WE OVERVIEWED THE MOST RECENT EVIDENCE OF THE ANTITUMORAL EFFECTS EXERTED BY DIETARY FLAVONOIDS, WITH A SPECIAL FOCUS ON THEIR EPIGENETIC ACTION IN PCA. EPIGENETIC ALTERATIONS HAVE BEEN IDENTIFIED AS KEY INITIATING EVENTS IN SEVERAL KINDS OF CANCER. MANY DIETARY FLAVONOIDS HAVE BEEN FOUND TO REVERSE DNA ABERRATIONS THAT PROMOTE NEOPLASTIC TRANSFORMATION, PARTICULARLY FOR PCA. THE EPIGENETIC TARGETS OF THE ACTIONS OF FLAVONOIDS INCLUDE ONCOGENES AND TUMOR SUPPRESSOR GENES, INDIRECTLY CONTROLLED THROUGH THE REGULATION OF EPIGENETIC ENZYMES SUCH AS DNA METHYLTRANSFERASE (DNMT), HISTONE ACETYLTRANSFERASE (HAT), AND HISTONE DEACETYLASE (HDAC). IN ADDITION, FLAVONOIDS WERE FOUND CAPABLE OF RESTORING MIRNA AND LNCRNA EXPRESSION THAT IS ALTERED DURING DISEASES. THE OPTIMIZATION OF THE USE OF FLAVONOIDS AS NATURAL EPIGENETIC MODULATORS FOR CHEMOPREVENTION AND AS A POSSIBLE TREATMENT OF PCA AND OTHER KINDS OF CANCERS COULD REPRESENT A PROMISING AND VALID STRATEGY TO INHIBIT CARCINOGENESIS AND FIGHT CANCER. 2020 4 6201 24 THE INFLAMMATORY MICROENVIRONMENT AND MICROBIOME IN PROSTATE CANCER DEVELOPMENT. CHRONIC INFLAMMATION PROMOTES THE DEVELOPMENT OF SEVERAL TYPES OF SOLID CANCERS AND MIGHT CONTRIBUTE TO PROSTATE CARCINOGENESIS. THIS HYPOTHESIS PARTLY ORIGINATES IN THE FREQUENT OBSERVATION OF INFLAMMATORY CELLS IN THE PROSTATE MICROENVIRONMENT OF ADULT MEN. INFLAMMATION IS ASSOCIATED WITH PUTATIVE PROSTATE CANCER PRECURSOR LESIONS, TERMED PROLIFERATIVE INFLAMMATORY ATROPHY. INFLAMMATION MIGHT DRIVE PROSTATE CARCINOGENESIS VIA OXIDATIVE STRESS AND GENERATION OF REACTIVE OXYGEN SPECIES THAT INDUCE MUTAGENESIS. ADDITIONALLY, INFLAMMATORY STRESS MIGHT CAUSE EPIGENETIC ALTERATIONS THAT PROMOTE NEOPLASTIC TRANSFORMATION. PROLIFERATIVE INFLAMMATORY ATROPHY IS ENRICHED FOR PROLIFERATIVE LUMINAL EPITHELIAL CELLS OF INTERMEDIATE PHENOTYPE THAT MIGHT BE PRONE TO GENOMIC ALTERATIONS LEADING TO PROSTATIC INTRAEPITHELIAL NEOPLASIA AND PROSTATE CANCER. STUDIES IN ANIMALS SUGGEST THAT INFLAMMATORY CHANGES IN THE PROSTATE MICROENVIRONMENT CONTRIBUTE TO REPROGRAMMING OF PROSTATE EPITHELIAL CELLS, A POSSIBLE STEP IN TUMOUR INITIATION. PROSTATIC INFECTION, CONCURRENT WITH EPITHELIAL BARRIER DISRUPTION, MIGHT BE A KEY DRIVER OF AN INFLAMMATORY MICROENVIRONMENT; THE DISCOVERY OF A URINARY MICROBIOME INDICATES A POTENTIAL SOURCE OF FREQUENT EXPOSURE OF THE PROSTATE TO A DIVERSE NUMBER OF MICROORGANISMS. HENCE, CURRENT EVIDENCE SUGGESTS THAT INFLAMMATION AND ATROPHY ARE INVOLVED IN PROSTATE CARCINOGENESIS AND SUGGESTS A ROLE FOR THE MICROBIOME IN ESTABLISHING AN INFLAMMATORY PROSTATE MICROENVIRONMENT THAT MIGHT PROMOTE PROSTATE CANCER DEVELOPMENT AND PROGRESSION. 2018 5 3688 34 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 6 723 29 CAN EPIGENETIC AND INFLAMMATORY BIOMARKERS IDENTIFY CLINICALLY AGGRESSIVE PROSTATE CANCER? PROSTATE CANCER (PCA) IS A HIGHLY PREVALENT MALIGNANCY AND CONSTITUTES A MAJOR CAUSE OF CANCER-RELATED MORBIDITY AND MORTALITY. IT EMERGES THROUGH THE ACQUISITION OF GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC MODIFICATIONS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNA DEREGULATION. THESE GENERATE HERITABLE TRANSFORMATIONS IN THE EXPRESSION OF GENES BUT DO NOT CHANGE THE DNA SEQUENCE. ALTERATIONS IN DNA METHYLATION (HYPO AND HYPERMETHYLATION) ARE THE MOST CHARACTERIZED IN PCA. THEY LEAD TO GENOMIC INSTABILITY AND INADEQUATE GENE EXPRESSION. MAJOR AND MINOR-SPECIFIC MODIFICATIONS IN CHROMATIN RECASTING ARE INVOLVED IN PCA, WITH SIGNS SUGGESTING A DYSFUNCTION OF ENZYMES MODIFIED BY HISTONES. MICRORNA DEREGULATION ALSO CONTRIBUTES TO THE INITIATION OF PCA, INCLUDING INVOLVEMENT IN ANDROGEN RECEPTOR SIGNALIZATION AND APOPTOSIS. THE INFLUENCE OF INFLAMMATION ON PROSTATE TUMOR CARCINOGENESIS IS CURRENTLY MUCH BETTER KNOWN. RECENT DISCOVERIES ABOUT MICROBIAL SPECIES RESIDENT IN THE URINARY TRACT SUGGEST THAT THESE ARE THE INITIATORS OF CHRONIC INFLAMMATION, PROMOTING PROSTATE INFLAMMATORY ATROPHY AND EVENTUALLY LEADING TO PCA. COMPLETE CHARACTERIZATION OF THE RELATIONSHIP BETWEEN THE URINARY MICROBIOME AND PROSTATIC CHRONIC INFLAMMATION WILL BE CRUCIAL TO DEVELOP PLANS FOR THE PREVENTION OF PCA. THE PREVALENT NATURE OF EPIGENETIC AND INFLAMMATORY ALTERATIONS MAY PROVIDE POTENTIAL BIOMARKERS FOR PCA DIAGNOSIS, TREATMENT DECISIONS, EVALUATION OF PROGNOSIS AND POSTTREATMENT SURVEILLANCE. 2020 7 4044 23 MACROPHAGES IN OXIDATIVE STRESS AND MODELS TO EVALUATE THE ANTIOXIDANT FUNCTION OF DIETARY NATURAL COMPOUNDS. ANTIOXIDANT TESTING OF NATURAL PRODUCTS HAS ATTRACTED INCREASING INTEREST IN RECENT YEARS, MAINLY DUE TO THE FACT THAT AN ANTIOXIDANT-RICH DIET MIGHT PROVIDE HEALTH BENEFITS. ACTIVATED MACROPHAGES ARE A MAJOR SOURCE OF REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES, AND PEROXYNITRITE GENERATED THROUGH THE SO-CALLED RESPIRATORY BURST. CONSTITUTIVELY RELEASED PROINFLAMMATORY CYTOKINE, ESPECIALLY TUMOR NECROSIS FACTOR-ALPHA, TRIGGERS NUCLEAR FACTOR-KAPPAB, AND ACTIVATOR PROTEIN-1 TRANSLOCATION LEADING TO THE OVER PRODUCTION OF REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN SPECIES IN MACROPHAGES. ACTIVATION OF TRANSCRIPTION FACTORS IN THE LONG-LIVED TISSUE-RESIDENT MACROPHAGES AND/OR MONOCYTE-DERIVED MACROPHAGES, TRIGGER EPIGENETIC MODIFICATIONS LEADING TO THE PATHOGENESIS OF CHRONIC DISEASES. NUTRACEUTICALS INCLUDING LIPID RAFT STRUCTURE DISRUPTION AGENT, CHOLESTEROL DEPLETION AGENT, FARNESYLTRANSFERASE INHIBITOR, NUCLEAR FACTOR-KAPPAB BLOCKER (ALPHA,BETA-UNSATURATED CARBONYL COMPOUNDS), GLUCOCORTICOID RECEPTOR AGONIST, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST HAVE LONG BEEN USED TO INACTIVE MACROPHAGE. THE INHIBITION EFFECTS ON THE FORMATION OF NITRIC OXIDE, SUPEROXIDE, AND NITRITE PEROXIDE MAY BE RESPONSIBLE FOR THE ANTI-INFLAMMATORY FUNCTIONALITIES. ACTIVATED MACROPHAGE MODELS COULD BE USED TO IDENTIFY THE ACTIVE COMPONENTS FOR FUNCTIONAL DIETS DEVELOPMENT THROUGH A MULTIPLE TARGETS STRATEGY. 2017 8 4666 30 NEW INSIGHTS AND OPTIONS INTO THE MECHANISMS AND EFFECTS OF COMBINED TARGETED THERAPY AND IMMUNOTHERAPY IN PROSTATE CANCER. CHRONIC INFLAMMATION IS BELIEVED TO DRIVE PROSTATE CARCINOGENESIS BY PRODUCING REACTIVE OXYGEN SPECIES OR REACTIVE NITROGEN SPECIES TO INDUCE DNA DAMAGE. THIS EFFECT MIGHT SUBSEQUENTLY CAUSE EPIGENETIC AND GENOMIC ALTERATIONS, LEADING TO MALIGNANT TRANSFORMATION. ALTHOUGH ESTABLISHED THERAPEUTIC ADVANCES HAVE EXTENDED OVERALL SURVIVAL, TUMORS IN PATIENTS WITH ADVANCED PROSTATE CANCER ARE PRONE TO METASTASIS, TRANSFORMATION INTO METASTATIC CASTRATION-RESISTANT PROSTATE CANCER, AND THERAPEUTIC RESISTANCE. THE TUMOR MICROENVIRONMENT (TME) OF PROSTATE CANCER IS INVOLVED IN CARCINOGENESIS, INVASION AND DRUG RESISTANCE. A PLETHORA OF PRECLINICAL STUDIES HAVE FOCUSED ON IMMUNE-BASED THERAPIES. UNDERSTANDING THE INTRICATE TME SYSTEM IN PROSTATE CANCER MAY HOLD MUCH PROMISE FOR DEVELOPING NOVEL THERAPIES, DESIGNING COMBINATIONAL THERAPEUTIC STRATEGIES, AND FURTHER OVERCOMING RESISTANCE TO ESTABLISHED TREATMENTS TO IMPROVE THE LIVES OF PROSTATE CANCER PATIENTS. IN THIS REVIEW, WE DISCUSS NONIMMUNE COMPONENTS AND VARIOUS IMMUNE CELLS WITHIN THE TME AND THEIR PUTATIVE ROLES DURING PROSTATE CANCER INITIATION, PROGRESSION, AND METASTASIS. WE ALSO OUTLINE THE UPDATED FUNDAMENTAL RESEARCH FOCUSING ON THERAPEUTIC ADVANCES OF TARGETED THERAPY AS WELL AS COMBINATIONAL OPTIONS FOR PROSTATE CANCER. 2023 9 3701 31 INFLAMMATORY RESPONSE TO REGULATED CELL DEATH IN GOUT AND ITS FUNCTIONAL IMPLICATIONS. GOUT, A CHRONIC INFLAMMATORY ARTHRITIS DISEASE, IS CHARACTERIZED BY HYPERURICEMIA AND CAUSED BY INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND METABOLIC FACTORS. ACUTE GOUT SYMPTOMS ARE TRIGGERED BY THE INFLAMMATORY RESPONSE TO MONOSODIUM URATE CRYSTALS, WHICH IS MEDIATED BY THE INNATE IMMUNE SYSTEM AND IMMUNE CELLS (E.G., MACROPHAGES AND NEUTROPHILS), THE NACHT, LRR, AND PYD DOMAINS-CONTAINING PROTEIN 3 (NLRP3) INFLAMMASOME ACTIVATION, AND PRO-INFLAMMATORY CYTOKINE (E.G., IL-1BETA) RELEASE. RECENT STUDIES HAVE INDICATED THAT THE MULTIPLE PROGRAMMED CELL DEATH PATHWAYS INVOLVED IN THE INFLAMMATORY RESPONSE INCLUDE PYROPTOSIS, NETOSIS, NECROPTOSIS, AND APOPTOSIS, WHICH INITIATE INFLAMMATORY REACTIONS. IN THIS REVIEW, WE EXPLORE THE CORRELATION AND INTERACTIONS AMONG THESE FACTORS AND THEIR ROLES IN THE PATHOGENESIS OF GOUT TO PROVIDE FUTURE RESEARCH DIRECTIONS AND POSSIBILITIES FOR IDENTIFYING POTENTIAL NOVEL THERAPEUTIC TARGETS AND ENHANCING OUR UNDERSTANDING OF GOUT PATHOGENESIS. 2022 10 3683 34 INFLAMMATION, MICROBIOTA, AND PROSTATE CANCER. CONTEXT: CHRONIC INFLAMMATION OF THE PROSTATE HAS BEEN ASSOCIATED WITH PRENEOPLASTIC LESIONS AND CANCER DEVELOPMENT. MULTIPLE CAUSES HAVE BEEN CONSIDERED FOR CHRONIC INFLAMMATION OF THE PROSTATE. INFLAMMATORY CYTOKINES SUCH AS INTERLEUKINS ARE IMPLICATED IN PROSTATE CARCINOGENESIS AND DEVELOPMENT. OBJECTIVE: TO EVALUATE LITERATURE PUBLISHED ON ETIOLOGICAL FACTORS, URINARY MICROBIOTA, MORPHOLOGICAL FEATURES OF PROLIFERATIVE INFLAMMATORY ATROPHY AND HIGH-GRADE PROSTATE INTRAEPITHELIAL NEOPLASIA, GENETIC POLYMORPHISMS, INFLAMMATORY STRESS, AND CYTOKINE SIGNALING. EVIDENCE ACQUISITION: WE SEARCHED LITERATURE FROM PUBMED FROM 2010 AND ALSO INCLUDED THE MOST IMPORTANT PUBLICATIONS FROM THE PREVIOUS PERIOD. EVIDENCE SYNTHESIS: PROSTATE CANCER INFLAMMATION AND PREMALIGNANT LESIONS HAVE BEEN FREQUENTLY DISCUSSED IN SCIENTIFIC LITERATURE. A LIMITED NUMBER OF MODELS ARE AVAILABLE FOR STUDYING INFLAMMATION AND PREMALIGNANT LESIONS. HOWEVER, MORPHOLOGICAL PATHOLOGY COULD BE COMPLEMENTED BY ANALYSIS OF GENE POLYMORPHISMS IN THESE PATIENTS AND APPROPRIATE FUNCTIONAL STUDIES. CONCLUSIONS: PROSTATITIS COULD BE CAUSED BY BACTERIAL OR VIRAL INFECTIONS, DIETARY COMPOUNDS, AND CHANGES IN TESTOSTERONE:ESTRADIOL RATIO. IN SOME CASES, THE MICROBIOTA CAN EXERT DIRECT EFFECTS ON CANCER DEVELOPMENT. PROSTATE INFLAMMATORY ATROPHY OR HIGH GRADE PROSTATE INTRAEPITHELIAL NEOPLASIA HAVE BEEN ASSOCIATED WITH RESPONSE TO CELLULAR STRESS AND HAVE BEEN DISCUSSED IN CONNECTION TO EARLY CANCER DEVELOPMENT. A LARGE NUMBER OF GENETIC POLYMORPHISMS HAVE BEEN IDENTIFIED IN INFLAMMATORY PROSTATE. GENETIC AND EPIGENETIC ALTERATIONS MAY BE A CONSEQUENCE OF THE PROINFLAMMATORY STRESS IN THE PROSTATE. PROINFLAMMATORY CYTOKINES INTERLEUKIN-6 AND -8 CONTRIBUTE TO PROSTATE MALIGNANCY; HOWEVER, THEIR FUNCTION WAS MORE FREQUENTLY INVESTIGATED IN CANCER TISSUE RATHER THAN IN INFLAMMATION. PATIENT SUMMARY: WE PERFORMED A REVIEW OF RECENT LITERATURE RELATED TO PROSTATE INFLAMMATION, MICROBIOTA, AND PROSTATE CANCER. NEW FUNCTIONAL APPROACHES ARE REQUIRED FOR A BETTER UNDERSTANDING OF THE ROLE OF INFLAMMATION AND CANCER DEVELOPMENT. 2016 11 5352 40 RE-ESTABLISHING THE COMPREHENSION OF PHYTOMEDICINE AND NANOMEDICINE IN INFLAMMATION-MEDIATED CANCER SIGNALING. RECENT MOUNTING EVIDENCE HAS REVEALED EXTENSIVE GENETIC HETEROGENEITY WITHIN TUMORS THAT DRIVE PHENOTYPIC VARIATION AFFECTING KEY CANCER PATHWAYS, MAKING CANCER TREATMENT EXTREMELY CHALLENGING. DIVERSE CANCER TYPES DISPLAY RESISTANCE TO TREATMENT AND SHOW PATTERNS OF RELAPSE FOLLOWING THERAPY. THEREFORE, EFFORTS ARE REQUIRED TO ADDRESS TUMOR HETEROGENEITY BY DEVELOPING A BROAD-SPECTRUM THERAPEUTIC APPROACH THAT COMBINES TARGETED THERAPIES. INFLAMMATION HAS BEEN PROGRESSIVELY DOCUMENTED AS A VITAL FACTOR IN TUMOR ADVANCEMENT AND HAS CONSEQUENCES IN EPIGENETIC VARIATIONS THAT SUPPORT TUMOR INSTIGATION, ENCOURAGING ALL THE TUMORIGENESIS PHASES. INCREASED DNA DAMAGE, DISRUPTED DNA REPAIR MECHANISMS, CELLULAR PROLIFERATION, APOPTOSIS, ANGIOGENESIS, AND ITS INCURSION ARE A FEW PRO-CANCEROUS OUTCOMES OF CHRONIC INFLAMMATION. A CLEAR UNDERSTANDING OF THE CELLULAR AND MOLECULAR SIGNALING MECHANISMS OF TUMOR-ENDORSING INFLAMMATION IS NECESSARY FOR FURTHER EXPANSION OF ANTI-CANCER THERAPEUTICS TARGETING THE CROSSTALK BETWEEN TUMOR DEVELOPMENT AND INFLAMMATORY PROCESSES. MULTIPLE INFLAMMATORY SIGNALING PATHWAYS, SUCH AS THE NF-KAPPAB SIGNALING PATHWAY, JAK-STAT SIGNALING PATHWAY, MAPK SIGNALING, PI3K/AKT/MTOR SIGNALING, WNT SIGNALING CASCADE, AND TGF-BETA/SMAD SIGNALING, HAVE BEEN FOUND TO REGULATE INFLAMMATION, WHICH CAN BE MODULATED USING VARIOUS FACTORS SUCH AS SMALL MOLECULE INHIBITORS, PHYTOCHEMICALS, RECOMBINANT CYTOKINES, AND NANOPARTICLES (NPS) IN CONJUGATION TO PHYTOCHEMICALS TO TREAT CANCER. RESEARCHERS HAVE IDENTIFIED MULTIPLE TARGETS TO SPECIFICALLY ALTER INFLAMMATION IN CANCER THERAPY TO RESTRICT MALIGNANT PROGRESSION AND IMPROVE THE EFFICACY OF CANCER THERAPY. SIRNA-AND SHRNA-LOADED NPS HAVE BEEN OBSERVED TO DOWNREGULATE STAT3 SIGNALING PATHWAYS AND HAVE BEEN EMPLOYED IN STUDIES TO TARGET TUMOR MALIGNANCIES. THIS REVIEW HIGHLIGHTS THE PATHWAYS INVOLVED IN THE INTERACTION BETWEEN TUMOR ADVANCEMENT AND INFLAMMATORY PROGRESSION, ALONG WITH THE NOVEL APPROACHES OF NANOTECHNOLOGY-BASED DRUG DELIVERY SYSTEMS CURRENTLY USED TO TARGET INFLAMMATORY SIGNALING PATHWAYS TO COMBAT CANCER. 2022 12 5803 29 STING SIGNALING ACTIVATION INHIBITS HBV REPLICATION AND ATTENUATES THE SEVERITY OF LIVER INJURY AND HBV-INDUCED FIBROSIS. THE COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) OF HBV PLAYS A CRUCIAL ROLE IN VIRAL PERSISTENCE AND IS ALSO A RISK FACTOR FOR DEVELOPING HBV-INDUCED DISEASES, INCLUDING LIVER FIBROSIS. STIMULATOR OF INTERFERON GENES (STING), A MASTER REGULATOR OF DNA-MEDIATED INNATE IMMUNE ACTIVATION, IS A POTENTIAL THERAPEUTIC TARGET FOR VIRAL INFECTION AND VIRUS-RELATED DISEASES. IN THIS STUDY, AGONIST-INDUCED STING SIGNALING ACTIVATION IN MACROPHAGES WAS REVEALED TO INHIBIT CCCDNA-MEDIATED TRANSCRIPTION AND HBV REPLICATION VIA EPIGENETIC MODIFICATION IN HEPATOCYTES. NOTABLY, STING ACTIVATION COULD EFFICIENTLY ATTENUATE THE SEVERITY OF LIVER INJURY AND FIBROSIS IN A CHRONIC RECOMBINANT CCCDNA (RCCCDNA) MOUSE MODEL, WHICH IS A PROVEN SUITABLE RESEARCH PLATFORM FOR HBV-INDUCED FIBROSIS. MECHANISTICALLY, STING-ACTIVATED AUTOPHAGIC FLUX COULD SUPPRESS MACROPHAGE INFLAMMASOME ACTIVATION, LEADING TO THE AMELIORATION OF LIVER INJURY AND HBV-INDUCED FIBROSIS. OVERALL, THE ACTIVATION OF STING SIGNALING COULD INHIBIT HBV REPLICATION THROUGH EPIGENETIC SUPPRESSION OF CCCDNA AND ALLEVIATE HBV-INDUCED LIVER FIBROSIS THROUGH THE SUPPRESSION OF MACROPHAGE INFLAMMASOME ACTIVATION BY ACTIVATING AUTOPHAGIC FLUX IN A CHRONIC HBV MOUSE MODEL. THIS STUDY SUGGESTS THAT TARGETING THE STING SIGNALING PATHWAY MAY BE AN IMPORTANT THERAPEUTIC STRATEGY TO PROTECT AGAINST PERSISTENT HBV REPLICATION AND HBV-INDUCED FIBROSIS. 2022 13 3678 33 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 14 3289 30 HIF-1ALPHA MEDIATES TUMOR HYPOXIA TO CONFER A PERPETUAL MESENCHYMAL PHENOTYPE FOR MALIGNANT PROGRESSION. ALTHOUGH TUMOR PROGRESSION INVOLVES GENETIC AND EPIGENETIC ALTERATIONS TO NORMAL CELLULAR BIOLOGY, THE UNDERLYING MECHANISMS OF THESE CHANGES REMAIN OBSCURE. NUMEROUS STUDIES HAVE SHOWN THAT HYPOXIA-INDUCIBLE FACTOR 1ALPHA (HIF-1ALPHA) IS OVEREXPRESSED IN MANY HUMAN CANCERS AND UP-REGULATES A HOST OF HYPOXIA-RESPONSIVE GENES FOR CANCER GROWTH AND SURVIVAL. WE RECENTLY IDENTIFIED AN ALTERNATIVE MECHANISM OF HIF-1ALPHA FUNCTION THAT INDUCES GENETIC ALTERATIONS BY SUPPRESSING DNA REPAIR. HERE, WE SHOW THAT LONG-TERM HYPOXIA, WHICH MIMICS THE TUMOR MICROENVIRONMENT, DRIVES A PERPETUAL EPITHELIAL-MESENCHYMAL TRANSITION (EMT) THROUGH UP-REGULATION OF THE ZINC FINGER E-BOX BINDING HOMEOBOX PROTEIN ZEB2, WHEREAS SHORT-TERM HYPOXIA INDUCES A REVERSIBLE EMT THAT REQUIRES THE TRANSCRIPTION FACTOR TWIST1. MOREOVER, WE SHOW THAT THE PERPETUAL EMT DRIVEN BY CHRONIC HYPOXIA DEPENDS ON HIF-1ALPHA INDUCTION OF GENETIC ALTERATIONS RATHER THAN ITS CANONICAL TRANSCRIPTIONAL ACTIVATOR FUNCTION. THESE MESENCHYMAL TUMOR CELLS NOT ONLY ACQUIRE TUMORIGENICITY BUT ALSO DISPLAY CHARACTERISTICS OF ADVANCED CANCERS, INCLUDING NECROSIS, AGGRESSIVE INVASION, AND METASTASIS. HENCE, THESE RESULTS REVEAL A MECHANISM BY WHICH HIF-1ALPHA PROMOTES A PERPETUAL MESENCHYMAL PHENOTYPE, THEREBY ADVANCING TUMOR PROGRESSION. 2011 15 329 41 ALPHA-OXOGLUTARATE INHIBITS THE PROLIFERATION OF IMMORTALIZED NORMAL BLADDER EPITHELIAL CELLS VIA AN EPIGENETIC SWITCH INVOLVING ARID1A. INTERSTITIAL CYSTITIS (IC) IS A CHRONIC URINARY TRACT DISEASE THAT IS CHARACTERIZED BY UNPLEASANT SENSATIONS, SUCH AS PERSISTENT PELVIC PAIN, IN THE ABSENCE OF INFECTION OR OTHER IDENTIFIABLE CAUSES. WE PREVIOUSLY PERFORMED COMPREHENSIVE METABOLOMICS PROFILING OF URINE SAMPLES FROM IC PATIENTS USING NUCLEAR MAGNETIC RESONANCE AND GAS-CHROMATOGRAPHY/MASS SPECTROMETRY AND FOUND THAT URINARY ALPHA-OXOGLUTARATE (ALPHA-OG), WAS SIGNIFICANTLY ELEVATED. ALPHA-OG, A TRICARBOXYLIC ACID (TCA) CYCLE INTERMEDIATE, REPORTEDLY FUNCTIONS TO SUPPRESS THE PROLIFERATION OF IMMORTALIZED NORMAL HUMAN BLADDER EPITHELIAL CELLS. HERE, WE IDENTIFIED AT-RICH INTERACTIVE DOMAIN 1 A (ARID1A), A KEY CHROMATIN REMODELER, AS BEING HYPOMETHYLATED AND UPREGULATED BY ALPHA-OG TREATMENT. THIS WAS DONE THROUGH EPIC DNA METHYLATION PROFILING AND SUBSEQUENT BIOCHEMICAL APPROACHES, INCLUDING QUANTITATIVE RT-PCR AND WESTERN BLOT ANALYSES. FURTHERMORE, WE FOUND THAT ALPHA-OG ALMOST COMPLETELY SUPPRESSES TEN-ELEVEN TRANSLOCATION (TET) ACTIVITY, BUT DOES NOT AFFECT DNA METHYLTRANSFERASE (DNMT) ACTIVITY. ALTOGETHER, OUR STUDIES REVEAL THE POTENTIAL ROLE OF ALPHA-OG IN EPIGENETIC REMODELING THROUGH ITS EFFECTS ON ARID1A AND TET EXPRESSION IN THE BLADDER. THIS MAY PROVIDE A NEW POSSIBLE THERAPEUTIC STRATEGY IN TREATING IC. 2018 16 2950 21 GENETIC AND EPIGENETIC DAMAGE INDUCED BY REACTIVE NITROGEN SPECIES: IMPLICATIONS IN CARCINOGENESIS. CHRONIC INFECTION AND INFLAMMATION ARE RECOGNIZED RISK FACTORS FOR HUMAN CANCER AT VARIOUS SITES. INFECTION AND INFLAMMATION CAN ACTIVATE AND INDUCE A VARIETY OF OXIDANT-GENERATING ENZYMES, INCLUDING NADPH OXIDASE AND INDUCIBLE NITRIC OXIDE SYNTHASE. REACTIVE OXYGEN AND NITROGEN SPECIES PRODUCED BY SUCH ENZYMES REACT WITH EACH OTHER TO GENERATE NEW AND MORE POTENT REACTIVE SPECIES. THESE OXIDANTS NOT ONLY CAN DAMAGE DNA AND INDUCE MUTATIONS, BUT ALSO CAN ACTIVATE ONCOGENE PRODUCTS AND/OR INACTIVATE TUMOR-SUPPRESSOR PROTEINS, THUS CONTRIBUTING TO MOST PROCESSES OF CARCINOGENESIS. APPROPRIATE TREATMENT OF INFLAMMATION SHOULD BE FURTHER EXPLORED FOR CHEMOPREVENTION OF HUMAN CANCERS, ESPECIALLY THOSE ASSOCIATED WITH CHRONIC INFLAMMATION. 2003 17 6887 37 [ROLE OF METAFLAMMATION AS A SYSTEMIC MANIFESTATION OF METABOLIC DISEASES]. VISCERAL OBESITY AS A COMPONENT OF THE METABOLIC SYNDROME IS CHARACTERIZED BY SYSTEMIC AND LOCAL INFLAMMATION, WHICH CAN BE QUANTIFIED IN ORGANS (METAFLAMMATION). THIS PROCESS CAN BE REGARDED AS A CHRONIC, STERILE, AND LOW-GRADE STATE OF INFLAMMATION WITHOUT INFECTION, TRAUMA, TUMOR OR AUTOIMMUNITY. IT IS CAUSED BY AN INFLAMMATION OF THE VISCERAL ADIPOSE TISSUE (ADIPOSE INFLAMMATION OR ADIPOFLAMMATION) DUE TO ADIPOCYTE HYPERTROPHY AND HYPERPLASIA WITH INCREASED INFILTRATION BY MONOCYTES AND MACROPHAGES. IMPORTANT IS THE PRESENCE OF PROINFLAMMATORY, SO-CALLED POLARIZED M1 MACROPHAGES THAT ARE INDUCED BY INTERFERON GAMMA (IFN-GAMMA) AND LIPOPOLYSACCHARIDES (LPS) WITH SECRETION OF INTERLEUKIN (IL)-6, TUMOR NECROSIS FACTOR (TNF) AND IL?1. IN CONTRAST, THE ANTI-INFLAMMATORY, SO-CALLED POLARIZED M2 MACROPHAGES INDUCED BY IL?4 AND IL-13 WITH SECRETION OF IL?8 AND IL-10 DECREASE. IN ADDITION, THE SECRETED ADIPOKINE PATTERN CHANGES FROM ANTI-INFLAMMATORY TO PROINFLAMMATORY. ADIPOCYTE NECROSIS, LOCAL HYPOXIA, DYSREGULATED AUTOPHAGY, ACTIVATION OF INFLAMMASOMES, MODULATION OF TOLL-LIKE RECEPTORS, AND EPIGENETIC FACTORS PLAY A COMPLEX ROLE. THIS MECHANISM RESULTS IN LOCAL INSULIN RESISTANCE AND SUBSEQUENTLY A SYSTEMIC INSULIN RESISTANCE OF PERIPHERAL ORGANS AS WELL AS A SPILLOVER OF LOCAL MEDIATORS OF INFLAMMATION INTO THE SYSTEMIC CIRCULATION (MEASURED AS OBESITY C?REACTIVE PROTEIN, CRP). THE ACTIVATION OF INFLAMMATORY SIGNAL TRANSDUCTION CASCADES LEADS TO INHIBITORY PHOSPHORYLATION OF THE INSULIN SIGNALING PATHWAY AND A WEAKENING OF THE EFFECT OF INSULIN. IN PARALLEL, ECTOPIC LIPID ACCUMULATION OCCURS IN THE LIVER, MUSCULATURE, PANCREAS, PERICARDIUM AND LUNGS. DIACYLGLYCEROL (DAG) ACTIVATES SPECIFIC ISOFORMS OF PROTEIN KINASE C (EPSILON IN THE LIVER AND TAU IN THE MUSCULATURE), WHICH IN TURN LEAD TO INHIBITION OF THE INSULIN SIGNALING PATHWAY. INSULIN RESISTANCE IN OBESITY AND TYPE 2 DIABETES MELLITUS IS AN INFLAMMATORY DISEASE. THE AIM OF FUTURE TRANSLATIONAL APPROACHES IS AN ANTI-INFLAMMATORY, MOLECULARLY INDIVIDUALIZED (PRECISION MEDICINE) TREATMENT IN ADIPOSE TISSUE (TARGETED THERAPY) AND IN ORGANS OF INSULIN RESISTANCE. 2023 18 2361 26 EPIGENETIC REGULATION OF SKELETAL TISSUE INTEGRITY AND OSTEOPOROSIS DEVELOPMENT. BONE TURNOVER IS SOPHISTICATEDLY BALANCED BY A DYNAMIC COUPLING OF BONE FORMATION AND RESORPTION AT VARIOUS RATES. THE ORCHESTRATION OF THIS CONTINUOUS REMODELING OF THE SKELETON FURTHER AFFECTS OTHER SKELETAL TISSUES THROUGH ORGAN CROSSTALK. CHRONIC EXCESSIVE BONE RESORPTION COMPROMISES BONE MASS AND ITS POROUS MICROSTRUCTURE AS WELL AS PROPER BIOMECHANICS. THIS ACCELERATES THE DEVELOPMENT OF OSTEOPOROTIC DISORDERS, A LEADING CAUSE OF SKELETAL DEGENERATION-ASSOCIATED DISABILITY AND PREMATURE DEATH. BONE-FORMING CELLS PLAY IMPORTANT ROLES IN MAINTAINING BONE DEPOSIT AND OSTEOCLASTIC RESORPTION. A POOR ORGANELLE MACHINERY, SUCH AS MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS, AND DEFECTIVE AUTOPHAGY, ETC., DYSREGULATES GROWTH FACTOR SECRETION, MINERALIZATION MATRIX PRODUCTION, OR OSTEOCLAST-REGULATORY CAPACITY IN OSTEOBLASTIC CELLS. A PLETHORA OF EPIGENETIC PATHWAYS REGULATE BONE FORMATION, SKELETAL INTEGRITY, AND THE DEVELOPMENT OF OSTEOPOROSIS. MICRORNAS INHIBIT PROTEIN TRANSLATION BY BINDING THE 3'-UNTRANSLATED REGION OF MRNAS OR PROMOTE TRANSLATION THROUGH POST-TRANSCRIPTIONAL PATHWAYS. DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATION OF HISTONES ALTER THE CHROMATIN STRUCTURE, HINDERING HISTONE ENRICHMENT IN PROMOTER REGIONS. MICRORNA-PROCESSING ENZYMES AND DNA AS WELL AS HISTONE MODIFICATION ENZYMES CATALYZE THESE MODIFYING REACTIONS. GAIN AND LOSS OF THESE EPIGENETIC MODIFIERS IN BONE-FORMING CELLS AFFECT THEIR EPIGENETIC LANDSCAPES, INFLUENCING BONE HOMEOSTASIS, MICROARCHITECTURAL INTEGRITY, AND OSTEOPOROTIC CHANGES. THIS ARTICLE CONVEYS PRODUCTIVE INSIGHTS INTO BIOLOGICAL ROLES OF DNA METHYLATION, MICRORNA, AND HISTONE MODIFICATION AND HIGHLIGHTS THEIR INTERACTIONS DURING SKELETAL DEVELOPMENT AND BONE LOSS UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. 2020 19 1173 28 CONTRIBUTION OF TLR SIGNALING TO THE PATHOGENESIS OF COLITIS-ASSOCIATED CANCER IN INFLAMMATORY BOWEL DISEASE. IN THE INTESTINE A BALANCE BETWEEN PROINFLAMMATORY AND REPAIR SIGNALS OF THE IMMUNE SYSTEM IS ESSENTIAL FOR THE MAINTENANCE OF INTESTINAL HOMEOSTASIS. THE INNATE IMMUNITY ENSURES A PRIMARY HOST RESPONSE TO MICROBIAL INVASION, WHICH INDUCES AN INFLAMMATORY PROCESS TO LOCALIZE THE INFECTION AND PREVENT SYSTEMIC DISSEMINATION OF PATHOGENS. THE KEY ELEMENTS OF THIS PROCESS ARE THE GERMLINE ENCODED PATTERN RECOGNITION RECEPTORS INCLUDING TOLL-LIKE RECEPTORS (TLRS). IF PATHOGENS CANNOT BE ELIMINATED, THEY MAY ELICIT CHRONIC INFLAMMATION, WHICH MAY BE PARTLY MEDIATED VIA TLRS. ADDITIONALLY, CHRONIC INFLAMMATION HAS LONG BEEN SUGGESTED TO TRIGGER TISSUE TUMOROUS TRANSFORMATION. INFLAMMATION, THE SEVENTH HALLMARK OF CANCER, MAY AFFECT ALL PHASES OF TUMOR DEVELOPMENT, AND EVADE THE IMMUNE SYSTEM. INFLAMMATION ACTS AS A CELLULAR STRESSOR AND MAY TRIGGER DNA DAMAGE OR GENETIC INSTABILITY. FURTHERMORE, CHRONIC INFLAMMATION CAN PROVOKE GENETIC MUTATIONS AND EPIGENETIC MECHANISMS THAT PROMOTE MALIGNANT CELL TRANSFORMATION. COLORECTAL CANCERS IN INFLAMMATORY BOWEL DISEASE PATIENTS ARE CONSIDERED TYPICAL EXAMPLES OF INFLAMMATION-RELATED CANCERS. ALTHOUGH DATA REGARDING THE ROLE OF TLRS IN THE PATHOMECHANISM OF CANCER-ASSOCIATED COLITIS ARE RATHER CONFLICTING, FUNCTIONALLY THESE MOLECULES CAN BE CLASSIFIED AS "LARGELY ANTITUMORIGENIC" AND "LARGELY PRO-TUMORIGENIC" WITH THE CAVEAT THAT THE UNDERLYING SIGNALING PATHWAYS ARE MAINLY CONTEXT (I.E., ORGAN-, TISSUE-, CELL-) AND LIGAND-DEPENDENT. 2014 20 1701 35 DYNAMIC IMMUNE/INFLAMMATION PRECISION MEDICINE: THE GOOD AND THE BAD INFLAMMATION IN INFECTION AND CANCER. NORMAL OR "GOOD" INFLAMMATION PROCESS STARTS FROM A LOCAL CELLULAR RESPONSE AGAINST INJURY OR ANY INFECTIOUS AGENT, WITH THE ACTIVATION OF NEUTROPHILS, MACROPHAGES, LANGERHANS CELLS, DENDRITIC CELLS, AND INNATE IMMUNE CELLS. CYTOKINES AND CHEMOKINES ARE PRODUCED TO AMPLIFY THE LOCAL INFLAMMATORY PROCESS FOLLOWED BY THE MIGRATION OF IMMUNE CELLS TO THE REGIONAL LYMPH NODES WHERE ADAPTIVE IMMUNE RESPONSE IS INITIATED. SYSTEMIC INFLAMMATION ENHANCES THE BIOLOGICAL RESPONSE TO MOBILIZE ADDITIONAL CELLS FROM CENTRAL AND PERIPHERAL IMMUNE/HEMATOPOIETIC SYSTEM. LOCAL MECHANISMS TO LIMIT INFLAMMATION ARE INITIATED AND LEAD TO HEALING. DURING THE NORMAL INFLAMMATORY PROCESS, THERE IS A BALANCE BETWEEN THE PRODUCTION OF INFLAMMATORY CHEMOKINES/CYTOKINES SUCH AS TUMOR NECROSIS FACTOR (TNF)-ALPHA, INTERLEUKIN (IL)-6 AND IL-1 AND THE PRODUCTION OF COMPOUNDS THAT LIMIT INFLAMMATION AND HAVE AN IMMUNE SUPPRESSIVE EFFECT, SUCH AS IL-10 AND TRANSFORMING FACTOR (TGF) BETA. IL-6 AND IL-6/SOLUBLE IL-6 RECEPTOR (R) COMPLEX STIMULATE LIVER CELLS TO PRODUCE INFLAMMATORY PROTEINS, WHICH REPRESENTS THE SYSTEMIC INFLAMMATION RESPONSE. THE MAGNITUDE AND THE DURATION OF THE SYSTEMIC INFLAMMATORY RESPONSE ARE LINKED TO THE CAUSE, UNDER GENETIC AND EPIGENETIC CONTROL. SIGNIFICANT INFLAMMATION AS SEEN IN SEPTIC SHOCK, IN SEVERE FORMS OF INFECTIONS OR IN CERTAIN ACTIVE CANCERS, REPRESENTS THE "BAD INFLAMMATION", CORRELATED WITH A POOR PROGNOSIS. IN ADDITION, THE PERSISTENCE OF A CHRONIC SMOLDERING INFLAMMATION MAY LEAD TO PATHOLOGICAL SITUATIONS WHICH ARE OBSERVED IN THE MAJORITY OF INFLAMMATORY, DEGENERATIVE, DYSMETABOLIC, OR DYSIMMUNE DISEASES AND CANCER. CHRONIC SMOLDERING INFLAMMATION IS A CROSS BETWEEN DIFFERENT PATHOLOGICAL SITUATIONS POSSIBLY LINKED. IN ADDITION, WITHIN THE TUMOR MICROENVIRONMENT, INFLAMMATORY PROCESS RESULTS FROM DIFFERENT CELLULAR MECHANISMS MODULATED BY METABOLIC AND VASCULAR CHANGES. ON THE CONTRARY, A LIMITED AND BALANCED INFLAMMATION INITIATES THE NORMAL IMMUNE RESPONSE, INCLUDING THE ADAPTIVE RESPONSE WHICH AMPLIFIES ANY IMMUNOTHERAPY, INCLUDING VACCINES. IMMUNE CHECKPOINT INHIBITORS AND CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS ARE ASSOCIATED WITH CYTOKINE RELEASE SYNDROME, A CLINICAL RISK LEADING TO THE USE OF ANTI-CYTOKINE DRUGS. NOWADAYS, IT IS TIME TO MONITOR THE DYNAMIC INFLAMMATORY PROCESS FOR A BETTER IMMUNE PRECISION MEDICINE IN BOTH INFECTIONS AND CANCER. 2021