1 4384 116 MITOCHONDRIAL EPIGENETICS REGULATING INFLAMMATION IN CANCER AND AGING. INFLAMMATION IS A DEFINING FACTOR IN DISEASE PROGRESSION; EPIGENETIC MODIFICATIONS OF THIS FIRST LINE OF DEFENCE PATHWAY CAN AFFECT MANY PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS, LIKE AGING AND TUMORIGENESIS. INFLAMMAGEING, ONE OF THE HALLMARKS OF AGING, REPRESENTS A CHRONIC, LOW KEY BUT A PERSISTENT INFLAMMATORY STATE. OXIDATIVE STRESS, ALTERATIONS IN MITOCHONDRIAL DNA (MTDNA) COPY NUMBER AND MIS-LOCALIZED EXTRA-MITOCHONDRIAL MTDNA ARE SUGGESTED TO DIRECTLY INDUCE VARIOUS IMMUNE RESPONSE PATHWAYS. THIS COULD ULTIMATELY PERTURB CELLULAR HOMEOSTASIS AND LEAD TO PATHOLOGICAL CONSEQUENCES. EPIGENETIC REMODELLING OF MTDNA BY DNA METHYLATION, POST-TRANSLATIONAL MODIFICATIONS OF MTDNA BINDING PROTEINS AND REGULATION OF MITOCHONDRIAL GENE EXPRESSION BY NUCLEAR DNA OR MTDNA ENCODED NON-CODING RNAS, ARE SUGGESTED TO DIRECTLY CORRELATE WITH THE ONSET AND PROGRESSION OF VARIOUS TYPES OF CANCER. MITOCHONDRIA ARE ALSO CAPABLE OF REGULATING IMMUNE RESPONSE TO VARIOUS INFECTIONS AND TISSUE DAMAGE BY PRODUCING PRO- OR ANTI-INFLAMMATORY SIGNALS. THIS OCCURS BY ALTERING THE LEVELS OF MITOCHONDRIAL METABOLITES AND REACTIVE OXYGEN SPECIES (ROS) LEVELS. SINCE MITOCHONDRIA ARE KNOWN AS THE GUARDIANS OF THE INFLAMMATORY RESPONSE, IT IS PLAUSIBLE THAT MITOCHONDRIAL EPIGENETICS MIGHT PLAY A PIVOTAL ROLE IN INFLAMMATION. HENCE, THIS REVIEW FOCUSES ON THE INTRICATE DYNAMICS OF EPIGENETIC ALTERATIONS OF INFLAMMATION, WITH EMPHASIS ON MITOCHONDRIA IN CANCER AND AGING. 2022 2 4898 38 OXIDATIVE STRESS INDUCED LUNG CANCER AND COPD: OPPORTUNITIES FOR EPIGENETIC THERAPY. REACTIVE OXYGEN SPECIES (ROS) FORM AS A NATURAL BY-PRODUCT OF THE NORMAL METABOLISM OF OXYGEN AND PLAY IMPORTANT ROLES WITHIN THE CELL. UNDER NORMAL CIRCUMSTANCES THE CELL IS ABLE TO MAINTAIN AN ADEQUATE HOMEOSTASIS BETWEEN THE FORMATION OF ROS AND ITS REMOVAL THROUGH PARTICULAR ENZYMATIC PATHWAYS OR VIA ANTIOXIDANTS. IF HOWEVER, THIS BALANCE IS DISTURBED A SITUATION CALLED OXIDATIVE STRESS OCCURS. CRITICALLY, OXIDATIVE STRESS PLAYS IMPORTANT ROLES IN THE PATHOGENESIS OF MANY DISEASES, INCLUDING CANCER. EPIGENETICS IS A PROCESS WHERE GENE EXPRESSION IS REGULATED BY HERITABLE MECHANISMS THAT DO NOT CAUSE ANY DIRECT CHANGES TO THE DNA SEQUENCE ITSELF, AND DISRUPTION OF EPIGENETIC MECHANISMS HAS IMPORTANT IMPLICATIONS IN DISEASE. EVIDENCE IS EMERGING THAT HISTONE DEACETYLASES (HDACS) PLAY DECISIVE ROLES IN REGULATING IMPORTANT CELLULAR OXIDATIVE STRESS PATHWAYS INCLUDING THOSE INVOLVED WITH SENSING OXIDATIVE STRESS AND THOSE INVOLVED WITH REGULATING THE CELLULAR RESPONSE TO OXIDATIVE STRESS. IN PARTICULAR ABERRANT REGULATION OF THESE PATHWAYS BY HDACS MAY PLAY CRITICAL ROLES IN CANCER PROGRESSION. IN THIS REVIEW WE DISCUSS THE CURRENT EVIDENCE LINKING EPIGENETICS AND OXIDATIVE STRESS AND CANCER, USING CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND NON-SMALL CELL LUNG CANCER TO ILLUSTRATE THE IMPORTANCE OF EPIGENETICS ON THESE PATHWAYS WITHIN THESE DISEASE SETTINGS. 2009 3 4372 47 MIRNAS, OXIDATIVE STRESS, AND CANCER: A COMPREHENSIVE AND UPDATED REVIEW. OXIDATIVE STRESS REFERS TO ELEVATED LEVELS OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS). ROS HOMEOSTASIS FUNCTIONS AS A SIGNALING PATHWAY FOR NORMAL CELL SURVIVAL AND APPROPRIATE CELL SIGNALING. CHRONIC INFLAMMATION INDUCED BY IMBALANCED LEVELS OF ROS CONTRIBUTES TO MANY DISEASES AND DIFFERENT TYPES OF CANCER. ROS CAN ALTER THE EXPRESSION OF ONCOGENES AND TUMOR SUPPRESSOR GENES THROUGH EPIGENETIC MODIFICATIONS, TRANSCRIPTION FACTORS, AND NON-CODING RNAS. MICRORNAS (MIRNAS) ARE SMALL NON-CODING RNAS THAT PLAY A KEY ROLE IN MOST BIOLOGICAL PATHWAYS. EACH MIRNA REGULATES HUNDREDS OF TARGET GENES BY INHIBITING PROTEIN TRANSLATION AND/OR PROMOTING MESSENGER RNA DEGRADATION. IN NORMAL CONDITIONS, MIRNAS PLAY A PHYSIOLOGICAL ROLE IN CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. HOWEVER, DIFFERENT FACTORS THAT CAN DYSREGULATE CELL SIGNALING AND CELLULAR HOMEOSTASIS CAN ALSO AFFECT MIRNA EXPRESSION. THE ALTERATION OF MIRNA EXPRESSION CAN WORK AGAINST DISTURBING FACTORS OR MEDIATE THEIR EFFECTS. OXIDATIVE STRESS IS ONE OF THESE FACTORS. CONSIDERING THE COMPLEX INTERPLAY BETWEEN ROS LEVEL AND MIRNA REGULATION AND BOTH OF THESE WITH CANCER DEVELOPMENT, WE REVIEW THE ROLE OF MIRNAS IN CANCER, FOCUSING ON THEIR FUNCTION IN OXIDATIVE STRESS. 2020 4 5581 32 ROLE OF NF-KAPPAB IN AGEING AND AGE-RELATED DISEASES: LESSONS FROM GENETICALLY MODIFIED MOUSE MODELS. AGEING IS A COMPLEX PROCESS, INDUCED BY MULTIFACETED INTERACTION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. IT IS MANIFESTED BY A DECLINE IN THE PHYSIOLOGICAL FUNCTIONS OF ORGANISMS AND ASSOCIATED TO THE DEVELOPMENT OF AGE-RELATED CHRONIC DISEASES AND CANCER DEVELOPMENT. IT IS CONSIDERED THAT AGEING FOLLOWS A STRICTLY-REGULATED PROGRAM, IN WHICH SOME SIGNALING PATHWAYS CRITICALLY CONTRIBUTE TO THE ESTABLISHMENT AND MAINTENANCE OF THE AGED STATE. CHRONIC INFLAMMATION IS A MAJOR MECHANISM THAT PROMOTES THE BIOLOGICAL AGEING PROCESS AND COMORBIDITY, WITH THE TRANSCRIPTION FACTOR NF-KAPPAB (NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS) AS A CRUCIAL MEDIATOR OF INFLAMMATORY RESPONSES. THIS, TOGETHER WITH THE FINDING THAT THE ACTIVATION OR INHIBITION OF NF-KAPPAB CAN INDUCE OR REVERSE RESPECTIVELY THE MAIN FEATURES OF AGED ORGANISMS, HAS BROUGHT IT UNDER CONSIDERATION AS A KEY TRANSCRIPTION FACTOR THAT ACTS AS A DRIVER OF AGEING. IN THIS REVIEW, WE FOCUSED ON THE DATA OBTAINED ENTIRELY THROUGH THE GENERATION OF KNOCKOUT AND TRANSGENIC MOUSE MODELS OF EITHER PROTEIN INVOLVED IN THE NF-KAPPAB SIGNALING PATHWAY THAT HAVE PROVIDED RELEVANT INFORMATION ABOUT THE INTRICATE PROCESSES OR MOLECULAR MECHANISMS THAT CONTROL AGEING. WE HAVE REVIEWED THE RELATIONSHIP OF NF-KAPPAB AND PREMATURE AGEING; THE DEVELOPMENT OF CANCER ASSOCIATED WITH AGEING AND THE IMPLICATION OF NF-KAPPAB ACTIVATION IN THE DEVELOPMENT OF AGE-RELATED DISEASES, SOME OF WHICH GREATLY INCREASE THE RISK OF DEVELOPING CANCER. 2021 5 6100 43 THE EMERGING ROLE OF EPIGENETIC MODIFIERS IN REPAIR OF DNA DAMAGE ASSOCIATED WITH CHRONIC INFLAMMATORY DISEASES. AT SITES OF CHRONIC INFLAMMATION EPITHELIAL CELLS ARE EXPOSED TO HIGH LEVELS OF REACTIVE OXYGEN SPECIES (ROS), WHICH CAN CONTRIBUTE TO THE INITIATION AND DEVELOPMENT OF MANY DIFFERENT HUMAN CANCERS. ABERRANT EPIGENETIC ALTERATIONS THAT CAUSE TRANSCRIPTIONAL SILENCING OF TUMOR SUPPRESSOR GENES ARE ALSO IMPLICATED IN MANY DISEASES ASSOCIATED WITH INFLAMMATION, INCLUDING CANCER. HOWEVER, IT IS NOT CLEAR HOW ALTERED EPIGENETIC GENE SILENCING IS INITIATED DURING CHRONIC INFLAMMATION. THE HIGH LEVEL OF ROS AT SITES OF INFLAMMATION IS KNOWN TO INDUCE OXIDATIVE DNA DAMAGE IN SURROUNDING EPITHELIAL CELLS. FURTHERMORE, DNA DAMAGE IS KNOWN TO TRIGGER SEVERAL RESPONSES, INCLUDING RECRUITMENT OF DNA REPAIR PROTEINS, TRANSCRIPTIONAL REPRESSION, CHROMATIN MODIFICATIONS AND OTHER CELL SIGNALING EVENTS. RECRUITMENT OF EPIGENETIC MODIFIERS TO CHROMATIN IN RESPONSE TO DNA DAMAGE RESULTS IN TRANSIENT COVALENT MODIFICATIONS TO CHROMATIN SUCH AS HISTONE UBIQUITINATION, ACETYLATION AND METHYLATION AND DNA METHYLATION. DNA DAMAGE ALSO ALTERS NON-CODING RNA EXPRESSION. ALL OF THESE ALTERATIONS HAVE THE POTENTIAL TO ALTER GENE EXPRESSION AT SITES OF DAMAGE. TYPICALLY, THESE MODIFICATIONS AND GENE TRANSCRIPTION ARE RESTORED BACK TO NORMAL ONCE THE REPAIR OF THE DNA DAMAGE IS COMPLETED. HOWEVER, CHRONIC INFLAMMATION MAY INDUCE SUSTAINED DNA DAMAGE AND DNA DAMAGE RESPONSES THAT RESULT IN THESE TRANSIENT COVALENT CHROMATIN MODIFICATIONS BECOMING MITOTICALLY STABLE EPIGENETIC ALTERATIONS. UNDERSTANDING HOW EPIGENETIC ALTERATIONS ARE INITIATED DURING CHRONIC INFLAMMATION WILL ALLOW US TO DEVELOP PHARMACEUTICAL STRATEGIES TO PREVENT OR TREAT CHRONIC INFLAMMATION-INDUCED CANCER. THIS REVIEW WILL FOCUS ON TYPES OF DNA DAMAGE AND EPIGENETIC ALTERATIONS ASSOCIATED WITH CHRONIC INFLAMMATORY DISEASES, THE TYPES OF DNA DAMAGE AND TRANSIENT COVALENT CHROMATIN MODIFICATIONS INDUCED BY INFLAMMATION AND OXIDATIVE DNA DAMAGE AND HOW THESE MODIFICATIONS MAY RESULT IN EPIGENETIC ALTERATIONS. 2019 6 3672 23 INFLAMMATION AND CANCER: AN ANCIENT LINK WITH NOVEL POTENTIALS. INFECTION AND CHRONIC INFLAMMATION CONTRIBUTE TO ABOUT 1 IN 4 OF ALL CANCER CASES. MEDIATORS OF THE INFLAMMATORY RESPONSE, E.G., CYTOKINES, FREE RADICALS, PROSTAGLANDINS AND GROWTH FACTORS, CAN INDUCE GENETIC AND EPIGENETIC CHANGES INCLUDING POINT MUTATIONS IN TUMOR SUPPRESSOR GENES, DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS, CAUSING ALTERATIONS IN CRITICAL PATHWAYS RESPONSIBLE FOR MAINTAINING THE NORMAL CELLULAR HOMEOSTASIS AND LEADING TO THE DEVELOPMENT AND PROGRESSION OF CANCER. RECENT DISCOVERY OF AN INTERACTION BETWEEN MICRORNAS AND INNATE IMMUNITY DURING INFLAMMATION HAS FURTHER STRENGTHENED THE ASSOCIATION BETWEEN INFLAMMATION AND CANCER. 2007 7 5943 33 TARGETING OXIDATIVE STRESS IN CANCER. IMPORTANCE OF THE FIELD: REACTIVE OXYGEN SPECIES (ROS) OCCUR AS NATURAL BY-PRODUCTS OF OXYGEN METABOLISM AND HAVE IMPORTANT CELLULAR FUNCTIONS. NORMALLY, THE CELL IS ABLE TO MAINTAIN AN ADEQUATE BALANCE BETWEEN THE FORMATION AND REMOVAL OF ROS EITHER VIA ANTI-OXIDANTS OR THROUGH THE USE SPECIFIC ENZYMATIC PATHWAYS. HOWEVER, IF THIS BALANCE IS DISTURBED, OXIDATIVE STRESS MAY OCCUR IN THE CELL, A SITUATION LINKED TO THE PATHOGENESIS OF MANY DISEASES, INCLUDING CANCER. AREAS COVERED IN THIS REVIEW: HDACS ARE IMPORTANT REGULATORS OF MANY OXIDATIVE STRESS PATHWAYS INCLUDING THOSE INVOLVED WITH BOTH SENSING AND COORDINATING THE CELLULAR RESPONSE TO OXIDATIVE STRESS. IN PARTICULAR ABERRANT REGULATION OF THESE PATHWAYS BY HISTONE DEACETYLASES MAY PLAY CRITICAL ROLES IN CANCER PROGRESSION. WHAT THE READER WILL GAIN: IN THIS REVIEW WE DISCUSS THE NOTION THAT TARGETING HDACS MAY BE A USEFUL THERAPEUTIC AVENUE IN THE TREATMENT OF OXIDATIVE STRESS IN CANCER, USING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), NSCLC AND HEPATOCELLULAR CARCINOMA (HCC) AS EXAMPLES TO ILLUSTRATE THIS POSSIBILITY. TAKE HOME MESSAGE: EPIGENETIC MECHANISMS MAY BE AN IMPORTANT NEW THERAPEUTIC AVENUE FOR TARGETING OXIDATIVE STRESS IN CANCER. 2010 8 4037 29 MACROPHAGE IMMUNOMETABOLISM AND INFLAMMAGING: ROLES OF MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, CD38, AND NAD. AGING IS A COMPLEX PROCESS THAT INVOLVES DYSFUNCTION ON MULTIPLE LEVELS, ALL OF WHICH SEEM TO CONVERGE ON INFLAMMATION. MACROPHAGES ARE INTIMATELY INVOLVED IN INITIATING AND RESOLVING INFLAMMATION, AND THEIR DYSREGULATION WITH AGE IS A PRIMARY CONTRIBUTOR TO INFLAMMAGING-A STATE OF CHRONIC, LOW-GRADE INFLAMMATION THAT DEVELOPS DURING AGING. AMONG THE AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES ARE A HEIGHTENED STATE OF BASAL INFLAMMATION AND DIMINISHED OR HYPERACTIVE INFLAMMATORY RESPONSES, WHICH SEEM TO BE DRIVEN BY METABOLIC-DEPENDENT EPIGENETIC CHANGES. IN THIS REVIEW ARTICLE WE PROVIDE A BRIEF OVERVIEW OF MITOCHONDRIAL FUNCTIONS AND AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES, WITH AN EMPHASIS ON HOW THE INFLAMMAGING ENVIRONMENT, SENESCENCE, AND NAD DECLINE CAN AFFECT THEIR METABOLISM, PROMOTE DYSREGULATION, AND CONTRIBUTE TO INFLAMMAGING AND AGE-RELATED PATHOLOGIES. 2020 9 6344 29 THE ROLE OF EPIGENETICS IN AGING AND AUTOIMMUNITY. THE DECLINE IN IMMUNOCOMPETENCE WITH AGE IS ACCOMPANIED BY THE INCREASE IN THE INCIDENCE OF AUTOIMMUNE DISEASES. AGING OF THE IMMUNE SYSTEM, OR IMMUNOSENESCENCE, IS CHARACTERIZED BY A DECLINE OF BOTH T AND B CELL FUNCTION, AND PARADOXICALLY THE PRESENCE OF LOW-GRADE CHRONIC INFLAMMATION. THERE IS GROWING EVIDENCE THAT EPIGENETICS, THE STUDY OF INHERITED CHANGES IN GENE EXPRESSION THAT ARE NOT ENCODED BY THE DNA SEQUENCE ITSELF, CHANGES WITH AGING. INTERESTINGLY, EMERGING EVIDENCE SUGGESTS A KEY ROLE FOR EPIGENETICS IN HUMAN PATHOLOGIES, INCLUDING INFLAMMATORY AND NEOPLASTIC DISORDERS. HERE, WE WILL REVIEW THE POTENTIAL MECHANISMS THAT CONTRIBUTE TO THE INCREASE IN AUTOIMMUNE RESPONSES IN AGING. IN PARTICULAR, WE WILL DISCUSS HOW EPIGENETIC ALTERATIONS, ESPECIALLY DNA METHYLATION AND HISTONE ACETYLATION, ARE ACCUMULATED DURING AGING AND HOW THESE EVENTS CONTRIBUTE TO AUTOIMMUNITY RISK. 2010 10 3921 36 LINKING INFLAMMATION TO CELL CYCLE PROGRESSION. RISK OF GASTROINTESTINAL CANCERS IS CLOSELY RELATED TO INCREASED LEVELS OF OXIDANTS IN THE BALANCE BETWEEN OXIDANT AND ANTI-OXIDANT AGENTS. A POSSIBLE EXPLANATION OF THIS EPIDEMIOLOGICAL OBSERVATION IS THE LOCAL LOSS OF THE EPITHELIAL BARRIER FUNCTION WITH A FOCAL INFLAMMATORY RESPONSE. ACCORDINGLY, CHRONIC INFLAMMATORY DISEASES REPRESENT WELL-KNOWN RISK FACTORS FOR CANCER AND, ON THE OTHER HAND, IT IS KNOWN THAT ANTI-INFLAMMATORY AGENTS, DEMULCENTS AND ANTIOXIDANTS MARKEDLY INHIBIT THE DEVELOPMENT OF COLON CANCER IN ANIMAL MODELS AS WELL IN HUMANS. AT MOLECULAR LEVEL A KEY ROLE IN THE PROCESS THAT LINK INFLAMMATION TO CELLULAR TRANSFORMATION SEEMS TO BE PLAYED BY ACTIVATION OF CYCLOOXYGENASE-2 (COX-2) TOGETHER WITH PRODUCTION OF REACTIVE OXYGEN INTERMEDIATE (ROI). BOTH THESE EVENTS HAVE BEEN STRICTLY LINKED WITH CELL PROLIFERATION AND TRANSFORMATION, ALTHOUGH THE INTRACELLULAR PATHWAYS INVOLVED IN THESE PROCESSES ARE STILL NOT COMPLETELY UNDERSTOOD. THE UNCONTROLLED PROLIFERATION, WHICH IS A LANDMARK OF CELLULAR TRANSFORMATION, IS ACCOMPANIED BY THE DEREGULATION OF PROTEINS INVOLVED IN THE CONTROL OF CELL CYCLE CHECKPOINTS. ALTERED EXPRESSION AND FUNCTION OF CYCLOOXYGENASE AND NITRIC OXIDE SYNTHASE SEEM TO INFLUENCE, AMONG OTHERS, THE EXPRESSION OF PROTEINS INVOLVED IN THE REGULATION OF CELL CYCLE PROGRESSION. SIMILARLY, ANTI-INFLAMMATORY AND ANTIOXIDANT AGENTS MAY ALSO ACT ON THE EXPRESSION AND FUNCTION OF SEVERAL CELL CYCLE REGULATING PROTEINS. UNDERSTANDING THE MECHANISMS BY WHICH CHRONIC INFLAMMATION CONTRIBUTES TO GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE REGULATION OF CRITICAL CELL CYCLE CHECKPOINTS MAY HELP TO DEVELOP MORE AND MORE SPECIFIC TREATMENT STRATEGIES FOR REDUCING MALIGNANT TRANSFORMATION OF THESE INFLAMMATORY DISEASES. 2004 11 5801 31 STIFFNESS AND AGING IN CARDIOVASCULAR DISEASES: THE DANGEROUS RELATIONSHIP BETWEEN FORCE AND SENESCENCE. BIOLOGICAL AGING IS A PROCESS ASSOCIATED WITH A GRADUAL DECLINE IN TISSUES' HOMEOSTASIS BASED ON THE PROGRESSIVE INABILITY OF THE CELLS TO SELF-RENEW. CELLULAR SENESCENCE IS ONE OF THE HALLMARKS OF THE AGING PROCESS, CHARACTERIZED BY AN IRREVERSIBLE CELL CYCLE ARREST DUE TO REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, TELOMERES SHORTENING, CHRONIC INFLAMMATORY ACTIVATION, AND CHROMATIN MODIFICATIONS. IN THIS REVIEW, WE WILL DESCRIBE THE EFFECTS OF SENESCENCE ON TISSUE STRUCTURE, EXTRACELLULAR MATRIX (ECM) ORGANIZATION, AND NUCLEUS ARCHITECTURE, AND SEE HOW THESE CHANGES AFFECT (ARE AFFECTED BY) MECHANO-TRANSDUCTION. IN OUR VIEW, THIS IS ESSENTIAL FOR A DEEPER UNDERSTANDING OF THE PROGRESSIVE PATHOLOGICAL EVOLUTION OF THE CARDIOVASCULAR SYSTEM AND ITS RELATIONSHIP WITH THE DETRIMENTAL EFFECTS OF RISK FACTORS, KNOWN TO ACT AT AN EPIGENETIC LEVEL. 2021 12 1864 34 EMERGING AVENUES LINKING INFLAMMATION AND CANCER. THE ROLE OF INFLAMMATION IN CARCINOGENESIS HAS BEEN EXTENSIVELY INVESTIGATED AND WELL DOCUMENTED. MANY BIOCHEMICAL PROCESSES THAT ARE ALTERED DURING CHRONIC INFLAMMATION HAVE BEEN IMPLICATED IN TUMORIGENESIS. THESE INCLUDE SHIFTING CELLULAR REDOX BALANCE TOWARD OXIDATIVE STRESS; INDUCTION OF GENOMIC INSTABILITY; INCREASED DNA DAMAGE; STIMULATION OF CELL PROLIFERATION, METASTASIS, AND ANGIOGENESIS; DEREGULATION OF CELLULAR EPIGENETIC CONTROL OF GENE EXPRESSION; AND INAPPROPRIATE EPITHELIAL-TO-MESENCHYMAL TRANSITION. A WIDE ARRAY OF PROINFLAMMATORY CYTOKINES, PROSTAGLANDINS, NITRIC OXIDE, AND MATRICELLULAR PROTEINS ARE CLOSELY INVOLVED IN PREMALIGNANT AND MALIGNANT CONVERSION OF CELLS IN A BACKGROUND OF CHRONIC INFLAMMATION. INAPPROPRIATE TRANSCRIPTION OF GENES ENCODING INFLAMMATORY MEDIATORS, SURVIVAL FACTORS, AND ANGIOGENIC AND METASTATIC PROTEINS IS THE KEY MOLECULAR EVENT IN LINKING INFLAMMATION AND CANCER. ABERRANT CELL SIGNALING PATHWAYS COMPRISING VARIOUS KINASES AND THEIR DOWNSTREAM TRANSCRIPTION FACTORS HAVE BEEN IDENTIFIED AS THE MAJOR CONTRIBUTORS IN ABNORMAL GENE EXPRESSION ASSOCIATED WITH INFLAMMATION-DRIVEN CARCINOGENESIS. THE POSTTRANSCRIPTIONAL REGULATION OF GENE EXPRESSION BY MICRORNAS ALSO PROVIDES THE MOLECULAR BASIS FOR LINKING INFLAMMATION TO CANCER. THIS REVIEW HIGHLIGHTS THE MULTIFACETED ROLE OF INFLAMMATION IN CARCINOGENESIS IN THE CONTEXT OF ALTERED CELLULAR REDOX SIGNALING. 2012 13 1523 28 DNA METHYLATION CHANGES AND INFLAMMAGING IN AGING-ASSOCIATED DISEASES. AGING AS AN INEVITABLE PHENOMENON IS ASSOCIATED WITH PERVASIVE CHANGES IN PHYSIOLOGICAL FUNCTIONS. THERE IS A RELATIONSHIP BETWEEN AGING AND THE INCREASE OF SEVERAL CHRONIC DISEASES. MOST AGE-RELATED DISORDERS ARE ACCOMPANIED BY AN UNDERLYING CHRONIC INFLAMMATORY STATE, AS DEMONSTRATED BY LOCAL INFILTRATION OF INFLAMMATORY CELLS AND GREATER LEVELS OF PROINFLAMMATORY CYTOKINES IN THE BLOODSTREAM. WITHIN INFLAMMAGING, MANY EPIGENETIC EVENTS, ESPECIALLY DNA METHYLATION, CHANGE. DURING THE AGING PROCESS, DUE TO ABERRATIONS OF DNA METHYLATION, BIOLOGICAL PROCESSES ARE DISRUPTED, LEADING TO THE EMERGENCE OR PROGRESSION OF A VARIETY OF HUMAN DISEASES, INCLUDING CANCER, NEURODEGENERATIVE DISORDERS, CARDIOVASCULAR DISEASE AND DIABETES. THE FOCUS OF THIS REVIEW IS ON DNA METHYLATION, WHICH IS INVOLVED IN INFLAMMAGING-RELATED ACTIVITIES, AND HOW ITS DYSREGULATION LEADS TO HUMAN DISORDERS. 2022 14 6395 37 THE ROLE OF THE MEDIATORS OF INFLAMMATION IN CANCER DEVELOPMENT. EPIGENETIC DISORDERS SUCH AS POINT MUTATIONS IN CELLULAR TUMOR SUPPRESSOR GENES, DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS ARE NEEDED TO TRANSFORMATION OF NORMAL CELLS INTO CANCER CELLS. THESE EVENTS RESULT IN ALTERATIONS IN CRITICAL PATHWAYS RESPONSIBLE FOR MAINTAINING THE NORMAL CELLULAR HOMEOSTASIS, TRIGGERING TO AN INFLAMMATORY RESPONSE WHICH CAN LEAD THE DEVELOPMENT OF CANCER. THE INFLAMMATORY RESPONSE IS A UNIVERSAL DEFENSE MECHANISM ACTIVATED IN RESPONSE TO AN INJURY TISSUE, OF ANY NATURE, THAT INVOLVES BOTH INNATE AND ADAPTIVE IMMUNE RESPONSES, THROUGH THE COLLECTIVE ACTION OF A VARIETY OF SOLUBLE MEDIATORS. MANY INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN SEVERAL TYPES OF CANCER, LINKING CHRONIC INFLAMMATION TO TUMORIGENESIS PROCESS. THUS, INFLAMMATORY RESPONSES PLAY DECISIVE ROLES AT DIFFERENT STAGES OF TUMOR DEVELOPMENT, INCLUDING INITIATION, PROMOTION, GROWTH, INVASION, AND METASTASIS, AFFECTING ALSO THE IMMUNE SURVEILLANCE. IMMUNE CELLS THAT INFILTRATE TUMORS ENGAGE IN AN EXTENSIVE AND DYNAMIC CROSSTALK WITH CANCER CELLS, AND SOME OF THE MOLECULAR EVENTS THAT MEDIATE THIS DIALOG HAVE BEEN REVEALED. A RANGE OF INFLAMMATION MEDIATORS, INCLUDING CYTOKINES, CHEMOKINES, FREE RADICALS, PROSTAGLANDINS, GROWTH AND TRANSCRIPTION FACTORS, MICRORNAS, AND ENZYMES AS, CYCLOOXYGENASE AND MATRIX METALLOPROTEINASE, COLLECTIVELY ACTS TO CREATE A FAVORABLE MICROENVIRONMENT FOR THE DEVELOPMENT OF TUMORS. IN THIS REVIEW ARE PRESENTED THE MAIN MEDIATORS OF THE INFLAMMATORY RESPONSE AND DISCUSSED THE LIKELY MECHANISMS THROUGH WHICH, THEY INTERACT WITH EACH OTHER TO CREATE A CONDITION FAVORABLE TO DEVELOPMENT OF CANCER. 2015 15 4377 31 MITOCHONDRIAL AGING: FOCUS ON MITOCHONDRIAL DNA DAMAGE IN ATHEROSCLEROSIS - A MINI-REVIEW. ATHEROSCLEROSIS IS A COMPLEX DISEASE WHICH CAN BE DESCRIBED AS AN EXCESSIVE FIBROFATTY, PROLIFERATIVE, INFLAMMATORY RESPONSE TO DAMAGE TO THE ARTERY WALL INVOLVING SEVERAL CELL TYPES SUCH AS SMOOTH MUSCLE CELLS, MONOCYTE-DERIVED MACROPHAGES, LYMPHOCYTES, DENDRITIC CELLS AND PLATELETS. ON THE OTHER HAND, ATHEROSCLEROSIS IS A TYPICAL AGE-RELATED DEGENERATIVE PATHOLOGY, WHICH IS CHARACTERIZED BY SIGNS OF CELL SENESCENCE IN THE ARTERIAL WALL INCLUDING REDUCED CELL PROLIFERATION, IRREVERSIBLE GROWTH ARREST AND APOPTOSIS, INCREASED DNA DAMAGE, THE PRESENCE OF EPIGENETIC MODIFICATIONS, SHORTENING OF TELOMERE LENGTH AND MITOCHONDRIAL DYSFUNCTION. THE MOST PROMINENT CHARACTERISTICS OF MITOCHONDRIAL AGING ARE THEIR STRUCTURAL ALTERATIONS AND MITOCHONDRIAL DNA DAMAGE. THE MECHANISMS OF MITOCHONDRIAL GENOME DAMAGE IN THE DEVELOPMENT OF CHRONIC AGE-RELATED DISEASES SUCH AS ATHEROSCLEROSIS ARE NOT YET WELL UNDERSTOOD. THIS REVIEW FOCUSES ON THE LATEST FINDINGS FROM STUDIES OF THOSE MUTATIONS OF THE MITOCHONDRIAL GENOME WHICH MAY PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF ATHEROSCLEROSIS AND WHICH ARE, AT THE SAME TIME, ALSO MARKERS OF MITOCHONDRIAL AGING AND CELL SENESCENCE. 2015 16 5410 34 REGULATION OF ADAPTIVE IMMUNE CELLS BY SIRTUINS. IT IS NOW WELL-ESTABLISHED THAT THE PATHWAYS THAT CONTROL LYMPHOCYTE METABOLISM AND FUNCTION ARE INTIMATELY LINKED, AND CHANGES IN LYMPHOCYTE METABOLISM CAN INFLUENCE AND DIRECT CELLULAR FUNCTION. INTERESTINGLY, A NUMBER OF RECENT ADVANCES INDICATE THAT LYMPHOCYTE IDENTITY AND METABOLISM IS PARTIALLY CONTROLLED VIA EPIGENETIC REGULATION. EPIGENETIC MECHANISMS, SUCH AS CHANGES IN DNA METHYLATION OR HISTONE ACETYLATION, HAVE BEEN FOUND TO ALTER IMMUNE FUNCTION AND PLAY A ROLE IN NUMEROUS CHRONIC DISEASE STATES. THERE ARE SEVERAL ENZYMES THAT CAN MEDIATE EPIGENETIC CHANGES; OF PARTICULAR INTEREST ARE SIRTUINS, PROTEIN DEACETYLASES THAT MEDIATE ADAPTIVE RESPONSES TO A VARIETY OF STRESSES (INCLUDING CALORIE RESTRICTION AND METABOLIC STRESS) AND ARE NOW UNDERSTOOD TO PLAY A SIGNIFICANT ROLE IN IMMUNITY. THIS REVIEW WILL FOCUS ON RECENT ADVANCES IN THE UNDERSTANDING OF HOW SIRTUINS AFFECT THE ADAPTIVE IMMUNE SYSTEM. THESE PATHWAYS ARE OF SIGNIFICANT INTEREST AS THERAPEUTIC TARGETS FOR THE TREATMENT OF AUTOIMMUNITY, CANCER, AND TRANSPLANT TOLERANCE. 2019 17 6309 29 THE REGULATION OF MIRNAS IN INFLAMMATION-RELATED CARCINOGENESIS. CHRONIC INFLAMMATION PLAYS IMPORTANT ROLES IN THE INITIATION AND DEVELOPMENT OF VARIOUS CANCERS, PARTICULARLY GASTROINTESTINAL CANCER. CANCER IS CHARACTERIZED BY STEPWISE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS OF GENES. AS A HIGH RISK FACTOR FOR CANCER, CHRONIC INFLAMMATORY RESPONSE PRODUCES GREAT AMOUNT OF MEDIATORS, INCLUDING CYTOKINES, REACTIVE OXYGEN AND NITROGEN SPECIES, PROTEINASES, WHICH CAN INDUCE GENETIC AND EPIGENETIC CHANGES OF CANCER-ASSOCIATED GENES AND PATHWAYS. FURTHERMORE, INFLAMMATION ALSO MODULATES THE EXPRESSION OF MIRNAS THAT NOT ONLY REGULATE THE EXPRESSION OF TUMOR-RELATED PROTEINS BUT ALSO ENHANCE THE TUMOR-PROMOTING INFLAMMATORY PROCESS. IN THE CURRENT REVIEW, WE SUMMARIZE THE MECHANISMS BY WHICH INFLAMMATORY MEDIATORS AND SIGNALING REGULATE THE BIOSYNTHESIS OF MIRNAS, AS WELL AS THE INVOLVEMENT OF MIRNAS IN THE FEEDBACK LOOPS PROMOTING INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2015 18 5932 33 TARGETING EPIGENETIC REGULATORS FOR INFLAMMATION: MECHANISMS AND INTERVENTION THERAPY. EMERGING EVIDENCE INDICATES THAT RESOLUTION OF INFLAMMATION IS A CRITICAL AND DYNAMIC ENDOGENOUS PROCESS FOR HOST TISSUES DEFENDING AGAINST EXTERNAL INVASIVE PATHOGENS OR INTERNAL TISSUE INJURY. IT HAS LONG BEEN KNOWN THAT AUTOIMMUNE DISEASES AND CHRONIC INFLAMMATORY DISORDERS ARE CHARACTERIZED BY DYSREGULATED IMMUNE RESPONSES, LEADING TO EXCESSIVE AND UNCONTROL TISSUE INFLAMMATION. THE DYSREGULATION OF EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS TO HISTONE PROTEINS, AND NONCODING RNA EXPRESSION HAS BEEN IMPLICATED IN A HOST OF INFLAMMATORY DISORDERS AND THE IMMUNE SYSTEM. THE INFLAMMATORY RESPONSE IS CONSIDERED AS A CRITICAL TRIGGER OF EPIGENETIC ALTERATIONS THAT IN TURN INTERCEDE INFLAMMATORY ACTIONS. THUS, UNDERSTANDING THE MOLECULAR MECHANISM THAT DICTATES THE OUTCOME OF TARGETING EPIGENETIC REGULATORS FOR INFLAMMATORY DISEASE IS REQUIRED FOR INFLAMMATION RESOLUTION. IN THIS ARTICLE, WE ELUCIDATE THE CRITICAL ROLE OF THE NUCLEAR FACTOR-KAPPAB SIGNALING PATHWAY, JAK/STAT SIGNALING PATHWAY, AND THE NLRP3 INFLAMMASOME IN CHRONIC INFLAMMATORY DISEASES. AND WE FORMULATE THE RELATIONSHIP BETWEEN INFLAMMATION, CORONAVIRUS DISEASE 2019, AND HUMAN CANCERS. ADDITIONALLY, WE REVIEW THE MECHANISM OF EPIGENETIC MODIFICATIONS INVOLVED IN INFLAMMATION AND INNATE IMMUNE CELLS. ALL THAT MATTERS IS THAT WE PROPOSE AND DISCUSS THE REJUVENATION POTENTIAL OF INTERVENTIONS THAT TARGET EPIGENETIC REGULATORS AND REGULATORY MECHANISMS FOR CHRONIC INFLAMMATION-ASSOCIATED DISEASES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 19 3703 25 INFLAMMATORY SIGNALLING AS MEDIATOR OF EPIGENETIC MODULATION IN TISSUE-SPECIFIC CHRONIC INFLAMMATION. RECENT SUCCESSES OF THERAPEUTIC INTERVENTION IN CHRONIC INFLAMMATORY DISEASES USING EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASE INHIBITORS AND INHIBITORS OF DNA METHYLATION SUGGEST THAT EPIGENETIC REPROGRAMMING PLAYS A ROLE IN THE AETIOLOGY OF THESE DISEASES. THE EPIGENETIC SIGNATURE OF A GIVEN IMMUNE CELL IS REFLECTED IN THE HISTORY OF MODIFICATIONS FROM DIFFERENT SIGNALS THE CELL HAS BEEN SUBJECTED TO DURING DIFFERENTIATION. LIKE OTHER CELLS, DIFFERENTIATING IMMUNE CELLS ARE DEPENDENT ON A COMPLEX COMBINATION OF INTER- AND INTRACELL SIGNALLING AS WELL AS TRANSCRIPTION MACHINERIES TO MODULATE THEIR EPIGENOMES IN ORDER TO MEDIATE DIFFERENTIATION. DESPITE EXTENSIVE RESEARCH INTO THESE PROCESSES, THE LINK BETWEEN CELLULAR SIGNALLING AND EPIGENETIC MODULATION REMAINS POORLY UNDERSTOOD. HERE, WE REVIEW RECENT PROGRESS AND DISCUSS KEY FACTORS DRIVING EPIGENETIC MODULATION IN CHRONIC INFLAMMATION. 2009 20 2854 36 FROM HEPATITIS TO HEPATOCELLULAR CARCINOMA: A PROPOSED MODEL FOR CROSS-TALK BETWEEN INFLAMMATION AND EPIGENETIC MECHANISMS. INFLAMMATION REPRESENTS THE BODY'S NATURAL RESPONSE TO TISSUE DAMAGE; HOWEVER, CHRONIC INFLAMMATION MAY ACTIVATE CELL PROLIFERATION AND INDUCE DEREGULATION OF CELL DEATH IN AFFECTED TISSUES. CHRONIC INFLAMMATION IS AN IMPORTANT FACTOR IN THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), ALTHOUGH THE PRECISE UNDERLYING MECHANISM REMAINS UNKNOWN. EPIGENETIC EVENTS, WHICH ARE CONSIDERED KEY MECHANISMS IN THE REGULATION OF GENE ACTIVITY STATES, ARE ALSO COMMONLY DEREGULATED IN HCC. HERE, WE REVIEW THE EVIDENCE THAT CHRONIC INFLAMMATION MIGHT DEREGULATE EPIGENETIC PROCESSES, THUS PROMOTING ONCOGENIC TRANSFORMATION, AND WE PROPOSE A WORKING HYPOTHESIS THAT EPIGENETIC DEREGULATION IS AN UNDERLYING MECHANISM BY WHICH INFLAMMATION MIGHT PROMOTE HCC DEVELOPMENT. IN THIS SCENARIO, DIFFERENT COMPONENTS OF THE INFLAMMATORY RESPONSE MIGHT DIRECTLY AND INDIRECTLY INDUCE CHANGES IN EPIGENETIC MACHINERIES ('EPIGENETIC SWITCH'), INCLUDING THOSE INVOLVED IN SETTING AND PROPAGATING NORMAL PATTERNS OF DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS IN HEPATOCYTES. WE DISCUSS THE POSSIBILITY THAT SELF-REINFORCING CROSS-TALK BETWEEN INFLAMMATION AND EPIGENETIC MECHANISMS MIGHT AMPLIFY INFLAMMATORY SIGNALS AND MAINTAIN A CHRONIC STATE OF INFLAMMATION CULMINATING IN CANCER DEVELOPMENT. THE POTENTIAL ROLE OF INFLAMMATION-EPIGENOME INTERACTIONS IN THE EMERGENCE AND MAINTENANCE OF CANCER STEM CELLS IS ALSO DISCUSSED. 2012