1 616 143 BIOACTIVE COMPOUNDS IN OXIDATIVE STRESS-MEDIATED DISEASES: TARGETING THE NRF2/ARE SIGNALING PATHWAY AND EPIGENETIC REGULATION. OXIDATIVE STRESS IS A PATHOLOGICAL CONDITION OCCURRING DUE TO AN IMBALANCE BETWEEN THE OXIDANTS AND ANTIOXIDANT DEFENSE SYSTEMS IN THE BODY. NUCLEAR FACTOR E2-RELATED FACTOR 2 (NRF2), ENCODED BY THE GENE NFE2L2, IS THE MASTER REGULATOR OF PHASE II ANTIOXIDANT ENZYMES THAT PROTECT AGAINST OXIDATIVE STRESS AND INFLAMMATION. NRF2/ARE SIGNALING HAS BEEN CONSIDERED AS A PROMISING TARGET AGAINST OXIDATIVE STRESS-MEDIATED DISEASES LIKE DIABETES, FIBROSIS, NEUROTOXICITY, AND CANCER. THE CONSUMPTION OF DIETARY PHYTOCHEMICALS ACTS AS AN EFFECTIVE MODULATOR OF NRF2/ARE IN VARIOUS ACUTE AND CHRONIC DISEASES. IN THE PRESENT REVIEW, WE DISCUSSED THE ROLE OF NRF2 IN DIABETES, ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), CANCER, AND ATHEROSCLEROSIS. ADDITIONALLY, WE DISCUSSED THE PHYTOCHEMICALS LIKE CURCUMIN, QUERCETIN, RESVERATROL, EPIGALLOCATECHIN GALLATE, APIGENIN, SULFORAPHANE, AND URSOLIC ACID THAT HAVE EFFECTIVELY MODIFIED NRF2 SIGNALING AND PREVENTED VARIOUS DISEASES IN BOTH IN VITRO AND IN VIVO MODELS. BASED ON THE LITERATURE, IT IS CLEAR THAT DIETARY PHYTOCHEMICALS CAN PREVENT DISEASES BY (1) BLOCKING OXIDATIVE STRESS-INHIBITING INFLAMMATORY MEDIATORS THROUGH INHIBITING KEAP1 OR ACTIVATING NRF2 EXPRESSION AND ITS DOWNSTREAM TARGETS IN THE NUCLEUS, INCLUDING HO-1, SOD, AND CAT; (2) REGULATING NRF2 SIGNALING BY VARIOUS KINASES LIKE GSK3BETA, PI3/AKT, AND MAPK; AND (3) MODIFYING EPIGENETIC MODULATION, SUCH AS METHYLATION, AT THE NRF2 PROMOTER REGION; HOWEVER, FURTHER INVESTIGATION INTO OTHER UPSTREAM SIGNALING MOLECULES LIKE NRF2 AND THE EFFECT OF PHYTOCHEMICALS ON THEM STILL NEED TO BE INVESTIGATED IN THE NEAR FUTURE. 2021 2 1416 49 DIETARY POLYPHENOLS REMODEL DNA METHYLATION PATTERNS OF NRF2 IN CHRONIC DISEASE. THE NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) IS A TRANSCRIPTION FACTOR CRUCIAL IN REGULATING CELLULAR HOMEOSTASIS AND APOPTOSIS. THE NRF2 GENE HAS BEEN IMPLICATED IN VARIOUS BIOLOGICAL ACTIVITIES, INCLUDING ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTICANCER PROPERTIES. NRF2 CAN BE REGULATED GENETICALLY AND EPIGENETICALLY AT THE TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND TRANSLATIONAL LEVELS. ALTHOUGH DNA METHYLATION IS ONE OF THE CRITICAL BIOLOGICAL PROCESSES VITAL FOR GENE EXPRESSION, SOMETIMES, ANOMALOUS METHYLATION PATTERNS RESULT IN THE DYSREGULATION OF GENES AND CONSEQUENT DISEASES AND DISORDERS. SEVERAL STUDIES HAVE REPORTED PROMOTER HYPERMETHYLATION DOWNREGULATED NRF2 EXPRESSION AND ITS DOWNSTREAM TARGETS. IN CONTRAST TO THE UNALTERABLE NATURE OF GENETIC PATTERNS, EPIGENETIC CHANGES CAN BE REVERSED, OPENING UP NEW POSSIBILITIES IN DEVELOPING THERAPIES FOR VARIOUS METABOLIC DISORDERS AND DISEASES. THIS REVIEW DISCUSSES THE CURRENT STATE OF THE NRF2-MEDIATED ANTIOXIDATIVE AND CHEMOPREVENTIVE ACTIVITIES OF SEVERAL NATURAL PHYTOCHEMICALS, INCLUDING SULFORAPHANE, RESVERATROL, CURCUMIN, LUTEOLIN, COROSOLIC ACID, APIGENIN, AND MOST OTHER COMPOUNDS THAT HAVE BEEN FOUND TO ACTIVATE NRF2. THIS EPIGENETIC REVERSAL OF HYPERMETHYLATED NRF2 STATES PROVIDES NEW OPPORTUNITIES FOR RESEARCH INTO DIETARY PHYTOCHEMISTRY THAT AFFECTS THE HUMAN EPIGENOME AND THE POSSIBILITY FOR CUTTING-EDGE APPROACHES TO TARGET NRF2-MEDIATED SIGNALING TO PREVENT CHRONIC DISORDERS. 2023 3 1413 39 DIETARY PHYTOCHEMICALS AND CANCER CHEMOPREVENTION: A PERSPECTIVE ON OXIDATIVE STRESS, INFLAMMATION, AND EPIGENETICS. OXIDATIVE STRESS OCCURS WHEN CELLULAR REACTIVE OXYGEN SPECIES LEVELS EXCEED THE SELF-ANTIOXIDANT CAPACITY OF THE BODY. OXIDATIVE STRESS INDUCES MANY PATHOLOGICAL CHANGES, INCLUDING INFLAMMATION AND CANCER. CHRONIC INFLAMMATION IS BELIEVED TO BE STRONGLY ASSOCIATED WITH THE MAJOR STAGES OF CARCINOGENESIS. THE NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) PATHWAY PLAYS A CRUCIAL ROLE IN REGULATING OXIDATIVE STRESS AND INFLAMMATION BY MANIPULATING KEY ANTIOXIDANT AND DETOXIFICATION ENZYME GENES VIA THE ANTIOXIDANT RESPONSE ELEMENT. MANY DIETARY PHYTOCHEMICALS WITH CANCER CHEMOPREVENTIVE PROPERTIES, SUCH AS POLYPHENOLS, ISOTHIOCYANATES, AND TRITERPENOIDS, EXERT ANTIOXIDANT AND ANTI-INFLAMMATORY FUNCTIONS BY ACTIVATING THE NRF2 PATHWAY. FURTHERMORE, EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS, AND MIRNA-MEDIATED POST-TRANSCRIPTIONAL ALTERATIONS, ALSO LEAD TO VARIOUS CARCINOGENESIS PROCESSES BY SUPPRESSING CANCER REPRESSOR GENE TRANSCRIPTION. USING EPIGENETIC RESEARCH TOOLS, INCLUDING NEXT-GENERATION SEQUENCING TECHNOLOGIES, MANY DIETARY PHYTOCHEMICALS ARE SHOWN TO MODIFY AND REVERSE ABERRANT EPIGENETIC/EPIGENOME CHANGES, POTENTIALLY LEADING TO CANCER PREVENTION/TREATMENT. THUS, THE BENEFICIAL EFFECTS OF DIETARY PHYTOCHEMICALS ON CANCER DEVELOPMENT WARRANT FURTHER INVESTIGATION TO PROVIDE ADDITIONAL IMPETUS FOR CLINICAL TRANSLATIONAL STUDIES. 2016 4 6045 43 THE COMPLEXITY OF THE NRF2 PATHWAY: BEYOND THE ANTIOXIDANT RESPONSE. THE NF-E2-RELATED FACTOR 2 (NRF2)-MEDIATED SIGNALLING PATHWAY PROVIDES LIVING ORGANISMS AN EFFICIENT AND PIVOTAL LINE OF DEFENSIVE TO COUNTERACT ENVIRONMENTAL INSULTS AND ENDOGENOUS STRESSORS. NRF2 COORDINATES THE BASAL AND INDUCIBLE EXPRESSION OF ANTIOXIDANT AND PHASE II DETOXIFICATION ENZYMES TO ADAPT TO DIFFERENT STRESS CONDITIONS. THE STABILITY AND CELLULAR DISTRIBUTION OF NRF2 IS TIGHTLY CONTROLLED BY ITS INHIBITORY BINDING PROTEIN KELCH-LIKE ECH-ASSOCIATED PROTEIN 1. NRF2 SIGNALLING IS ALSO REGULATED BY POSTTRANSLATIONAL, TRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS, AS WELL AS BY OTHER PROTEIN PARTNERS, INCLUDING P62, P21 AND IQ MOTIF-CONTAINING GTPASE ACTIVATING PROTEIN 1. MANY STUDIES HAVE DEMONSTRATED THAT NRF2 IS A PROMISING TARGET FOR PREVENTING CARCINOGENESIS AND OTHER CHRONIC DISEASES, INCLUDING CARDIOVASCULAR DISEASES, NEURODEGENERATIVE DISEASES AND PULMONARY INJURY. HOWEVER, CONSTITUTIVE ACTIVATION OF NRF2 IN ADVANCED CANCER CELLS MAY CONFER DRUG RESISTANCE. HERE, WE REVIEW THE MOLECULAR MECHANISMS OF NRF2 SIGNALLING, THE DIVERSE CLASSES OF NRF2 ACTIVATORS, INCLUDING BIOACTIVE NUTRIENTS AND OTHER CHEMICALS, AND THE CELLULAR FUNCTIONS AND DISEASE RELEVANCE OF NRF2 AND DISCUSS THE DUAL ROLE OF NRF2 IN DIFFERENT CONTEXTS. 2015 5 4427 41 MOLECULAR BASIS OF ELECTROPHILIC AND OXIDATIVE DEFENSE: PROMISES AND PERILS OF NRF2. INDUCTION OF DRUG-METABOLIZING ENZYMES THROUGH THE ANTIOXIDANT RESPONSE ELEMENT (ARE)-DEPENDENT TRANSCRIPTION WAS INITIALLY IMPLICATED IN CHEMOPREVENTION AGAINST CANCER BY ANTIOXIDANTS. RECENT PROGRESS IN UNDERSTANDING THE BIOLOGY AND MECHANISM OF INDUCTION REVEALED A CRITICAL ROLE OF INDUCTION IN CELLULAR DEFENSE AGAINST ELECTROPHILIC AND OXIDATIVE STRESS. INDUCTION IS MEDIATED THROUGH A NOVEL SIGNALING PATHWAY VIA TWO REGULATORY PROTEINS, THE NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) AND THE KELCH-LIKE ERYTHROID CELL-DERIVED PROTEIN WITH CNC HOMOLOGY-ASSOCIATED PROTEIN 1 (KEAP1). NRF2 BINDS TO KEAP1 AT A TWO SITE-BINDING INTERFACE AND IS UBIQUITINATED BY THE KEAP1/CULLIN 3/RING BOX PROTEIN-1-UBIQUITIN LIGASE, RESULTING IN A RAPID TURNOVER OF NRF2 PROTEIN. ELECTROPHILES AND OXIDANTS MODIFY CRITICAL CYSTEINE THIOLS OF KEAP1 AND NRF2 TO INHIBIT NRF2 UBIQUITINATION, LEADING TO NRF2 ACTIVATION AND INDUCTION. INDUCTION INCREASES STRESS RESISTANCE CRITICAL FOR CELL SURVIVAL, BECAUSE KNOCKOUT OF NRF2 IN MICE INCREASED SUSCEPTIBILITY TO A VARIETY OF TOXICITY AND DISEASE PROCESSES. COLLATERAL TO DIVERSE FUNCTIONS OF NRF2, GENOME-WIDE SEARCH HAS LED TO THE IDENTIFICATION OF A PLETHORA OF ARE-DEPENDENT GENES REGULATED BY NRF2 IN AN INDUCER-, TISSUE-, AND DISEASE-DEPENDENT MANNER TO CONTROL DRUG METABOLISM, ANTIOXIDANT DEFENSE, STRESS RESPONSE, PROTEASOMAL DEGRADATION, AND CELL PROLIFERATION. THE PROTECTIVE NATURE OF NRF2 COULD ALSO BE HIJACKED IN A NUMBER OF PATHOLOGICAL CONDITIONS BY MEANS OF SOMATIC MUTATION, EPIGENETIC ALTERATION, AND ACCUMULATION OF DISRUPTOR PROTEINS, PROMOTING DRUG RESISTANCE IN CANCER AND PATHOLOGIC LIVER FEATURES IN AUTOPHAGY DEFICIENCY. THE REPERTOIRE OF ARE INDUCERS HAS EXPANDED ENORMOUSLY; THE THERAPEUTIC POTENTIAL OF THE INDUCERS HAS BEEN EXAMINED BEYOND CANCER PREVENTION. DEVELOPING POTENT AND SPECIFIC ARE INDUCERS AND NRF2 INHIBITORS HOLDS CERTAIN NEW PROMISE FOR THE PREVENTION AND THERAPY AGAINST CANCER, CHRONIC DISEASE, AND TOXICITY. 2012 6 4836 40 ONCOGENIC FUNCTIONS OF THE TRANSCRIPTION FACTOR NRF2. NUCLEAR FACTOR E2-RELATED FACTOR 2 (NRF2) IS A TRANSCRIPTION FACTOR THAT CONTROLS THE EXPRESSION OF A LARGE POOL OF ANTIOXIDANT AND CYTOPROTECTIVE GENES REGULATING THE CELLULAR RESPONSE TO OXIDATIVE AND ELECTROPHILIC STRESS. NRF2 IS NEGATIVELY REGULATED BY KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (KEAP1) AND, UPON STIMULATION BY AN OXIDATIVE OR ELECTROPHILIC INSULT, IS RAPIDLY ACTIVATED BY PROTEIN STABILIZATION. OWING TO ITS CYTOPROTECTIVE FUNCTIONS, NRF2 HAS BEEN TRADITIONALLY STUDIED IN THE FIELD OF CHEMOPREVENTION; HOWEVER, THERE IS ACCUMULATED EVIDENCE THAT KEAP1/NRF2 MUTATIONS OR UNBALANCED REGULATION THAT LEADS TO OVEREXPRESSION OR HYPERACTIVATION OF NRF2 MAY PARTICIPATE IN TUMORIGENESIS AND BE INVOLVED IN CHEMORESISTANCE OF A WIDE NUMBER OF SOLID CANCERS AND LEUKEMIAS. IN ADDITION TO PROTECTING CELLS FROM REACTIVE OXYGEN SPECIES, NRF2 SEEMS TO PLAY A DIRECT ROLE IN CELL GROWTH CONTROL AND IS RELATED TO APOPTOSIS-REGULATING PATHWAYS. MOREOVER, NRF2 ACTIVITY IS CONNECTED WITH ONCOGENIC KINASE PATHWAYS, STRUCTURAL PROTEINS, HORMONAL REGULATION, OTHER TRANSCRIPTION FACTORS, AND EPIGENETIC ENZYMES INVOLVED IN THE PATHOGENESIS OF VARIOUS TYPES OF TUMORS. THE AIM OF THIS REVIEW IS TO COMPILE AND SUMMARIZE EXISTING KNOWLEDGE OF THE ONCOGENIC FUNCTIONS OF NRF2 TO PROVIDE A SOLID BASIS FOR ITS POTENTIAL USE AS A MOLECULAR MARKER AND PHARMACOLOGICAL TARGET IN CANCER. 2013 7 2352 43 EPIGENETIC REGULATION OF NRF2/KEAP1 BY PHYTOCHEMICALS. EPIGENETICS HAS PROVIDED A NEW DIMENSION TO OUR UNDERSTANDING OF NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2/KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (HUMAN NRF2/KEAP1 AND MURINE NRF2/KEAP1) SIGNALING. UNLIKE THE GENETIC CHANGES AFFECTING DNA SEQUENCE, THE REVERSIBLE NATURE OF EPIGENETIC ALTERATIONS PROVIDES AN ATTRACTIVE AVENUE FOR CANCER INTERCEPTION. THUS, TARGETING EPIGENETIC MECHANISMS IN THE CORRESPONDING SIGNALING NETWORKS REPRESENTS AN ENTICING STRATEGY FOR THERAPEUTIC INTERVENTION WITH DIETARY PHYTOCHEMICALS ACTING AT TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND POST-TRANSLATIONAL LEVELS. THIS REGULATION INVOLVES THE INTERPLAY OF HISTONE MODIFICATIONS AND DNA METHYLATION STATES IN THE HUMAN NFE2L2/KEAP1 AND MURINE NFE2L2/KEAP1 GENES, ACETYLATION OF LYSINE RESIDUES IN NRF2 AND NRF2, INTERACTION WITH BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) ACETYL "READER" PROTEINS, AND NON-CODING RNAS SUCH AS MICRORNA (MIRNA) AND LONG NON-CODING RNA (LNCRNA). PHYTOCHEMICALS DOCUMENTED TO MODULATE NRF2 SIGNALING ACT BY REVERSING HYPERMETHYLATED STATES IN THE CPG ISLANDS OF NFE2L2 OR NFE2L2, VIA THE INHIBITION OF DNA METHYLTRANSFERASES (DNMTS) AND HISTONE DEACETYLASES (HDACS), THROUGH THE INDUCTION OF TEN-ELEVEN TRANSLOCATION (TET) ENZYMES, OR BY INDUCING MIRNA TO TARGET THE 3'-UTR OF THE CORRESPONDING MRNA TRANSCRIPTS. TO DATE, FEWER THAN TWENTY PHYTOCHEMICALS HAVE BEEN REPORTED AS NRF2 EPIGENETIC MODIFIERS, INCLUDING CURCUMIN, SULFORAPHANE, RESVERATROL, RESERPINE, AND URSOLIC ACID. THIS OPENS AVENUES FOR EXPLORING ADDITIONAL DIETARY PHYTOCHEMICALS THAT REGULATE THE HUMAN EPIGENOME, AND THE POTENTIAL FOR NOVEL STRATEGIES TO TARGET NRF2 SIGNALING WITH A VIEW TO BENEFICIAL INTERCEPTION OF CANCER AND OTHER CHRONIC DISEASES. 2020 8 2339 44 EPIGENETIC REGULATION OF KEAP1-NRF2 SIGNALING. THE KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (KEAP1)-NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) SIGNALING AXIS SERVES AS A "MASTER REGULATOR" IN RESPONSE TO OXIDATIVE/ELECTROPHILIC STRESSES AND CHEMICAL INSULTS THROUGH THE COORDINATED INDUCTION OF A WIDE ARRAY OF CYTOPROTECTIVE GENES. THEREFORE, ACTIVATION OF NRF2 IS CONSIDERED TO BE AN IMPORTANT APPROACH FOR PREVENTING CHRONIC DISEASES TRIGGERED BY STRESSES AND TOXINS, INCLUDING CANCER. DESPITE EXTENSIVE STUDIES SUGGESTED THAT THE KEAP1-NRF2 SIGNALING PATHWAY IS SUBJECT TO MULTIPLE LAYERS OF REGULATION AT THE TRANSCRIPTIONAL, TRANSLATIONAL, AND POST-TRANSLATIONAL LEVELS, THE POTENTIAL EPIGENETIC REGULATION OF NRF2 AND KEAP1 HAS BEGUN TO BE RECOGNIZED ONLY IN RECENT YEARS. EPIGENETIC MODIFICATIONS, HERITABLE ALTERATIONS IN GENE EXPRESSION THAT OCCUR WITHOUT CHANGES IN THE PRIMARY DNA SEQUENCE, HAVE BEEN REPORTED TO BE PROFOUNDLY INVOLVED IN OXIDATIVE STRESS RESPONSES. IN THIS REVIEW, WE DISCUSS THE LATEST FINDINGS REGARDING THE EPIGENETIC REGULATION OF KEAP1-NRF2 SIGNALING BY DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNAS. THE CROSSTALK AMONG THESE EPIGENETIC MODIFICATIONS IN THE REGULATION OF KEAP1-NRF2 SIGNALING PATHWAYS IS ALSO DISCUSSED. STUDIES OF THE EPIGENETIC MODIFICATION OF NRF2 AND KEAP1 HAVE NOT ONLY ENHANCED OUR UNDERSTANDING OF THIS COMPLEX CELLULAR DEFENSE SYSTEM BUT HAVE ALSO PROVIDED POTENTIAL NEW THERAPEUTIC TARGETS FOR THE PREVENTION OF CERTAIN DISEASES. 2015 9 4987 36 PATTERNS OF CALCIUM SIGNALING: A LINK BETWEEN CHRONIC EMOTIONS AND CANCER. INTRA AND INTER-CELLULAR CALCIUM SIGNALING IS PRESENT IN ALL TYPES OF CELLS AND BODY TISSUES. IN THE HUMAN BRAIN, CALCIUM CURRENTS AND WAVES ARE RELATED TO MENTAL ACTIVITIES, INCLUDING EMOTIONS. WE PRESENT A THEORETICAL INTERPRETATION OF THESE PHENOMENA SUGGESTING THEIR INVOLVEMENT IN CHRONIC EMOTIONAL PATTERNS AND IN THE PATHOLOGY OF CANCER. RECENT DEVELOPMENTS ON BIOPHYSICS, TRANSLATIONAL BIOLOGY AND PSYCHONEUROENDOCRINOIMMUNOLOGY (PNEI) CAN SUPPORT EXPLANATORY HYPOTHESES ABOUT THE LINK BETWEEN EMOTIONAL STRESSES AND THE ORIGIN AND DEVELOPMENT OF DIFFERENT TYPES OF TUMOR CELLS. CHRONIC STRESSES MAY CAUSE PERTURBATIONS OF RHYTHMS OF THE PNEI SYSTEM, EXCESSIVE ACTIVATION OF HPA AXIS AND ABNORMAL ACTIVATION OF CALCIUM SIGNALS IN SOMATIC TISSUES, WITH DELETERIOUS EFFECTS ON DIFFERENT PARTS OF THE BODY. THE INCREASING OF CALCIUM SIGNALING INSIDE CELLS MAY LEAD TO A DEREGULATION OF DIFFERENT PATHWAYS AND EPIGENETIC SYSTEMS THAT PROMOTE THE PRODUCTION OF GENOMIC MUTATIONS IN A SECOND PHASE. IN PARTICULAR, THE HYPERACTIVATION OF THE TRANSCRIPTION NUCLEAR FACTOR KAPPAB (NF-KAPPAB), IF IS NOT COUNTERBALANCED BY THE FOLLOWING ACTIVATION OF THE NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE 2 (NFE2L2 OR NRF2), INCREASES THE PRODUCTION OF OXIDATIVE CATABOLITES, AS THE ADVANCED GLYCATION END PRODUCTS (AGE), WHICH PLAY A KEY ROLE IN THE PROGRESSION OF DIFFERENT TYPES OF CANCER AND OTHER DEGENERATIVE DISEASES. CORTISOL BINDING TO GLUCOCORTICOID RECEPTOR (GR) REDUCES THE ACTIVITY OF BOTH NF-KAPPAB AND NRF2 INSIDE THE CELLS BUT INHIBITS THE CELLULAR IMMUNITY AND THE ANABOLIC PROCESSES OF TISSUE REGENERATION. THE TISSUE ATROPHY AND THE DEFECTIVE ANTI-AGEING MECHANISMS PROMOTES THE TUMORAL CELLS GROWTH AND THEIR ESCAPE FROM THE IMMUNE-SURVEILLANCE. 2017 10 4453 36 MOLECULAR MECHANISMS AND PATHWAYS AS TARGETS FOR CANCER PREVENTION AND PROGRESSION WITH DIETARY COMPOUNDS. A UNIQUE FEATURE OF BIOACTIVE FOOD INGREDIENTS IS THEIR BROAD ANTIOXIDANT FUNCTION. ANTIOXIDANTS HAVING A WIDE SPECTRUM OF CHEMICAL STRUCTURE AND ACTIVITY BEYOND BASIC NUTRITION; DISPLAY DIFFERENT HEALTH BENEFITS BY THE PREVENTION AND PROGRESSION OF CHRONIC DISEASES. FUNCTIONAL FOOD COMPONENTS ARE CAPABLE OF ENHANCING THE NATURAL ANTIOXIDANT DEFENSE SYSTEM BY SCAVENGING REACTIVE OXYGEN AND NITROGEN SPECIES, PROTECTING AND REPAIRING DNA DAMAGE, AS WELL AS MODULATING THE SIGNAL TRANSDUCTION PATHWAYS AND GENE EXPRESSION. MAJOR PATHWAYS AFFECTED BY BIOACTIVE FOOD INGREDIENTS INCLUDE THE PRO-INFLAMMATORY PATHWAYS REGULATED BY NUCLEAR FACTOR KAPPA B (NF-KAPPAB), AS WELL AS THOSE ASSOCIATED WITH CYTOKINES AND CHEMOKINES. THE PRESENT REVIEW SUMMARIZES THE IMPORTANCE OF PLANT BIOACTIVES AND THEIR ROLES IN THE REGULATION OF INFLAMMATORY PATHWAYS. BIOACTIVES INFLUENCE SEVERAL PHYSIOLOGICAL PROCESSES SUCH AS GENE EXPRESSION, CELL CYCLE REGULATION, CELL PROLIFERATION, CELL MIGRATION, ETC., RESULTING IN CANCER PREVENTION. CANCER INITIATION IS ASSOCIATED WITH CHANGES IN METABOLIC PATHWAYS SUCH AS GLUCOSE METABOLISM, AND THE EFFECT OF BIOACTIVES IN NORMALIZING THIS PROCESS HAS BEEN PROVIDED. INITIATION AND PROGRESSION OF INFLAMMATORY BOWEL DISEASES (IBD) WHICH INCREASE THE CHANCES OF DEVELOPING OF COLORECTAL CANCERS CAN BE DOWNREGULATED BY PLANT BIOACTIVES. SEVERAL ASPECTS OF THE POTENTIAL ROLES OF MICRORNAS AND EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF CANCERS HAVE ALSO BEEN PRESENTED. 2017 11 4792 43 NUTRITIONAL EPIGENETICS AND PHYTOCHEMICALS IN CANCER FORMATION. NUTRIGENETICS AND NUTRIGENOMICS ARE TWO CONCEPTS IN THE AREA OF NUTRITIONAL GENOMICS. EPIGENETICS IS A NEW DISCIPLINE WITH SIGNIFICANT POTENTIAL IN THE PREVENTION AND MANAGEMENT OF CERTAIN CARCINOMAS AND DISEASES. EPIGENETICS CONSISTS OF DNA METHYLATION, HISTONE MODIFICATION, NON-CODING RNAS, AND TELOMERASE ACTIVITY. EPIGENETIC-BASED MECHANISMS ACT ON THE INHIBITION OF CANCER CELLS BY MODULATING ENZYMES SUCH AS DNA METHYLTRANSFERASE AND HISTONE DEACETYLASE, AS WELL AS NON-CODING RNAS. PHYTOCHEMICALS ARE NATURAL BIOACTIVE COMPONENTS OF PLANT ORIGIN THAT HAVE ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTI-ANGIOGENIC EFFECTS ON VARIOUS DISEASES, ESPECIALLY CANCER. THE EPIGENETIC DIET IS A NUTRITIONAL MODEL BASED ON THE CONSUMPTION OF VARIOUS PHYTOCHEMICALS SUCH AS EPIGALLOCATECHIN-3-GALLATE, MORIN, CAFFEIC ACID PHENYL ESTER, APIGENIN, GENISTEIN, CURCUMIN, RESVERATROL, AND SULFORAPHANE. PHYTOCHEMICALS EXERT THEIR EFFECTS ON CANCER-BASED BY REDUCING CELL PROLIFERATION, INVASION, AND METASTASIS AND INCREASING CELL APOPTOSIS. SIMULTANEOUSLY, IT HAS FUNCTIONS SUCH AS REDUCING ONCOGENES THAT HAVE EFFECTS ON CANCER ETIOLOGY AND INCREASING TUMOR SUPPRESSOR GENES.KEY TEACHING POINTSCANCER IS A CHRONIC DISEASE WITH A HIGH MORTALITY RATE, IN WHICH VARIOUS GENETIC AND ENVIRONMENTAL FACTORS ARE INVOLVED IN ITS ETIOLOGY.PROTOONCOGENES, TUMOR SUPPRESSOR GENES, AND DNA REPAIR GENES ARE AMONG THE GENE GROUPS THAT FORM THE BASIS OF CANCER AND GENETIC STRUCTURE.THE BIDIRECTIONAL INTERACTION BETWEEN NUTRITION AND THE HUMAN GENOME HAS BEEN EFFECTIVE IN THE EMERGENCE OF THE CONCEPTS OF NUTRIGENETICS AND NUTRIGENOMICS.EPIGENETIC DIET IS A DIET BASED ON THE CONSUMPTION OF FOODS SUCH AS SOY, GRAPES, BLUEBERRIES, TURMERIC, CRUCIFEROUS VEGETABLES, AND GREEN TEA, WHICH INDUCE EPIGENETIC MECHANISMS THAT PROTECT AGAINST CANCER AND AGING. 2023 12 4597 23 NATURAL PRODUCTS WITH ANTI-AGING POTENTIAL: AFFECTED TARGETS AND MOLECULAR MECHANISMS. IN RECENT YEARS, THERE HAS BEEN A GREAT DEAL OF ATTENTION TOWARD THE MOLECULAR MACHINERY RELEVANT TO AGE-RELATED PROGRESSION CONTROLLED THROUGH THE EXTERNAL INTERVENTION OF POLYPHENOLS- AN EPIGENETIC-MODULATING DIET. NATURAL PRODUCTS MODULATE CELLULAR LONGEVITY THROUGH HISTONE POST-TRANSLATIONAL MODIFICATION AND CAN ALSO INDUCE THE UPREGULATION OF AUTOPHAGY, THUS REDUCING THE LEVEL OF ACETYL COENZYME A (ACCOA). IN ADDITION, THE EFFECT OF CALORIC RESTRICTION (CR) ON CANCER-RELATED CHRONIC INFLAMMATION IS OF GREAT SIGNIFICANCE IN AGING. IN LINE WITH THIS, SIRT1 PROTEIN LEVELS ARE EXPANDED IN RESPONSE TO CALORIE RESTRICTION MIMETICS (CRM), IN THIS WAY ACTING AS AUTOPHAGY INDUCERS RELEVANT TO CANCER PREVENTION. 2018 13 4764 35 NRF2: FRIEND OR FOE FOR CHEMOPREVENTION? HEALTH REFLECTS THE ABILITY OF AN ORGANISM TO ADAPT TO STRESS. STRESSES--METABOLIC, PROTEOTOXIC, MITOTIC, OXIDATIVE AND DNA-DAMAGE STRESSES--NOT ONLY CONTRIBUTE TO THE ETIOLOGY OF CANCER AND OTHER CHRONIC DEGENERATIVE DISEASES BUT ARE ALSO HALLMARKS OF THE CANCER PHENOTYPE. ACTIVATION OF THE KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (KEAP1)-NF-E2-RELATED FACTOR 2 (NRF2)-SIGNALING PATHWAY IS AN ADAPTIVE RESPONSE TO ENVIRONMENTAL AND ENDOGENOUS STRESSES AND SERVES TO RENDER ANIMALS RESISTANT TO CHEMICAL CARCINOGENESIS AND OTHER FORMS OF TOXICITY, WHILST DISRUPTION OF THE PATHWAY EXACERBATES THESE OUTCOMES. THIS PATHWAY CAN BE INDUCED BY THIOL-REACTIVE SMALL MOLECULES THAT DEMONSTRATE PROTECTIVE EFFICACY IN PRECLINICAL CHEMOPREVENTION MODELS AND IN CLINICAL TRIALS. HOWEVER, MUTATIONS AND EPIGENETIC MODIFICATIONS AFFECTING THE REGULATION AND FATE OF NRF2 CAN LEAD TO CONSTITUTIVE DOMINANT HYPERACTIVATION OF SIGNALING THAT PRESERVES RATHER THAN ATTENUATES CANCER PHENOTYPES BY PROVIDING SELECTIVE RESISTANCE TO STRESSES. THIS REVIEW PROVIDES A SYNOPSIS OF KEAP1-NRF2 SIGNALING, COMPARES THE IMPACT OF GENETIC VERSUS PHARMACOLOGIC ACTIVATION AND CONSIDERS BOTH THE ATTRIBUTES AND CONCERNS OF TARGETING THE PATHWAY IN CHEMOPREVENTION. 2010 14 4534 38 MULTIPLE REGULATIONS OF KEAP1/NRF2 SYSTEM BY DIETARY PHYTOCHEMICALS. KEAP1/NRF2 SYSTEM PLAYS A CRITICAL ROLE ON CELLULAR PROTECTION BY REGULATING MANY ANTIOXIDANT AND DETOXIFICATION ENZYME GENES THROUGH THE ANTIOXIDANT RESPONSE ELEMENT (ARE). THUS, IT MUST WORK CONSTANTLY TO PREVENT THE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) BECAUSE EXCESS ROS ARE ASSOCIATED WITH MANY DISEASES SUCH AS CANCER, CARDIOVASCULAR COMPLICATIONS, INFLAMMATION, AND NEURODEGENERATION. DIETARY PHYTOCHEMICALS WIDELY DISTRIBUTING IN FRUITS AND VEGETABLES HAVE BEEN CONSIDERED TO POSSESS CANCER CHEMOPREVENTIVE POTENTIAL THROUGH THE INDUCTION OF KEAP1/NRF2 SYSTEM-MEDIATED ANTIOXIDANT AND DETOXIFICATION ENZYMES IN A VARIETY OF MANNERS. THE DATA ARE EXTENSIVE AND ARE NOT WELL CLASSIFIED ON THE MOLECULAR MECHANISMS. IN THIS REVIEW, WE FIRST BRIEFLY INTRODUCE THE CURRENT KNOWLEDGE ON KEAP1/NRF2 SYSTEM REGULATION INCLUDING KEAP1-DEPENDENT AND KEAP1-INDEPENDENT CASCADES, AND EPIGENETIC PATHWAY. THEN, WE SUMMARIZE THE MOLECULAR TARGETS OF KEAP1/NRF2 SYSTEM BY DIETARY PHYTOCHEMICALS, AND FINALLY REVIEW THE CROSSTALK BETWEEN KEAP1/NRF2 SYSTEM AND OTHER CELLULAR SIGNALING PATHWAYS TO REGULATE DIVERSE CHRONIC DISEASES BY DIETARY PHYTOCHEMICALS. THESE COMPREHENSIVE DATA WILL HELP US TO UNDERSTAND THE POTENTIAL EFFECTS OF DIETARY PHYTOCHEMICALS ON THE PREVENTION OF CHRONIC DISEASES AND MAINTENANCE OF HUMAN HEALTH. 2016 15 4902 32 OXIDATIVE-STRESS-INDUCED EPIGENETIC CHANGES IN CHRONIC DIABETIC COMPLICATIONS. OXIDATIVE STRESS PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC DIABETIC COMPLICATIONS. DIABETES CAUSES MITOCHONDRIAL SUPEROXIDE OVERPRODUCTION IN THE ENDOTHELIAL CELLS OF BOTH LARGE AND SMALL VESSELS. THIS INCREASED SUPEROXIDE PRODUCTION CAUSES THE ACTIVATION OF SEVERAL SIGNAL PATHWAYS INVOLVED IN THE PATHOGENESIS OF CHRONIC COMPLICATIONS. IN PARTICULAR, ENDOTHELIAL CELLS ARE MAJOR TARGETS OF GLUCOSE-INDUCED OXIDATIVE DAMAGE IN THE TARGET ORGANS. OXIDATIVE STRESS ACTIVATES CELLULAR SIGNALING PATHWAYS AND TRANSCRIPTION FACTORS IN ENDOTHELIAL CELLS INCLUDING PROTEIN KINASE C (PKC), C-JUN-N-TERMINAL KINASE (JNK), P38 MITOGEN-ACTIVATED PROTEIN KINASE (MAPK), FORKHEAD BOX O (FOXO), AND NUCLEAR FACTOR KAPPA-B (NF-KAPPAB). OXIDATIVE STRESS ALSO CAUSES DNA DAMAGE AND ACTIVATES DNA NUCLEOTIDE EXCISION REPAIR ENZYMES INCLUDING THE EXCISION REPAIR CROSS COMPLIMENTING 1(ERCC1), ERCC4, AND POLY(ADP-RIBOSE) POLYMERASE (PARP). AUGMENTED PRODUCTION OF HISTONE ACETYLTRANSFERASE P300, AND ALTERATIONS OF HISTONE DEACETYLASES, INCLUDING CLASS III DEACETYLASES SIRTUINS, ARE ALSO INVOLVED IN THIS PROCESS. RECENT RESEARCH HAS FOUND THAT SMALL NONCODING RNAS, LIKE MICRORNA, ARE A NEW KIND OF REGULATOR ASSOCIATED WITH CHRONIC DIABETIC COMPLICATIONS. THERE ARE EXTENSIVE AND COMPLICATED INTERACTIONS AND AMONG THESE MOLECULES. THE PURPOSE OF THIS REVIEW IS TO DEMONSTRATE THE ROLE OF OXIDATIVE STRESS IN THE DEVELOPMENT OF DIABETIC COMPLICATIONS IN RELATION TO EPIGENETIC CHANGES SUCH AS ACETYLATION AND MICRORNA ALTERATIONS. 2013 16 4652 32 NEUROPROTECTION WITH NATURAL ANTIOXIDANTS AND NUTRACEUTICALS IN THE CONTEXT OF BRAIN CELL DEGENERATION: THE EPIGENETIC CONNECTION. BIOACTIVE ANTIOXIDANT AGENTS PRESENT IN SELECTED PLANTS ARE KNOWN TO PROVIDE THE FIRST LINE OF BIOLOGICAL DEFENSE AGAINST OXIDATIVE STRESS. IN PARTICULAR, SOLUBLE VITAMIN C, E, CAROTENOIDS AND PHENOLIC COMPOUNDS HAVE DEMONSTRATED CRUCIAL BIOLOGICAL EFFECTS IN CELLS AGAINST OXIDATIVE DAMAGE, PREVENTING PREVALENT CHRONIC DISEASES, SUCH AS DIABETES, CANCER AND CARDIOVASCULAR DISEASE. THE REPORTED WIDE RANGE OF EFFECTS THAT INCLUDED ANTI-AGING, ANTI-ATHEROSCLEROSIS, ANTI-INFLAMMATORY AND ANTICANCER ACTIVITY WERE STUDIED AGAINST DEGENERATIVE PATHOLOGIES OF THE BRAIN. VITAMINS AND DIFFERENT PHYTOCHEMICALS ARE IMPORTANT EPIGENETIC MODIFIERS THAT PREVENT NEURODEGENERATION. IN ORDER TO EXPLORE THE POTENTIAL ANTIOXIDANT SOURCES IN FUNCTIONAL FOODS AND NUTRACEUTICALS AGAINST NEURODEGENERATION, THE PRESENT PAPER AIMS TO SHOW A COMPREHENSIVE ASSESSMENT OF ANTIOXIDANT ACTIVITY AT CHEMICAL AND CELLULAR LEVELS. THE EFFECTS OF THE DIFFERENT BIOACTIVE COMPOUNDS AVAILABLE AND THEIR ANTIOXIDANT ACTIVITY THROUGH AN EPIGENETIC POINT OF VIEW ARE ALSO DISCUSSED. 2019 17 1254 33 CURRENT PROGRESS ON THE MECHANISMS OF HYPERHOMOCYSTEINEMIA-INDUCED VASCULAR INJURY AND USE OF NATURAL POLYPHENOL COMPOUNDS. CARDIOVASCULAR DISEASE IS ONE OF THE MOST COMMON DISEASES IN THE ELDERLY POPULATION, AND ITS INCIDENCE HAS RAPIDLY INCREASED WITH THE PROLONGATION OF LIFE EXPECTANCY. HYPERHOMOCYSTEINEMIA IS AN INDEPENDENT RISK FACTOR FOR VARIOUS CARDIOVASCULAR DISEASES, INCLUDING ATHEROSCLEROSIS, AND DAMAGE TO VASCULAR FUNCTION PLAYS AN INITIAL ROLE IN ITS PATHOGENESIS. THIS REVIEW PRESENTS THE LATEST KNOWLEDGE ON THE MECHANISMS OF VASCULAR INJURY CAUSED BY HYPERHOMOCYSTEINEMIA, INCLUDING OXIDATIVE STRESS, ENDOPLASMIC RETICULUM STRESS, PROTEIN N-HOMOCYSTEINIZATION, AND EPIGENETIC MODIFICATION, AND DISCUSSES THE THERAPEUTIC TARGETS OF NATURAL POLYPHENOLS. STUDIES HAVE SHOWN THAT NATURAL POLYPHENOLS IN PLANTS CAN REDUCE HOMOCYSTEINE LEVELS AND REGULATE DNA METHYLATION BY ACTING ON OXIDATIVE STRESS AND ENDOPLASMIC RETICULUM STRESS-RELATED SIGNALING PATHWAYS, THUS IMPROVING HYPERHOMOCYSTEINEMIA-INDUCED VASCULAR INJURY. NATURAL POLYPHENOLS OBTAINED VIA DAILY DIET ARE SAFER AND HAVE MORE PRACTICAL SIGNIFICANCE IN THE PREVENTION AND TREATMENT OF CHRONIC DISEASES THAN TRADITIONAL DRUGS. 2021 18 6333 37 THE ROLE OF DIETARY PHENOLIC COMPOUNDS IN EPIGENETIC MODULATION INVOLVED IN INFLAMMATORY PROCESSES. A BETTER UNDERSTANDING OF THE INTERACTIONS BETWEEN DIETARY PHENOLIC COMPOUNDS AND THE EPIGENETICS OF INFLAMMATION MAY IMPACT PATHOLOGICAL CONDITIONS AND THEIR TREATMENT. PHENOLIC COMPOUNDS ARE WELL-KNOWN FOR THEIR ANTIOXIDANT, ANTI-INFLAMMATORY, ANTI-ANGIOGENIC, AND ANTI-CANCER PROPERTIES, WITH POTENTIAL BENEFITS IN THE TREATMENT OF VARIOUS HUMAN DISEASES. EMERGING STUDIES BRING EVIDENCE THAT NUTRITION MAY PLAY AN ESSENTIAL ROLE IN IMMUNE SYSTEM MODULATION ALSO BY ALTERING GENE EXPRESSION. THIS REVIEW DISCUSSES EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATION, AND NON-CODING MICRORNA ACTIVITY THAT REGULATE THE GENE EXPRESSION OF MOLECULES INVOLVED IN INFLAMMATORY PROCESSES. SPECIAL ATTENTION IS PAID TO THE MOLECULAR BASIS OF NF-KAPPAB MODULATION BY DIETARY PHENOLIC COMPOUNDS. THE REGULATION OF HISTONE ACETYLTRANSFERASE AND HISTONE DEACETYLASE ACTIVITY, WHICH ALL INFLUENCE NF-KAPPAB SIGNALING, SEEMS TO BE A CRUCIAL MECHANISM OF THE EPIGENETIC CONTROL OF INFLAMMATION BY PHENOLIC COMPOUNDS. MOREOVER, CHRONIC INFLAMMATORY PROCESSES ARE REPORTED TO BE CLOSELY CONNECTED TO THE MAJOR STAGES OF CARCINOGENESIS AND OTHER NON-COMMUNICABLE DISEASES. THEREFORE, DIETARY PHENOLIC COMPOUNDS-TARGETED EPIGENETICS IS BECOMING AN ATTRACTIVE APPROACH FOR DISEASE PREVENTION AND INTERVENTION. 2020 19 6022 34 THE BENEFICIAL EFFECTS OF ZN ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES. ZINC IS ONE OF THE ESSENTIAL TRACE ELEMENTS AND PARTICIPATES IN NUMEROUS PHYSIOLOGICAL PROCESSES. ABNORMALITIES IN ZINC HOMEOSTASIS OFTEN RESULT IN THE PATHOGENESIS OF VARIOUS CHRONIC METABOLIC DISORDERS, SUCH AS DIABETES AND ITS COMPLICATIONS. ZINC HAS INSULIN-MIMETIC AND ANTI-DIABETIC EFFECTS AND DEFICIENCY HAS BEEN SHOWN TO AGGRAVATE DIABETES-INDUCED OXIDATIVE STRESS AND TISSUE INJURY IN DIABETIC RODENT MODELS AND HUMAN SUBJECTS WITH DIABETES. AKT SIGNALING PATHWAY PLAYS A CENTRAL ROLE IN INSULIN-STIMULATED GLUCOSE METABOLISM AND CELL SURVIVAL. ANTI-DIABETIC EFFECTS OF ZINC ARE LARGELY DEPENDENT ON THE ACTIVATION OF AKT SIGNALING. ZN IS ALSO AN INDUCER OF METALLOTHIONEIN THAT PLAYS IMPORTANT ROLE IN ANTI-OXIDATIVE STRESS AND DAMAGE. HOWEVER, THE EXACT MOLECULAR MECHANISMS UNDERLYING ZINC-INDUCED ACTIVATION OF AKT SIGNALING PATHWAY REMAINS TO BE ELUCIDATED. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN DECIPHERING THE POSSIBLE MECHANISMS OF ZINC ON AKT-MEDIATED INSULIN AND CELL SURVIVAL SIGNALING PATHWAYS IN DIABETES CONDITIONS. INSIGHTS INTO THE EFFECTS OF ZINC ON EPIGENETIC REGULATION AND AUTOPHAGY IN DIABETIC NEPHROPATHY ARE ALSO DISCUSSED IN THE LATTER PART OF THIS REVIEW. 2018 20 1383 41 DIABETES AND ITS CARDIOVASCULAR COMPLICATIONS: POTENTIAL ROLE OF THE ACETYLTRANSFERASE P300. DIABETES HAS BEEN SHOWN TO ACCELERATE VASCULAR SENESCENCE, WHICH IS ASSOCIATED WITH CHRONIC INFLAMMATION AND OXIDATIVE STRESS, BOTH IMPLICATED IN THE DEVELOPMENT OF ENDOTHELIAL DYSFUNCTION. THIS CONDITION REPRESENTS THE INITIAL ALTERATION LINKING DIABETES TO RELATED CARDIOVASCULAR (CV) COMPLICATIONS. RECENTLY, IT HAS BEEN HYPOTHESISED THAT THE ACETYLTRANSFERASE, P300, MAY CONTRIBUTE TO ESTABLISHING AN EARLY VASCULAR SENESCENT PHENOTYPE, PLAYING A RELEVANT ROLE IN DIABETES-ASSOCIATED INFLAMMATION AND OXIDATIVE STRESS, WHICH DRIVE ENDOTHELIAL DYSFUNCTION. SPECIFICALLY, P300 CAN MODULATE VASCULAR INFLAMMATION THROUGH EPIGENETIC MECHANISMS AND TRANSCRIPTION FACTORS ACETYLATION. INDEED, IT REGULATES THE INFLAMMATORY PATHWAY BY INTERACTING WITH NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS P65 SUBUNIT (NF-KAPPAB P65) OR BY INDUCING ITS ACETYLATION, SUGGESTING A CRUCIAL ROLE OF P300 AS A BRIDGE BETWEEN NF-KAPPAB P65 AND THE TRANSCRIPTIONAL MACHINERY. ADDITIONALLY, P300-MEDIATED EPIGENETIC MODIFICATIONS COULD BE UPSTREAM OF THE ACTIVATION OF INFLAMMATORY CYTOKINES, AND THEY MAY INDUCE OXIDATIVE STRESS BY AFFECTING THE PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS). BECAUSE SEVERAL IN VITRO AND IN VIVO STUDIES SHED LIGHT ON THE POTENTIAL USE OF ACETYLTRANSFERASE INHIBITORS, A BETTER UNDERSTANDING OF THE MECHANISMS UNDERLYING THE ROLE OF P300 IN DIABETIC VASCULAR DYSFUNCTION COULD HELP IN FINDING NEW STRATEGIES FOR THE CLINICAL MANAGEMENT OF CV DISEASES RELATED TO DIABETES. 2023