1 5301 101 PROTEIN PHOSPHATASE 2A CATALYTIC SUBUNIT ALPHA PLAYS A MYD88-DEPENDENT, CENTRAL ROLE IN THE GENE-SPECIFIC REGULATION OF ENDOTOXIN TOLERANCE. MYD88, THE INTRACELLULAR ADAPTOR OF MOST TLRS, MEDIATES EITHER PROINFLAMMATORY OR IMMUNOSUPPRESSIVE SIGNALING THAT CONTRIBUTES TO CHRONIC INFLAMMATION-ASSOCIATED DISEASES. ALTHOUGH GENE-SPECIFIC CHROMATIN MODIFICATIONS REGULATE INFLAMMATION, THE ROLE OF MYD88 SIGNALING IN ESTABLISHING SUCH EPIGENETIC LANDSCAPES UNDER DIFFERENT INFLAMMATORY STATES REMAINS ELUSIVE. USING QUANTITATIVE PROTEOMICS TO ENUMERATE THE INFLAMMATION-PHENOTYPIC CONSTITUENTS OF THE MYD88 INTERACTOME, WE FOUND THAT IN ENDOTOXIN-TOLERANT MACROPHAGES, PROTEIN PHOSPHATASE 2A CATALYTIC SUBUNIT ALPHA (PP2AC) ENHANCES ITS ASSOCIATION WITH MYD88 AND IS CONSTITUTIVELY ACTIVATED. KNOCKDOWN OF PP2AC PREVENTS SUPPRESSION OF PROINFLAMMATORY GENES AND RESISTANCE TO APOPTOSIS. THROUGH SITE-SPECIFIC DEPHOSPHORYLATION, CONSTITUTIVELY ACTIVE PP2AC DISRUPTS THE SIGNAL-PROMOTING TLR4-MYD88 COMPLEX AND BROADLY SUPPRESSES THE ACTIVITIES OF MULTIPLE PROINFLAMMATORY/PROAPOPTOTIC PATHWAYS AS WELL, SHIFTING PROINFLAMMATORY MYD88 SIGNALING TO A PROSURVIVAL MODE. CONSTITUTIVELY ACTIVE PP2AC TRANSLOCATED WITH MYD88 INTO THE NUCLEI OF TOLERANT MACROPHAGES ESTABLISHES THE IMMUNOSUPPRESSIVE PATTERN OF CHROMATIN MODIFICATIONS AND REPRESSES CHROMATIN REMODELING TO SELECTIVELY SILENCE PROINFLAMMATORY GENES, COORDINATING THE MYD88-DEPENDENT INFLAMMATION CONTROL AT BOTH SIGNALING AND EPIGENETIC LEVELS UNDER ENDOTOXIN-TOLERANT CONDITIONS. 2013 2 4585 24 NAD(+) AND VASCULAR DYSFUNCTION: FROM MECHANISMS TO THERAPEUTIC OPPORTUNITIES. NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)) IS AN ESSENTIAL AND PLEIOTROPIC COENZYME INVOLVED NOT ONLY IN CELLULAR ENERGY METABOLISM, BUT ALSO IN CELL SIGNALING, EPIGENETIC REGULATION, AND POST-TRANSLATIONAL PROTEIN MODIFICATIONS. VASCULAR DISEASE RISK FACTORS ARE ASSOCIATED WITH ABERRANT NAD(+) METABOLISM. CONVERSELY, THE THERAPEUTIC INCREASE OF NAD(+) LEVELS THROUGH THE ADMINISTRATION OF NAD(+) PRECURSORS OR INHIBITORS OF NAD(+)-CONSUMING ENZYMES REDUCES CHRONIC LOW-GRADE INFLAMMATION, REACTIVATES AUTOPHAGY AND MITOCHONDRIAL BIOGENESIS, AND ENHANCES OXIDATIVE METABOLISM IN VASCULAR CELLS OF HUMANS AND RODENTS WITH VASCULAR PATHOLOGIES. AS SUCH, NAD(+) HAS EMERGED AS A POTENTIAL TARGET FOR COMBATTING AGE-RELATED CARDIOVASCULAR AND CEREBROVASCULAR DISORDERS. THIS REVIEW DISCUSSES NAD(+)-REGULATED MECHANISMS CRITICAL FOR VASCULAR HEALTH AND SUMMARIZES NEW ADVANCES IN NAD(+) RESEARCH DIRECTLY RELATED TO VASCULAR AGING AND DISEASE, INCLUDING HYPERTENSION, ATHEROSCLEROSIS, CORONARY ARTERY DISEASE, AND AORTIC ANEURYSMS. FINALLY, WE ENUMERATE CHALLENGES AND OPPORTUNITIES FOR NAD(+) REPLETION THERAPY WHILE ANTICIPATING THE FUTURE OF THIS EXCITING RESEARCH FIELD, WHICH WILL HAVE A MAJOR IMPACT ON VASCULAR MEDICINE. 2022 3 4097 18 MATRIX STIFFNESS REGULATES MACROPHAGE POLARIZATION IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE AND THE PATHOLOGICAL BASIS OF MANY FATAL CARDIOVASCULAR DISEASES. MACROPHAGES, THE MAIN INFLAMMATORY CELLS IN ATHEROSCLEROTIC PLAQUE, HAVE A PARADOX ROLE IN DISEASE PROGRESSION. IN RESPONSE TO DIFFERENT MICROENVIRONMENTS, MACROPHAGES MAINLY HAVE TWO POLARIZED DIRECTIONS: PRO-INFLAMMATORY MACROPHAGES AND ANTI-INFLAMMATORY MACROPHAGES. MORE AND MORE EVIDENCE SHOWS THAT MACROPHAGE IS MECHANOSENSITIVE AND MATRIX STIFFNESS REGULATE MACROPHAGE PHENOTYPES IN ATHEROSCLEROSIS. HOWEVER, THE MOLECULAR MECHANISM OF MATRIX STIFFNESS REGULATING MACROPHAGE POLARIZATION STILL LACKS IN-DEPTH RESEARCH, WHICH HINDERS THE DEVELOPMENT OF NEW ANTI-ATHEROSCLEROTIC THERAPIES. IN THIS REVIEW, WE DISCUSS THE IMPORTANT ROLE OF MATRIX STIFFNESS IN REGULATING MACROPHAGE POLARIZATION THROUGH MECHANICAL SIGNAL TRANSDUCTION (HIPPO, PIEZO, CYTOSKELETON, AND INTEGRIN) AND EPIGENETIC MECHANISMS (MIRNA, DNA METHYLATION, AND HISTONE). WE HOPE TO PROVIDE A NEW PERSPECTIVE FOR ATHEROSCLEROSIS THERAPY BY TARGETING MATRIX STIFFNESS AND MACROPHAGE POLARIZATION. 2022 4 6467 24 TISSUE-SPECIFIC EFFECTS OF EXERCISE AS NAD(+) -BOOSTING STRATEGY: CURRENT KNOWLEDGE AND FUTURE PERSPECTIVES. NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+) ) IS AN EVOLUTIONARILY HIGHLY CONSERVED COENZYME WITH MULTI-FACETED CELL FUNCTIONS, INCLUDING ENERGY METABOLISM, MOLECULAR SIGNALING PROCESSES, EPIGENETIC REGULATION, AND DNA REPAIR. SINCE THE DISCOVERY THAT LOWER NAD(+) LEVELS ARE A SHARED CHARACTERISTIC OF VARIOUS DISEASES AND AGING PER SE, SEVERAL NAD(+) -BOOSTING STRATEGIES HAVE EMERGED. OTHER THAN PHARMACOLOGICAL AND NUTRITIONAL APPROACHES, EXERCISE IS THOUGHT TO RESTORE NAD(+) HOMEOSTASIS THROUGH METABOLIC ADAPTION TO CHRONICALLY RECURRING STATES OF INCREASED ENERGY DEMAND. IN THIS REVIEW WE DISCUSS THE IMPACT OF ACUTE EXERCISE AND EXERCISE TRAINING ON TISSUE-SPECIFIC NAD(+) METABOLISM OF RODENTS AND HUMANS TO HIGHLIGHT THE POTENTIAL VALUE AS NAD(+) -BOOSTING STRATEGY. BY INTERCONNECTING RESULTS FROM DIFFERENT INVESTIGATIONS, WE AIM TO DRAW ATTENTION TO TISSUE-SPECIFIC ALTERATIONS IN NAD(+) METABOLISM AND THE ASSOCIATED IMPLICATIONS FOR WHOLE-BODY NAD(+) HOMEOSTASIS. ACUTE EXERCISE LED TO PROFOUND ALTERATIONS OF INTRACELLULAR NAD(+) METABOLISM IN VARIOUS INVESTIGATIONS, WITH THE MAGNITUDE AND DIRECTION OF CHANGES BEING STRONGLY DEPENDENT ON THE APPLIED EXERCISE MODALITY, CELL TYPE, AND INVESTIGATED ANIMAL MODEL OR HUMAN POPULATION. EXERCISE TRAINING ELEVATED NAD(+) LEVELS AND NAD(+) METABOLISM ENZYMES IN VARIOUS TISSUES. BASED ON THESE RESULTS, WE DISCUSS MOLECULAR MECHANISMS THAT MIGHT CONNECT ACUTE EXERCISE-INDUCED DISRUPTIONS OF NAD(+) /NADH HOMEOSTASIS TO CHRONIC EXERCISE ADAPTIONS IN NAD(+) METABOLISM. TAKING THIS HYPOTHESIS-DRIVEN APPROACH, WE HOPE TO INSPIRE FUTURE RESEARCH ON THE MOLECULAR MECHANISMS OF EXERCISE AS NAD(+) -MODIFYING LIFESTYLE INTERVENTION, THEREBY ELUCIDATING THE POTENTIAL THERAPEUTIC VALUE IN NAD(+) -RELATED PATHOLOGIES. 2023 5 5423 20 REGULATION OF MACROPHAGE ACTIVATION AND DIFFERENTIATION IN ATHEROSCLEROSIS. CHRONIC INFLAMMATION IS A HALLMARK OF ATHEROSCLEROSIS AND MACROPHAGES PLAY A CENTRAL ROLE IN CONTROLLING INFLAMMATION AT ALL STAGES OF ATHEROSCLEROSIS. IN ATHEROSCLEROSIS, MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES ARE CONTINUOUSLY EXPOSED TO CHOLESTEROL, OXIDIZED LIPIDS, CELL DEBRIS, CYTOKINES, AND CHEMOKINES. NOT ONLY DO THESE STIMULI INDUCE A SPECIFIC MACROPHAGE PHENOTYPE, BUT THEY ALSO INTERACT EXTENSIVELY, LEADING TO MACROPHAGE HETEROGENEITY IN ATHEROSCLEROTIC PLAQUES. HEREIN, WE REVIEW THE DIVERSE PHENOTYPES OF MACROPHAGES, THE MECHANISMS UNDERLYING MACROPHAGE ACTIVATION, AND THE CONTRIBUTIONS OF MACROPHAGES TO ATHEROSCLEROSIS IN THIS CONTEXT. WE ALSO SUMMARIZE RECENT STUDIES ON FOAMY MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES IN PLAQUE DURING DISEASE PROGRESSION. WE PROVIDE A COMPREHENSIVE OVERVIEW OF TRANSCRIPTIONAL, EPIGENETIC, AND METABOLIC REPROGRAMMING OF MACROPHAGES AND DISCUSS THE EMERGING CONCEPTS OF TARGETING CYTOKINES AND MACROPHAGES TO MODULATE ATHEROSCLEROSIS. 2021 6 6888 14 [ROLE OF VASCULAR AGING IN THE PATHOGENESIS OF ABDOMINAL AORTIC ANEURYSM AND POTENTIAL THERAPEUTIC TARGETS]. ABDOMINAL AORTIC ANEURYSM(AAA)IS A COMMON AORTIC DEGENERATIVE DISEASE IN THE ELDERLY,AND ITS INCIDENCE IS GRADUALLY INCREASING WITH THE AGING OF THE POPULATION.THERE ARE NO SPECIFIC DRUGS AVAILABLE TO DELAY THE EXPANSION OF AAA.ONCE THE ANEURYSM RUPTURES,THE MORTALITY WILL EXCEED 90%,WHICH SERIOUSLY THREATENS THE LIFE OF PATIENTS.GIVEN THE HIGH INCIDENCE OF AAA IN THE ELDERLY,THIS REVIEW DISCUSSES THE ROLE OF VASCULAR AGING IN THE PATHOGENESIS OF AAA,INVOLVING CHRONIC INFLAMMATION,OXIDATIVE STRESS,MITOCHONDRIAL DYSFUNCTION,PROTEIN HOMEOSTASIS IMBALANCE,INCREASED APOPTOSIS AND NECROSIS,EXTRACELLULAR MATRIX REMODELING,NUTRITIONAL SENSING DISORDERS,EPIGENETIC CHANGES,AND INCREASED PRO-AGING FACTORS.MEANWHILE,SEVERAL POTENTIAL AGING-RELATED DRUG TARGETS OF AAA ARE LISTED.THIS REVIEW PROVIDES NEW IDEAS FOR BASIC AND TRANSLATIONAL MEDICAL RESEARCH OF AAA. 2021 7 2821 22 FINE-TUNING AUTOPHAGY: FROM TRANSCRIPTIONAL TO POSTTRANSLATIONAL REGULATION. MACROAUTOPHAGY (HEREAFTER CALLED AUTOPHAGY) IS A VACUOLAR LYSOSOMAL PATHWAY FOR DEGRADATION OF INTRACELLULAR MATERIAL IN EUKARYOTIC CELLS. AUTOPHAGY PLAYS CRUCIAL ROLES IN TISSUE HOMEOSTASIS, IN ADAPTATION TO STRESS SITUATIONS, AND IN IMMUNE AND INFLAMMATORY RESPONSES. ALTERATION OF AUTOPHAGY IS ASSOCIATED WITH CANCER, DIABETES AND OBESITY, CARDIOVASCULAR DISEASE, NEURODEGENERATIVE DISEASE, AUTOIMMUNE DISEASE, INFECTION, AND CHRONIC INFLAMMATORY DISEASE. AUTOPHAGY IS CONTROLLED BY AUTOPHAGY-RELATED (ATG) PROTEINS THAT ACT IN A COORDINATED MANNER TO BUILD UP THE INITIAL AUTOPHAGIC VACUOLE NAMED THE AUTOPHAGOSOME. IT IS NOW KNOWN THAT THE ACTIVITIES OF ATG PROTEINS ARE MODULATED BY POSTTRANSLATIONAL MODIFICATIONS SUCH AS PHOSPHORYLATION, UBIQUITINATION, AND ACETYLATION. MOREOVER, TRANSCRIPTIONAL AND EPIGENETIC CONTROLS ARE INVOLVED IN THE REGULATION OF AUTOPHAGY IN STRESS SITUATIONS. HERE WE SUMMARIZE AND DISCUSS HOW POSTTRANSLATIONAL MODIFICATIONS AND TRANSCRIPTIONAL AND EPIGENETIC CONTROLS REGULATE THE INVOLVEMENT OF AUTOPHAGY IN THE PROTEOSTASIS NETWORK. 2016 8 6214 25 THE INTRACELLULAR SIGNALING PATHWAYS GOVERNING MACROPHAGE ACTIVATION AND FUNCTION IN HUMAN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY LIPID ACCUMULATION AND PLAQUE FORMATION IN ARTERIAL VESSEL WALLS. ATHEROSCLEROTIC PLAQUES NARROW THE ARTERIAL LUMEN TO INCREASE THE RISK OF HEART ATTACKS, ISCHEMIC STROKE AND PERIPHERAL VASCULAR DISEASE, WHICH ARE MAJOR AND WORLDWIDE HEALTH AND ECONOMIC BURDENS. MACROPHAGE ACCUMULATION WITHIN PLAQUES IS CHARACTERISTIC OF ALL STAGES OF ATHEROSCLEROSIS AND THEIR PRESENCE IS A POTENTIAL MARKER OF DISEASE ACTIVITY AND PLAQUE STABILITY. MACROPHAGES ENGULF LIPIDS AND MODIFIED LIPOPROTEINS TO FORM FOAM CELLS THAT EXPRESS PRO-INFLAMMATORY AND CHEMOTACTIC EFFECTOR MOLECULES, STRESS INDUCING FACTORS AND REACTIVE OXYGEN SPECIES. THEY CONTROL PLAQUE STABILITY AND RUPTURE THROUGH SECRETION OF METALLOPROTEINASES AND EXTRACELLULAR MATRIX DEGRADATION. ALTHOUGH MACROPHAGES CAN WORSEN DISEASE BY PROPAGATING INFLAMMATION, THEY CAN STABILIZE ATHEROSCLEROTIC PLAQUES THROUGH TISSUE REMODELING, PROMOTING THE FORMATION OF A FIBROUS CAP, CLEARING APOPTOTIC CELLS TO PREVENT NECROTIC CORE FORMATION AND THROUGH VASCULAR REPAIR. IN ATHEROSCLEROSIS, MACROPHAGES RESPOND TO DYSLIPIDAEMIA, CYTOKINES, DYING CELLS, METABOLIC FACTORS, LIPIDS, PHYSICAL STIMULI AND EPIGENETIC FACTORS AND EXHIBIT HETEROGENEITY IN THEIR ACTIVATION DEPENDING ON THE STIMULI THEY RECEIVE. UNDERSTANDING THESE SIGNALS AND THE PATHWAYS DRIVING MACROPHAGE FUNCTION WITHIN DEVELOPING AND ESTABLISHED PLAQUES AND HOW THEY CAN BE PHARMACOLOGICALLY MODULATED, REPRESENTS A STRATEGY FOR THE PREVENTION AND TREATMENT OF ATHEROSCLEROSIS. THIS REVIEW FOCUSSES ON THE CURRENT UNDERSTANDING OF FACTORS CONTROLLING MACROPHAGE HETEROGENEITY AND FUNCTION IN ATHEROSCLEROSIS. PARTICULAR ATTENTION IS GIVEN TO THE MACROPHAGE INTRACELLULAR SIGNALING PATHWAYS AND TRANSCRIPTION FACTORS ACTIVATED BY BIOCHEMICAL AND BIOPHYSICAL STIMULI WITHIN PLAQUES, AND HOW THEY ARE INTEGRATED TO REGULATE PLAQUE FORMATION AND STABILITY. 2022 9 5719 16 SIRTUINS IN NEURODEGENERATIVE DISEASES: AN UPDATE ON POTENTIAL MECHANISMS. SILENT INFORMATION REGULATOR 2 PROTEINS (SIRTUINS OR SIRTS) ARE A GROUP OF DEACETYLASES (OR DEACYLASES) WHOSE ACTIVITIES ARE DEPENDENT ON AND REGULATED BY NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)). COMPELLING EVIDENCE SUPPORTS THAT SIRTUINS PLAY MAJOR ROLES IN MANY ASPECTS OF PHYSIOLOGY, ESPECIALLY IN PATHWAYS RELATED TO AGING - THE PREDOMINANT AND UNIFYING RISK FACTOR FOR NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE HIGHLIGHT THE MOLECULAR MECHANISMS UNDERLYING THE PROTECTIVE EFFECTS OF SIRTUINS IN NEURODEGENERATIVE DISEASES, FOCUSING ON PROTEIN HOMEOSTASIS, NEURAL PLASTICITY, MITOCHONDRIAL FUNCTION, AND SUSTAINED CHRONIC INFLAMMATION. WE WILL ALSO EXAMINE THE POTENTIAL AND CHALLENGES OF TARGETING SIRTUIN PATHWAYS TO BLOCK THESE PATHOGENIC PATHWAYS. 2013 10 3734 25 INNATE IMMUNE MEMORY IN MONOCYTES AND MACROPHAGES: THE POTENTIAL THERAPEUTIC STRATEGIES FOR ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A COMPLEX METABOLIC DISEASE CHARACTERIZED BY THE DYSFUNCTION OF LIPID METABOLISM AND CHRONIC INFLAMMATION IN THE INTIMAL SPACE OF THE VESSEL. AS THE MOST ABUNDANT INNATE IMMUNE CELLS, MONOCYTE-DERIVED MACROPHAGES PLAY A PIVOTAL ROLE IN THE INFLAMMATORY RESPONSE, CHOLESTEROL METABOLISM, AND FOAM CELL FORMATION. IN RECENT DECADES, IT HAS BEEN DEMONSTRATED THAT MONOCYTES AND MACROPHAGES CAN ESTABLISH INNATE IMMUNE MEMORY (ALSO TERMED TRAINED IMMUNITY) VIA ENDOGENOUS AND EXOGENOUS ATHEROGENIC STIMULI AND EXHIBIT A LONG-LASTING PROINFLAMMATORY PHENOTYPE. THE IMPORTANT CELLULAR METABOLISM PROCESSES, INCLUDING GLYCOLYSIS, OXIDATIVE PHOSPHORYLATION (OXPHOS), THE TRICARBOXYLIC ACID (TCA) CYCLE, FATTY ACID SYNTHESIS, AND CHOLESTEROL SYNTHESIS, ARE REPROGRAMMED. TRAINED MONOCYTES/MACROPHAGES WITH INNATE IMMUNE MEMORY CAN BE PERSISTENTLY HYPERACTIVATED AND CAN UNDERGO EXTENSIVE EPIGENETIC REWIRING, WHICH CONTRIBUTES TO THE PATHOPHYSIOLOGICAL DEVELOPMENT OF ATHEROSCLEROSIS VIA INCREASED PROINFLAMMATORY CYTOKINE PRODUCTION AND LIPID ACCUMULATION. HERE, WE PROVIDE AN OVERVIEW OF THE REGULATION OF CELLULAR METABOLIC PROCESSES AND EPIGENETIC MODIFICATIONS OF INNATE IMMUNE MEMORY IN MONOCYTES/MACROPHAGES AS WELL AS THE POTENTIAL ENDOGENOUS AND EXOGENOUS STIMULATIONS INVOLVED IN THE PROGRESSION OF ATHEROSCLEROSIS THAT HAVE BEEN REPORTED RECENTLY. THESE ELUCIDATIONS MIGHT BE BENEFICIAL FOR FURTHER UNDERSTANDING INNATE IMMUNE MEMORY AND THE DEVELOPMENT OF THERAPEUTIC STRATEGIES FOR INFLAMMATORY DISEASES AND ATHEROSCLEROSIS. 2022 11 4037 20 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 12 1874 23 EMERGING ROLE OF NF-KAPPAB SIGNALING IN THE INDUCTION OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). THE MAJOR HALLMARK OF CELLULAR SENESCENCE IS AN IRREVERSIBLE CELL CYCLE ARREST AND THUS IT IS A POTENT TUMOR SUPPRESSOR MECHANISM. GENOTOXIC INSULTS, E.G. OXIDATIVE STRESS, ARE IMPORTANT INDUCERS OF THE SENESCENT PHENOTYPE WHICH IS CHARACTERIZED BY AN ACCUMULATION OF SENESCENCE-ASSOCIATED HETEROCHROMATIC FOCI (SAHF) AND DNA SEGMENTS WITH CHROMATIN ALTERATIONS REINFORCING SENESCENCE (DNA-SCARS). INTERESTINGLY, SENESCENT CELLS SECRETE PRO-INFLAMMATORY FACTORS AND THUS THE CONDITION HAS BEEN CALLED THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). EMERGING DATA HAS REVEALED THAT NF-KAPPAB SIGNALING IS THE MAJOR SIGNALING PATHWAY WHICH STIMULATES THE APPEARANCE OF SASP. IT IS KNOWN THAT DNA DAMAGE PROVOKES NF-KAPPAB SIGNALING VIA A VARIETY OF SIGNALING COMPLEXES CONTAINING NEMO PROTEIN, AN NF-KAPPAB ESSENTIAL MODIFIER, AS WELL AS VIA THE ACTIVATION OF SIGNALING PATHWAYS OF P38MAPK AND RIG-1, RETINOIC ACID INDUCIBLE GENE-1. GENOMIC INSTABILITY EVOKED BY CELLULAR STRESS TRIGGERS EPIGENETIC CHANGES, E.G. RELEASE OF HMGB1 PROTEINS WHICH ARE ALSO POTENT ENHANCERS OF INFLAMMATORY RESPONSES. MOREOVER, ENVIRONMENTAL STRESS AND CHRONIC INFLAMMATION CAN STIMULATE P38MAPK AND CERAMIDE SIGNALING AND INDUCE CELLULAR SENESCENCE WITH PRO-INFLAMMATORY RESPONSES. ON THE OTHER HAND, TWO CYCLIN-DEPENDENT KINASE INHIBITORS, P16INK4A AND P14ARF, ARE EFFECTIVE INHIBITORS OF NF-KAPPAB SIGNALING. WE WILL REVIEW IN DETAIL THE SIGNALING PATHWAYS WHICH ACTIVATE NF-KAPPAB SIGNALING AND TRIGGER SASP IN SENESCENT CELLS. 2012 13 5720 19 SIRTUINS LINK INFLAMMATION AND METABOLISM. SIRTUINS (SIRT), FIRST DISCOVERED IN YEAST AS NAD+ DEPENDENT EPIGENETIC AND METABOLIC REGULATORS, HAVE COMPARABLE ACTIVITIES IN HUMAN PHYSIOLOGY AND DISEASE. MOUNTING EVIDENCE SUPPORTS THAT THE SEVEN-MEMBER MAMMALIAN SIRTUIN FAMILY (SIRT1-7) GUARD HOMEOSTASIS BY SENSING BIOENERGY NEEDS AND RESPONDING BY MAKING ALTERATIONS IN THE CELL NUTRIENTS. SIRTUINS PLAY A CRITICAL ROLE IN RESTORING HOMEOSTASIS DURING STRESS RESPONSES. INFLAMMATION IS DESIGNED TO "DEFEND AND MEND" AGAINST THE INVADING ORGANISMS. EMERGING EVIDENCE SUPPORTS THAT METABOLISM AND BIOENERGY REPROGRAMMING DIRECT THE SEQUENTIAL COURSE OF INFLAMMATION; FAILURE OF HOMEOSTASIS RETRIEVAL RESULTS IN MANY CHRONIC AND ACUTE INFLAMMATORY DISEASES. ANABOLIC GLYCOLYSIS QUICKLY INDUCED (COMPARED TO OXIDATIVE PHOSPHORYLATION) FOR ROS AND ATP GENERATION IS NEEDED FOR IMMUNE ACTIVATION TO "DEFEND" AGAINST INVADING MICROORGANISMS. LIPOLYSIS/FATTY ACID OXIDATION, ESSENTIAL FOR CELLULAR PROTECTION/HIBERNATION AND CELL SURVIVAL IN ORDER TO "MEND," LEADS TO IMMUNE REPRESSION. ACUTE/CHRONIC INFLAMMATIONS ARE LINKED TO ALTERED GLYCOLYSIS AND FATTY ACID OXIDATION, AT LEAST IN PART, BY NAD+ DEPENDENT FUNCTION OF SIRTUINS. THERAPEUTICALLY TARGETING SIRTUINS MAY PROVIDE A NEW CLASS OF INFLAMMATION AND IMMUNE REGULATORS. THIS REVIEW DISCUSSES HOW SIRTUINS INTEGRATE METABOLISM, BIOENERGETICS, AND IMMUNITY DURING INFLAMMATION AND HOW SIRTUIN-DIRECTED TREATMENT IMPROVES OUTCOME IN CHRONIC INFLAMMATORY DISEASES AND IN THE EXTREME STRESS RESPONSE OF SEPSIS. 2016 14 3115 28 GEROMETABOLITES: THE PSEUDOHYPOXIC AGING SIDE OF CANCER ONCOMETABOLITES. ONCOMETABOLITES ARE DEFINED AS SMALL-MOLECULE COMPONENTS (OR ENANTIOMERS) OF NORMAL METABOLISM WHOSE ACCUMULATION CAUSES SIGNALING DYSREGULATION TO ESTABLISH A MILIEU THAT INITIATES CARCINOGENESIS. IN A SIMILAR MANNER, WE PROPOSE THE TERM "GEROMETABOLITES" TO REFER TO SMALL-MOLECULE COMPONENTS OF NORMAL METABOLISM WHOSE DEPLETION CAUSES SIGNALING DYSREGULATION TO ESTABLISH A MILIEU THAT DRIVES AGING. IN AN INVESTIGATION OF THE PATHOGENIC ACTIVITIES OF THE CURRENTLY RECOGNIZED ONCOMETABOLITES R(-)-2-HYDROXYGLUTARATE (2-HG), FUMARATE, AND SUCCINATE, WHICH ACCUMULATE DUE TO MUTATIONS IN ISOCITRATE DEHYDROGENASES (IDH), FUMARATE HYDRATASE (FH), AND SUCCINATE DEHYDROGENASE (SDH), RESPECTIVELY, WE ILLUSTRATE THE FACT THAT METABOLIC PSEUDOHYPOXIA, THE ACCUMULATION OF HYPOXIA-INDUCIBLE FACTOR (HIFALPHA) UNDER NORMOXIC CONDITIONS, AND THE SUBSEQUENT WARBURG-LIKE REPROGRAMMING THAT SHIFTS GLUCOSE METABOLISM FROM THE OXIDATIVE PATHWAY TO AEROBIC GLYCOLYSIS ARE THE SAME MECHANISMS THROUGH WHICH THE DECLINE OF THE "GEROMETABOLITE" NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD)(+) REVERSIBLY DISRUPTS NUCLEAR-MITOCHONDRIAL COMMUNICATION AND CONTRIBUTES TO THE DECLINE IN MITOCHONDRIAL FUNCTION WITH AGE. FROM AN EVOLUTIONARY PERSPECTIVE, IT IS REASONABLE TO VIEW NAD(+)-DRIVEN MITOCHONDRIAL HOMEOSTASIS AS A CONSERVED RESPONSE TO CHANGES IN ENERGY SUPPLIES AND OXYGEN LEVELS. SIMILARLY, THE NATURAL ABILITY OF 2-HG TO SIGNIFICANTLY ALTER EPIGENETICS MIGHT REFLECT AN EVOLUTIONARILY ANCIENT ROLE OF CERTAIN METABOLITES TO SIGNAL FOR ELEVATED GLUTAMINE/GLUTAMATE METABOLISM AND/OR OXYGEN DEFICIENCY. HOWEVER, WHEN CHRONICALLY ALTERED, THESE RESPONSES BECOME CONSERVED CAUSES OF AGING AND CANCER. BECAUSE HIFALPHA-DRIVEN PSEUDOHYPOXIA MIGHT DRIVE THE OVERPRODUCTION OF 2-HG, THE INTRIGUING POSSIBILITY EXISTS THAT THE DECLINE OF GEROMETABOLITES SUCH AS NAD(+) COULD PROMOTE THE CHRONIC ACCUMULATION OF ONCOMETABOLITES IN NORMAL CELLS DURING AGING. IF THE SOLE ACTIVATION OF A WARBURG-LIKE METABOLIC REPROGRAMMING IN NORMAL TISSUES MIGHT BE ABLE TO SIGNIFICANTLY INCREASE THE ENDOGENOUS PRODUCTION OF BONA FIDE ETIOLOGICAL DETERMINANTS IN CANCER, SUCH AS ONCOMETABOLITES, THIS UNDESIRABLE TRADE-OFF BETWEEN MITOCHONDRIAL DYSFUNCTION AND ACTIVATION OF ONCOMETABOLITES PRODUCTION MIGHT THEN PAVE THE WAY FOR THE EPIGENETIC INITIATION OF CARCINOGENESIS IN A STRICTLY METABOLIC-DEPENDENT MANNER. PERHAPS IT IS TIME TO DEFINITELY ADOPT THE VIEW THAT AGING AND AGING DISEASES INCLUDING CANCER ARE GOVERNED BY A PIVOTAL REGULATORY ROLE OF METABOLIC REPROGRAMMING IN CELL FATE DECISIONS. 2014 15 2378 14 EPIGENETIC REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING IN ATHEROSCLEROTIC ARTERY REMODELING: A MINI-REVIEW. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY EXTENSIVE REMODELING OF MEDIUM AND LARGE-SIZED ARTERIES. INWARD REMODELING (=LUMEN SHRINKAGE) OF THE VASCULAR WALLS IS THE UNDERLYING CAUSE FOR ISCHEMIA IN TARGET ORGANS. THEREFORE, INWARD REMODELING CAN BE CONSIDERED THE PREDOMINANT FEATURE OF ATHEROSCLEROTIC PATHOLOGY. OUTWARD REMODELING (=LUMEN ENLARGEMENT) IS A PHYSIOLOGICAL RESPONSE COMPENSATING FOR LUMEN SHRINKAGE CAUSED BY NEOINTIMAL HYPERPLASIA, BUT AS A PATHOLOGICAL RESPONSE TO CHANGES IN BLOOD FLOW, OUTWARD REMODELING LEADS TO SUBSTANTIAL ARTERIAL WALL THINNING. THINNED VASCULAR WALLS ARE PRONE TO RUPTURE, AND SUBSEQUENT THROMBUS FORMATION ACCOUNTS FOR THE MAJORITY OF ACUTE CARDIOVASCULAR EVENTS. PATHOLOGICAL REMODELING IS DRIVEN BY INFLAMMATORY CELLS WHICH INDUCE VASCULAR SMOOTH MUSCLE CELLS TO SWITCH FROM QUIESCENT TO A PROLIFERATIVE AND MIGRATORY PHENOTYPE. AFTER DECADES OF INTENSIVE RESEARCH, THE MOLECULAR MECHANISMS OF ARTERIAL REMODELING ARE STARTING TO UNFOLD. IN THIS MINI-REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING FROM THE CONTRACTILE TO THE SYNTHETIC PHENOTYPE INVOLVED IN ARTERIAL REMODELING AND DISCUSS POTENTIAL THERAPEUTIC OPTIONS. 2021 16 2384 23 EPIGENETIC REGULATOR UHRF1 ORCHESTRATES PROINFLAMMATORY GENE EXPRESSION IN RHEUMATOID ARTHRITIS IN A SUPPRESSIVE MANNER. RHEUMATOID ARTHRITIS (RA) IS CHARACTERIZED BY CHRONIC SYNOVIAL INFLAMMATION WITH ABERRANT EPIGENETIC ALTERATIONS, EVENTUALLY LEADING TO JOINT DESTRUCTION. HOWEVER, THE EPIGENETIC REGULATORY MECHANISMS UNDERLYING RA PATHOGENESIS REMAIN LARGELY UNKNOWN. HERE, WE SHOWED THAT UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IS A CENTRAL EPIGENETIC REGULATOR THAT ORCHESTRATES MULTIPLE PATHOGENESES IN RA IN A SUPPRESSIVE MANNER. UHRF1 EXPRESSION WAS REMARKABLY UPREGULATED IN SYNOVIAL FIBROBLASTS (SFS) FROM ARTHRITIS MODEL MICE AND PATIENTS WITH RA. MICE WITH SF-SPECIFIC UHRF1 CONDITIONAL KNOCKOUT SHOWED MORE SEVERE ARTHRITIC PHENOTYPES THAN LITTERMATE CONTROLS. UHRF1-DEFICIENT SFS ALSO EXHIBITED ENHANCED APOPTOSIS RESISTANCE AND UPREGULATED EXPRESSION OF SEVERAL CYTOKINES, INCLUDING CCL20. IN PATIENTS WITH RA, DAS28, CRP, AND TH17 ACCUMULATION AND APOPTOSIS RESISTANCE WERE NEGATIVELY CORRELATED WITH UHRF1 EXPRESSION IN SYNOVIUM. FINALLY, RYUVIDINE ADMINISTRATION STABILIZED UHRF1 AMELIORATED ARTHRITIS PATHOGENESES IN A MOUSE MODEL OF RA. THIS STUDY DEMONSTRATED THAT UHRF1 EXPRESSED IN RA SFS CAN CONTRIBUTE TO NEGATIVE FEEDBACK MECHANISMS THAT SUPPRESS MULTIPLE PATHOGENIC EVENTS IN ARTHRITIS, SUGGESTING THAT TARGETING UHRF1 COULD BE ONE OF THE THERAPEUTIC STRATEGIES FOR RA. 2022 17 3261 28 HEPATITIS C VIRUS-INDUCED UP-REGULATION OF PROTEIN PHOSPHATASE 2A INHIBITS HISTONE MODIFICATION AND DNA DAMAGE REPAIR. THE MOLECULAR MECHANISMS UNDERLYING HEPATOCARCINOGENESIS IN CHRONIC VIRAL HEPATITIS ARE POORLY UNDERSTOOD. A POTENTIAL TUMORIGENIC PATHWAY COULD INVOLVE PROTEIN PHOSPHATASE 2A (PP2A) AND PROTEIN ARGININE METHYLTRANSFERASE 1 (PRMT1), BECAUSE BOTH ENZYMES ARE DYSREGULATED IN CHRONIC HEPATITIS C, AND BOTH ENZYMES HAVE BEEN INVOLVED IN CHROMATIN REMODELING AND DNA DAMAGE REPAIR. WE USED CELL LINES THAT ALLOW THE INDUCIBLE EXPRESSION OF HEPATITIS C VIRUS PROTEINS (UHCV57.3) AND OF THE CATALYTIC SUBUNIT OF PP2A (UPP2A-C8) AS WELL AS HUH7.5 CELLS INFECTED WITH RECOMBINANT CELL CULTURE-DERIVED HEPATITIS C VIRUS (HCVCC) TO STUDY EPIGENETIC HISTONE MODIFICATIONS AND DNA DAMAGE REPAIR. THE INDUCTION OF VIRAL PROTEINS, THE OVEREXPRESSION OF PP2AC, OR THE INFECTION OF HUH7.5 CELLS WITH HCVCC RESULTED IN AN INHIBITION OF HISTONE H4 METHYLATION/ACETYLATION AND HISTONE H2AX PHOSPHORYLATION, IN A SIGNIFICANTLY CHANGED EXPRESSION OF GENES IMPORTANT FOR HEPATOCARCINOGENESIS, AND INHIBITED DNA DAMAGE REPAIR. OVEREXPRESSION OF PP2AC IN NIH-3T3 CELLS INCREASED ANCHORAGE-INDEPENDENT GROWTH. THESE CHANGES WERE PARTIALLY REVERSED BY THE TREATMENT OF CELLS WITH THE METHYL-GROUP DONOR S-ADENOSYL-L-METHIONINE (SAME). CONCLUSION: HEPATITIS C VIRUS-INDUCED OVEREXPRESSION OF PP2AC CONTRIBUTES TO HEPATOCARCINOGENESIS THROUGH DYSREGULATION OF EPIGENETIC HISTONE MODIFICATIONS. THE CORRECTION OF DEFECTIVE HISTONE MODIFICATIONS BY S-ADENOSYL-L-METHIONINE MAKES THIS DRUG A CANDIDATE FOR CHEMOPREVENTIVE THERAPIES IN PATIENTS WITH CHRONIC HEPATITIS C WHO ARE AT RISK FOR DEVELOPING HEPATOCELLULAR CARCINOMA. 2010 18 4380 29 MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS IN RHEUMATOID ARTHRITIS. CONTROL OF EXCESSIVE MITOCHONDRIAL OXIDATIVE STRESS COULD PROVIDE NEW TARGETS FOR BOTH PREVENTIVE AND THERAPEUTIC INTERVENTIONS IN THE TREATMENT OF CHRONIC INFLAMMATION OR ANY PATHOLOGY THAT DEVELOPS UNDER AN INFLAMMATORY SCENARIO, SUCH AS RHEUMATOID ARTHRITIS (RA). INCREASING EVIDENCE HAS DEMONSTRATED THE ROLE OF MITOCHONDRIAL ALTERATIONS IN AUTOIMMUNE DISEASES MAINLY DUE TO THE INTERPLAY BETWEEN METABOLISM AND INNATE IMMUNITY, BUT ALSO IN THE MODULATION OF INFLAMMATORY RESPONSE OF RESIDENT CELLS, SUCH AS SYNOVIOCYTES. THUS, MITOCHONDRIAL DYSFUNCTION DERIVED FROM SEVERAL DANGER SIGNALS COULD ACTIVATE TRICARBOXYLIC ACID (TCA) DISRUPTION, THEREBY FAVORING A VICIOUS CYCLE OF OXIDATIVE/MITOCHONDRIAL STRESS. MITOCHONDRIAL DYSFUNCTION CAN ACT THROUGH MODULATING INNATE IMMUNITY VIA REDOX-SENSITIVE INFLAMMATORY PATHWAYS OR DIRECT ACTIVATION OF THE INFLAMMASOME. BESIDES, MITOCHONDRIA ALSO HAVE A CENTRAL ROLE IN REGULATING CELL DEATH, WHICH IS DEEPLY ALTERED IN RA. ADDITIONALLY, MULTIPLE EVIDENCE SUGGESTS THAT PATHOLOGICAL PROCESSES IN RA CAN BE SHAPED BY EPIGENETIC MECHANISMS AND THAT IN TURN, MITOCHONDRIA ARE INVOLVED IN EPIGENETIC REGULATION. FINALLY, WE WILL DISCUSS ABOUT THE INVOLVEMENT OF SOME DIETARY COMPONENTS IN THE ONSET AND PROGRESSION OF RA. 2022 19 4044 20 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 20 3688 25 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