1 5392 144 REDOXISOME AND DIABETIC RETINOPATHY: PATHOPHYSIOLOGY AND THERAPEUTIC INTERVENTIONS. DIABETIC RETINOPATHY (DR) IS A CHRONIC MICROVASCULAR COMPLICATION OF DIABETES MELLITUS (DM). IT IS A WORLDWIDE GROWING EPIDEMIC DISEASE CONSIDERED TO BE THE LEADING CAUSE OF VISION-LOSS AND BLINDNESS IN PEOPLE WITH DM. REDOX REACTIONS OCCURRING AT THE EXTRA- AND INTRACELLULAR LEVELS ARE ESSENTIAL FOR THE MAINTENANCE OF CELLULAR HOMEOSTASIS. DYSREGULATION OF REDOX HOMEOSTASIS ARE IMPLICATED IN THE ONSET AND DEVELOPMENT OF DR. THIOREDOXIN1 (TRX1) AND THIOREDOXIN2 (TRX2) ARE CYTOPLASMIC AND MITOCHONDRIALLY LOCALIZED ANTIOXIDANT PROTEINS UBIQUITOUSLY EXPRESSED IN VARIOUS CELLS AND CONTROL CELLULAR REACTIVE OXYGEN SPECIES (ROS) BY REDUCING THE DISULFIDES INTO THIOL GROUPS. THIOREDOXIN-INTERACTING PROTEIN (TXNIP) BINDS TO TRX SYSTEM AND INHIBITS THE ACTIVE REDUCED FORM OF TRX THROUGH DISULFIDE EXCHANGE REACTION. RECENT STUDIES INDICATE THE ASSOCIATION OF TRX/TXNIP WITH REDOX SIGNAL TRANSDUCTION PATHWAYS INCLUDING ACTIVATION OF NOD-LIKE RECEPTOR PYRIN DOMAIN CONTAINING PROTEIN-3 (NLRP3) INFLAMMASOME, APOPTOSIS, AUTOPHAGY/MITOPHAGY, EPIGENETIC MODIFICATIONS IN A REDOX-DEPENDENT MANNER. THUS, IT IS IMPORTANT TO GAIN A MORE IN-DEPTH UNDERSTANDING ABOUT THE CELLULAR AND MOLECULAR MECHANISMS THAT LINKS REDOXISOME AND ER/MITOCHONDRIAL DYSFUNCTION TO DRIVE THE PROGRESSION OF DR. THE PURPOSE OF THIS REVIEW IS TO PROVIDE A MECHANISTIC UNDERSTANDING OF THE COMPLEX MOLECULAR MECHANISMS AND PATHOPHYSIOLOGICAL ROLES ASSOCIATED WITH REDOXISOME, THE TRX/TXNIP REDOX SIGNALING COMPLEX UNDER OXIDATIVE STRESS IN THE DEVELOPMENT OF DR. ALSO, THE MOLECULAR TARGETS OF FDA APPROVED DRUGS AND CLINICAL TRIALS IN ADDITION TO EFFECTIVE ANTIOXIDANT STRATEGIES FOR THE TREATMENT OF DIABETIC RETINOPATHY ARE REVIEWED. 2022 2 5046 48 PHARMACOLOGICAL AND DIETARY ANTIOXIDANT THERAPIES FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE PROGRESSION AND EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE INTIMATELY ASSOCIATED WITH TOBACCO SMOKE/BIOMASS FUEL-INDUCED OXIDATIVE AND ALDEHYDE/CARBONYL STRESS. ALTERATIONS IN REDOX SIGNALING PROINFLAMMATORY KINASES AND TRANSCRIPTION FACTORS, STEROID RESISTANCE, UNFOLDED PROTEIN RESPONSE, MUCUS HYPERSECRETION, EXTRACELLULAR MATRIX REMODELING, AUTOPHAGY/APOPTOSIS, EPIGENETIC CHANGES, CELLULAR SENESCENCE/AGING, ENDOTHELIAL DYSFUNCTION, AUTOIMMUNITY, AND SKELETAL MUSCLE DYSFUNCTION ARE SOME OF THE PATHOLOGICAL HALLMARKS OF COPD. IN LIGHT OF THE ABOVE IT WOULD BE PRUDENT TO TARGET SYSTEMIC AND LOCAL OXIDATIVE STRESS WITH AGENTS THAT CAN MODULATE THE ANTIOXIDANTS/ REDOX SYSTEM OR BY BOOSTING THE ENDOGENOUS LEVELS OF ANTIOXIDANTS FOR THE TREATMENT AND MANAGEMENT OF COPD. IDENTIFICATION OF VARIOUS ANTIOXIDANT AGENTS, SUCH AS THIOL MOLECULES (GLUTATHIONE AND MUCOLYTIC DRUGS, SUCH AS N-ACETYL-L-CYSTEINE, N-ACYSTELYN, ERDOSTEINE, FUDOSTEINE, ERGOTHIONEINE, AND CARBOCYSTEINE LYSINE SALT), DIETARY NATURAL PRODUCT-DERIVED POLYPHENOLS AND OTHER COMPOUNDS (CURCUMIN, RESVERATROL, GREEN TEA CATECHINS, QUERCETIN SULFORAPHANE, LYCOPENE, ACAI, ALPHA-LIPOIC ACID, TOCOTRIENOLS, AND APOCYNIN) HAVE MADE IT POSSIBLE TO MODULATE VARIOUS BIOCHEMICAL ASPECTS OF COPD. VARIOUS RESEARCHES AND CLINICAL TRIALS HAVE REVEALED THAT THESE ANTIOXIDANTS CAN DETOXIFY FREE RADICALS AND OXIDANTS, CONTROL EXPRESSION OF REDOX AND GLUTATHIONE BIOSYNTHESIS GENES, CHROMATIN REMODELING, AND ULTIMATELY INFLAMMATORY GENE EXPRESSION. IN ADDITION, MODULATION OF CIGARETTE SMOKE-INDUCED OXIDATIVE STRESS AND RELATED CELLULAR CHANGES HAVE ALSO BEEN REPORTED TO BE EFFECTED BY SYNTHETIC MOLECULES. THIS INCLUDES SPECIFIC SPIN TRAPS LIKE ALPHA-PHENYL-N-TERT-BUTYL NITRONE, A CATALYTIC ANTIOXIDANT (ECSOD MIMETIC), PORPHYRINS (AEOL 10150 AND AEOL 10113), AND A SUPEROXIDE DISMUTASE MIMETIC M40419, LIPID PEROXIDATION AND PROTEIN CARBONYLATION BLOCKERS/INHIBITORS, SUCH AS EDARAVONE AND LAZAROIDS/TIRILAZAD, MYELOPEROXIDASE INHIBITORS, AS WELL AS SPECIALIZED PRO-RESOLVING MEDIATORS/INFLAMMATORY RESOLVING LIPID MEDIATORS, OMEGA-3 FATTY ACIDS, VITAMIN D, AND HYDROGEN SULFIDE. ACCORDING TO VARIOUS STUDIES IT APPEARS THAT THE ADMINISTRATION OF MULTIPLE ANTIOXIDANTS COULD BE A MORE EFFECTIVE MODE USED IN THE TREATMENT OF COPD. IN THIS REVIEW, VARIOUS PHARMACOLOGICAL AND DIETARY APPROACHES TO ENHANCE LUNG ANTIOXIDANT LEVELS AND BENEFICIAL EFFECTS OF ANTIOXIDANT THERAPEUTICS IN TREATING OR INTERVENING THE PROGRESSION OF COPD HAVE BEEN DISCUSSED. 2013 3 1866 33 EMERGING CROSSTALK BETWEEN LONG NON-CODING RNAS AND NRF2 SIGNALING. DIVERSE STIMULI TRIGGER NRF2 SIGNALING, WHICH IN TURN TRANSCRIPTIONALLY REGULATES AN ARRAY OF DOWNSTREAM TARGETS, PROVIDING FOR MULTIPLE LAYERS OF CONTROL. WHILE NRF2 ACTIVITY LARGELY IS GOVERNED BY POSTTRANSLATIONAL MODIFICATION OF CRITICAL THIOL RESIDUES IN THE PROTEIN PARTNER AND REDOX SENSOR KEAP1, FINE-TUNING IS PROVIDED BY ADDITIONAL MECHANISMS - INCLUDING EPIGENETIC REGULATION. HEREIN, WE REVIEW THE EMERGING SIGNIFICANCE OF LONG NON-CODING RNAS (LNCRNA) AS DOWNSTREAM TARGETS AND UPSTREAM REGULATORS OF THE NRF2 SIGNALING PATHWAY. AMONG THE ~16000 LNCRNAS IN GENCODE, SOME HAVE BEEN VALIDATED AS TRANSCRIPTIONALLY REGULATED BY NRF2 (E.G., LUCAT1, NMRAL2P, ODRUL, ROR AND TUG1), AND OTHERS HAVE BEEN IDENTIFIED AS UPSTREAM REGULATORS OF NRF2 EXPRESSION (E.G., HOTAIR, MALAT1, MEG1, NRAL AND UCA1). BIOINFORMATIC ANALYSES OF ANNOTATED HUMAN LNCRNAS IDENTIFIED PUTATIVE NRF2 BINDING SITES IN THE PROMOTER REGIONS OF 13,285 LNCRNAS. FURTHER INVESTIGATION IS WARRANTED TO VALIDATE THE MANY NOVEL LNCRNAS AS BONA FIDE NRF2-REGULATED TARGETS, AND THEIR ROLES IN NRF2 SIGNALING. NRF2 IS CONSIDERED A PROMISING THERAPEUTIC CANDIDATE FOR CANCER AND OTHER CHRONIC DISEASES; THUS, TARGETING THE ASSOCIATED LNCRNAS MIGHT PROVIDE FOR A MORE REFINED FINE-TUNING OF THE SYSTEM, DEPENDING ON CELLULAR AND PATHOPHYSIOLOGICAL CONTEXT. 2020 4 616 34 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 5 6441 34 THERAPEUTIC APPROACHES FOR NONALCOHOLIC FATTY LIVER DISEASE: ESTABLISHED TARGETS AND DRUGS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), AS A MULTISYSTEMIC DISEASE, IS THE MOST PREVALENT CHRONIC LIVER DISEASE CHARACTERIZED BY EXTREMELY COMPLEX PATHOGENIC MECHANISMS AND MULTIFACTORIAL ETIOLOGY, WHICH OFTEN DEVELOPS AS A CONSEQUENCE OF OBESITY, METABOLIC SYNDROME. PATHOPHYSIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF NAFLD INCLUDE DIET, OBESITY, INSULIN RESISTANCE (IR), GENETIC AND EPIGENETIC DETERMINANTS, INTESTINAL DYSBIOSIS, OXIDATIVE/NITROSATIVE STRESS, AUTOPHAGY DYSREGULATION, HEPATIC INFLAMMATION, GUT-LIVER AXIS, GUT MICROBES, IMPAIRED MITOCHONDRIAL METABOLISM AND REGULATION OF HEPATIC LIPID METABOLISM. SOME OF THE NEW DRUGS FOR THE TREATMENT OF NAFLD ARE INTRODUCED HERE. ALL OF THEM ACHIEVE THERAPEUTIC OBJECTIVES BY INTERFERING WITH CERTAIN PATHOPHYSIOLOGICAL PATHWAYS OF NAFLD, INCLUDING FIBROBLAST GROWTH FACTORS (FGF) ANALOGUES, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARS) AGONISTS, GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS, G PROTEIN-COUPLED RECEPTORS (GPCRS), SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS (SGLT-2I), FARNESOID X RECEPTOR (FXR), FATTY ACID SYNTHASE INHIBITOR (FASNI), ANTIOXIDANTS, ETC. THIS REVIEW DESCRIBES SOME PATHOPHYSIOLOGICAL MECHANISMS OF NAFLD AND ESTABLISHED TARGETS AND DRUGS. 2023 6 449 26 APOCYNIN PREVENTS ANXIETY-LIKE BEHAVIOR AND HISTONE DEACETYLASES OVEREXPRESSION INDUCED BY SUB-CHRONIC STRESS IN MICE. ANXIETY DISORDERS ARE COMMON MENTAL HEALTH DISEASES AFFECTING UP TO 7% OF PEOPLE AROUND THE WORLD. STRESS IS CONSIDERED ONE OF THE MAJOR ENVIRONMENTAL RISK FACTORS TO PROMOTE ANXIETY DISORDERS THROUGH MECHANISMS INVOLVING EPIGENETIC CHANGES. MOREOVER, ALTERATION IN REDOX BALANCE AND INCREASED REACTIVE OXYGEN SPECIES (ROS) PRODUCTION HAVE BEEN DETECTED IN ANXIETY PATIENTS AND IN STRESSED-ANIMAL MODELS OF ANXIETY. HERE WE TESTED IF THE ADMINISTRATION OF APOCYNIN, A NATURAL ORIGIN ANTIOXIDANT, MAY PREVENT THE ANXIETY-LIKE PHENOTYPE AND REDUCTION OF HISTONE ACETYLATION INDUCED BY A SUBCHRONIC FORCED SWIMMING STRESS (FSS) PARADIGM. WE FOUND THAT APOCYNIN PREVENTED THE ENHANCED LATENCY TIME IN THE NOVELTY-SUPPRESSED FEEDING TEST, AND THE PRODUCTION OF MALONDIALDEHYDE INDUCED BY FSS. MOREOVER, APOCYNIN WAS ABLE TO BLOCK THE UPREGULATION OF P47PHOX, A KEY SUBUNIT OF THE NADPH OXIDASE COMPLEX. FINALLY, APOCYNIN PREVENTED THE RISE OF HIPPOCAMPAL HDAC1, HDAC4 AND HDAC5, AND THE REDUCTION OF HISTONE-3 ACETYLATION LEVELS PROMOTED BY FSS EXPOSURE. IN CONCLUSION, OUR RESULTS PROVIDE EVIDENCE THAT APOCYNIN REDUCES THE DELETERIOUS EFFECT OF STRESS AND SUGGESTS THAT OXIDATIVE STRESS MAY REGULATE EPIGENETIC MECHANISMS. 2021 7 5052 38 PHARMACOLOGICAL TARGETING OF HEME OXYGENASE-1 IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGING-ASSOCIATED DISEASE THAT CLINICALLY MANIFESTS AS JOINT PAIN, MOBILITY LIMITATIONS, AND COMPROMISED QUALITY OF LIFE. TODAY, OA TREATMENT IS LIMITED TO PAIN MANAGEMENT AND JOINT ARTHROPLASTY AT THE LATER STAGES OF DISEASE PROGRESSION. OA PATHOGENESIS IS PREDOMINANTLY MEDIATED BY OXIDATIVE DAMAGE TO JOINT CARTILAGE EXTRACELLULAR MATRIX AND LOCAL CELLS SUCH AS CHONDROCYTES, OSTEOCLASTS, OSTEOBLASTS, AND SYNOVIAL FIBROBLASTS. UNDER NORMAL CONDITIONS, CELLS PREVENT THE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) UNDER OXIDATIVELY STRESSFUL CONDITIONS THROUGH THEIR ADAPTIVE CYTOPROTECTIVE MECHANISMS. HEME OXYGENASE-1 (HO-1) IS AN IRON-DEPENDENT CYTOPROTECTIVE ENZYME THAT FUNCTIONS AS THE INDUCIBLE FORM OF HO. HO-1 AND ITS METABOLITES CARBON MONOXIDE AND BILIVERDIN CONTRIBUTE TOWARDS THE MAINTENANCE OF REDOX HOMEOSTASIS. HO-1 EXPRESSION IS PRIMARILY REGULATED AT THE TRANSCRIPTIONAL LEVEL THROUGH TRANSCRIPTIONAL FACTOR NUCLEAR FACTOR ERYTHROID 2 (NF-E2)-RELATED FACTOR 2 (NRF2), SPECIFICITY PROTEIN 1 (SP1), TRANSCRIPTIONAL REPRESSOR BTB-AND-CNC HOMOLOGY 1 (BACH1), AND EPIGENETIC REGULATION. SEVERAL STUDIES REPORT THAT HO-1 EXPRESSION CAN BE REGULATED USING VARIOUS ANTIOXIDATIVE FACTORS AND CHEMICAL COMPOUNDS, SUGGESTING THERAPEUTIC IMPLICATIONS IN OA PATHOGENESIS AS WELL AS IN THE WIDER CONTEXT OF JOINT DISEASE. HERE, WE REVIEW THE PROTECTIVE ROLE OF HO-1 IN OA WITH A FOCUS ON THE REGULATORY MECHANISMS THAT MEDIATE HO-1 ACTIVITY. 2021 8 5580 41 ROLE OF NEUROTOXICANTS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE: A MECHANISTIC INSIGHT. ALZHEIMER'S DISEASE (AD) IS THE MOST CONSPICUOUS CHRONIC NEURODEGENERATIVE SYNDROME, WHICH HAS BECOME A SIGNIFICANT CHALLENGE FOR THE GLOBAL HEALTHCARE SYSTEM. MULTIPLE STUDIES HAVE CORROBORATED A CLEAR ASSOCIATION OF NEUROTOXICANTS WITH AD PATHOGENICITY, SUCH AS AMYLOID BETA (ABETA) PROTEINS AND NEUROFIBRILLARY TANGLES (NFTS), SIGNALLING PATHWAY MODIFICATIONS, CELLULAR STRESS, COGNITIVE DYSFUNCTIONS, NEURONAL APOPTOSIS, NEUROINFLAMMATION, EPIGENETIC MODIFICATION, AND SO ON. THIS REVIEW, THEREFORE, AIMED TO ADDRESS SEVERAL ESSENTIAL MECHANISMS AND SIGNALLING CASCADES, INCLUDING WNT (WINGLESS AND INT.) SIGNALLING PATHWAY, AUTOPHAGY, MAMMALIAN TARGET OF RAPAMYCIN (MTOR), PROTEIN KINASE C (PKC) SIGNALLING CASCADES, CELLULAR REDOX STATUS, ENERGY METABOLISM, GLUTAMATERGIC NEUROTRANSMISSIONS, IMMUNE CELL STIMULATIONS (E.G. MICROGLIA, ASTROCYTES) AS WELL AS AN AMYLOID PRECURSOR PROTEIN (APP), PRESENILIN-1 (PSEN1), PRESENILIN-2 (PSEN2) AND OTHER AD-RELATED GENE EXPRESSIONS THAT HAVE BEEN PRETENTIOUS AND MODULATED BY THE VARIOUS NEUROTOXICANTS. THIS REVIEW CONCLUDED THAT NEUROTOXICANTS PLAY A MOMENTOUS ROLE IN DEVELOPING AD THROUGH MODULATING VARIOUS SIGNALLING CASCADES. NEVERTHELESS, COMPREHENSION OF THIS RISK AGENT-INDUCED NEUROTOXICITY IS FAR TOO LITTLE. MORE IN-DEPTH EPIDEMIOLOGICAL AND SYSTEMATIC INVESTIGATIONS ARE NEEDED TO UNDERSTAND THE POTENTIAL MECHANISMS BETTER TO ADDRESS THESE NEUROTOXICANTS AND IMPROVE APPROACHES TO THEIR RISK EXPOSURE THAT AID IN AD PATHOGENESIS.KEY MESSAGESINEVITABLE CASCADE MECHANISMS OF HOW ALZHEIMER'S DISEASE-RELATED (AD-RELATED) GENE EXPRESSIONS ARE MODULATED BY NEUROTOXICANTS HAVE BEEN DISCUSSED.INVOLVEMENT OF THE NEUROTOXICANTS-INDUCED PATHWAYS CAUSED AN EXTENDED RISK OF AD IS EXPLICITED.INTEGRATION OF CELL CULTURE, ANIMALS AND POPULATION-BASED ANALYSIS ON THE CLINICAL SEVERITY OF AD IS ADDRESSED. 2021 9 6453 40 THIOREDOXIN INTERACTING PROTEIN (TXNIP) INDUCES INFLAMMATION THROUGH CHROMATIN MODIFICATION IN RETINAL CAPILLARY ENDOTHELIAL CELLS UNDER DIABETIC CONDITIONS. CHRONIC HYPERGLYCEMIA AND ACTIVATION OF RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) ARE KNOWN RISK FACTORS FOR MICROVASCULAR DISEASE DEVELOPMENT IN DIABETIC RETINOPATHY. THIOREDOXIN-INTERACTING PROTEIN (TXNIP), AN ENDOGENOUS INHIBITOR OF ANTIOXIDANT THIOREDOXIN (TRX), PLAYS A CAUSATIVE ROLE IN DIABETES AND ITS VASCULAR COMPLICATIONS. HEREIN WE INVESTIGATE WHETHER HG AND RAGE INDUCE INFLAMMATION IN RAT RETINAL ENDOTHELIAL CELLS (EC) UNDER DIABETIC CONDITIONS IN CULTURE THROUGH TXNIP ACTIVATION AND WHETHER EPIGENETIC MECHANISMS PLAY A ROLE IN INFLAMMATORY GENE EXPRESSION. WE SHOW THAT RAGE ACTIVATION BY ITS LIGAND S100B OR HG TREATMENT OF RETINAL EC INDUCES THE EXPRESSION OF TXNIP AND INFLAMMATORY GENES SUCH AS COX2, VEGF-A, AND ICAM1. TXNIP SILENCING BY SIRNA IMPEDES RAGE AND HG EFFECTS WHILE STABLE OVER-EXPRESSION OF A CDNA FOR HUMAN TXNIP IN EC ELEVATES INFLAMMATION. P38 MAPK-NF-KAPPAB SIGNALING PATHWAY AND HISTONE H3 LYSINE (K) NINE MODIFICATIONS ARE INVOLVED IN TXNIP-INDUCED INFLAMMATION. CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAYS REVEAL THAT TXNIP OVER-EXPRESSION IN EC ABOLISHES H3K9 TRI-METHYLATION, A MARKER FOR GENE INACTIVATION, AND INCREASES H3K9 ACETYLATION, AN INDICATOR OF GENE INDUCTION, AT PROXIMAL COX2 PROMOTER BEARING THE NF-KAPPAB-BINDING SITE. THESE FINDINGS HAVE IMPORTANT IMPLICATIONS TOWARD UNDERSTANDING THE MOLECULAR MECHANISMS OF OCULAR INFLAMMATION AND ENDOTHELIAL DYSFUNCTION IN DIABETIC RETINOPATHY. 2009 10 4598 23 NATURAL PRODUCTS: THE ROLE AND MECHANISM IN LOW-DENSITY LIPOPROTEIN OXIDATION AND ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY, METABOLIC, AND EPIGENETIC DISEASE, WHICH LEADS TO THE LIFE-THREATENING CORONARY ARTERY DISEASE. EMERGING STUDIES FROM BENCH TO BEDSIDE HAVE DEMONSTRATED THE PIVOTAL ROLE OF LOW-DENSITY LIPOPROTEIN (LDL) OXIDATION IN THE INITIATION AND PROGRESSION OF ATHEROSCLEROSIS. THIS ARTICLE HEREBY REVIEWS OXIDATION MECHANISM OF LDL, AND THE PRO-ATHEROGENIC AND BIOMARKER ROLE OF OXIDIZED LDL IN ATHEROSCLEROSIS. WE ALSO REVIEW THE PHARMACOLOGICAL EFFECTS OF SEVERAL REPRESENTATIVE NATURAL PRODUCTS (VITAMIN E, RESVERATROL, QUERCETIN, PROBUCOL, TANSHINONE IIA, EPIGALLOCATECHIN GALLATE, AND LYCOPENE) IN PROTECTING AGAINST LDL OXIDATION AND ATHEROSCLEROSIS. CLINICAL AND BASIC RESEARCH SUPPORTS THE BENEFICIAL EFFECTS OF THESE NATURAL PRODUCTS IN INHIBITING LDL OXIDATION AND PREVENTING ATHEROSCLEROSIS, BUT THE DATA ARE STILL CONTROVERSIAL. THIS MAY BE RELATED TO FACTORS SUCH AS THE POPULATION AND THE DOSAGE AND TIME OF TAKING NATURAL PRODUCTS INVOLVED IN DIFFERENT STUDIES. UNDERSTANDING THE MECHANISM OF LDL OXIDATION AND EFFECT OF OXIDIZED LDL HELP RESEARCHERS TO FIND NOVEL THERAPIES AGAINST ATHEROSCLEROSIS. 2021 11 6045 26 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 12 4396 28 MODULATION OF CHRONIC INFLAMMATION BY QUERCETIN: THE BENEFICIAL EFFECTS ON OBESITY. OBESITY HAS BECOME A MAJOR RISK FACTOR FOR THE DEVELOPMENT OF CHRONIC DISEASES SUCH AS INSULIN RESISTANCE, TYPE 2 DIABETES MELLITUS, AND CARDIOVASCULAR DISEASE. MOREOVER, OBESITY INDUCES CHRONIC INFLAMMATION IN ADIPOSE TISSUE, LIVER, SKELETAL MUSCLE, AND THE VASCULAR SYSTEM. QUERCETIN IS THE MAJOR REPRESENTATIVE OF THE FLAVONOID SUBCLASS OF FLAVONOLS, WHICH IS UBIQUITOUSLY CONTAINED WITHIN NATURAL PLANTS SUCH AS GREEN TEA, AND VEGETABLES, INCLUDING ONIONS AND APPLES. RESEARCHERS HAVE FOCUSED GREATER ATTENTION TO THE BENEFICIAL PHYSIOLOGICAL ROLES OF QUERCETIN, WHICH HAS ANTI-OXIDATIVE, ANTI-INFLAMMATORY, AND ANTI-FIBROTIC EFFECTS ON INSULIN RESISTANCE AND ATHEROSCLEROSIS IN OBESITY-RELATED DISEASES. ALSO, THE ANTI-INFLAMMATORY EFFECTS OF QUERCETIN ON INTESTINAL MICROBIOTA HAVE BEEN DEMONSTRATED IN OBESITY. IN ADDITION, THERE IS INCREASING EVIDENCE THAT QUERCETIN IS ASSOCIATED WITH EPIGENETIC ACTIVITIES IN CANCER, AND IN MATERNAL UNDERNUTRITION DURING GESTATION AND LACTATION. IN THIS REVIEW, WE FOCUS ON THE CHEMICAL PROPERTIES OF QUERCETIN, ITS DIETARY SOURCES IN OBESITY, AND ITS ANTI-INFLAMMATORY EFFECTS ON INSULIN RESISTANCE, ATHEROSCLEROSIS, INTESTINAL MICROBIOTA, AND MATERNAL UNDER-NUTRITION WITH EPIGENETIC ACTIVITY. 2020 13 6403 33 THE ROLES OF INDUCIBLE CHROMATIN AND TRANSCRIPTIONAL MEMORY IN CELLULAR DEFENSE SYSTEM RESPONSES TO REDOX-ACTIVE POLLUTANTS. PEOPLE ARE EXPOSED TO WIDE RANGE OF REDOX-ACTIVE ENVIRONMENTAL POLLUTANTS. AIR POLLUTION, HEAVY METALS, PESTICIDES, AND ENDOCRINE DISRUPTING CHEMICALS CAN DISRUPT CELLULAR REDOX STATUS. REDOX-ACTIVE POLLUTANTS IN OUR ENVIRONMENT ALL TRIGGER THEIR OWN SETS OF SPECIFIC CELLULAR RESPONSES, BUT THEY ALSO ACTIVATE A COMMON SET OF GENERAL STRESS RESPONSES THAT BUFFER THE CELL AGAINST HOMEOSTATIC INSULTS. THESE CELLULAR DEFENSE SYSTEM (CDS) PATHWAYS INCLUDE THE HEAT SHOCK RESPONSE, THE OXIDATIVE STRESS RESPONSE, THE HYPOXIA RESPONSE, THE UNFOLDED PROTEIN RESPONSE, THE DNA DAMAGE RESPONSE, AND THE GENERAL STRESS RESPONSE MEDIATED BY THE STRESS-ACTIVATED P38 MITOGEN-ACTIVATED PROTEIN KINASE. OVER THE PAST TWO DECADES, THE FIELD OF ENVIRONMENTAL EPIGENETICS HAS INVESTIGATED EPIGENETIC RESPONSES TO ENVIRONMENTAL POLLUTANTS, INCLUDING REDOX-ACTIVE POLLUTANTS. STUDIES OF THESE RESPONSES HIGHLIGHT THE ROLE OF CHROMATIN MODIFICATIONS IN CONTROLLING THE TRANSCRIPTIONAL RESPONSE TO POLLUTANTS AND THE ROLE OF TRANSCRIPTIONAL MEMORY, OFTEN REFERRED TO AS "EPIGENETIC REPROGRAMMING", IN PREDISPOSING PREVIOUSLY EXPOSED INDIVIDUALS TO MORE POTENT TRANSCRIPTIONAL RESPONSES ON SECONDARY CHALLENGE. MY CENTRAL THESIS IN THIS REVIEW IS THAT HIGH DOSE OR CHRONIC EXPOSURE TO REDOX-ACTIVE POLLUTANTS LEADS TO TRANSCRIPTIONAL MEMORIES AT CDS TARGET GENES THAT INFLUENCE THE CELL'S ABILITY TO MOUNT PROTECTIVE RESPONSES. TO SUPPORT THIS THESIS, I WILL: (1) SUMMARIZE THE KNOWN CHROMATIN FEATURES REQUIRED FOR INDUCIBLE GENE ACTIVATION; (2) REVIEW THE KNOWN FORMS OF TRANSCRIPTIONAL MEMORY; (3) DISCUSS THE ROLES OF INDUCIBLE CHROMATIN AND TRANSCRIPTIONAL MEMORY IN CDS RESPONSES THAT ARE ACTIVATED BY REDOX-ACTIVE ENVIRONMENTAL POLLUTANTS; AND (4) PROPOSE A CONCEPTUAL FRAMEWORK FOR CDS PATHWAY RESPONSIVENESS AS A READOUT OF TOTAL CELLULAR EXPOSURE TO REDOX-ACTIVE POLLUTANTS. 2021 14 4763 30 NRF2-RELATED EPIGENETIC MODIFICATIONS IN CARDIAC AND VASCULAR COMPLICATIONS OF DIABETES MELLITUS. DIABETES MELLITUS (DM) IS A HIGHLY PREVALENT CHRONIC DISEASE THAT IS ACCOMPANIED WITH SERIOUS COMPLICATIONS, ESPECIALLY CARDIAC AND VASCULAR COMPLICATIONS. THUS, THERE IS AN URGENT NEED TO IDENTIFY NEW STRATEGIES TO TREAT DIABETIC CARDIAC AND VASCULAR COMPLICATIONS. NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) HAS BEEN VERIFIED AS A CRUCIAL TARGET FOR THE PREVENTION AND TREATMENT OF DIABETIC COMPLICATIONS. THE FUNCTION OF NRF2 IN THE TREATMENT OF DIABETIC COMPLICATIONS HAS BEEN WIDELY REPORTED, BUT THE ROLE OF NRF2-RELATED EPIGENETIC MODIFICATIONS REMAINS UNCLEAR. THE PURPOSE OF THIS REVIEW IS TO SUMMARIZE THE RECENT ADVANCES IN TARGETING NRF2-RELATED EPIGENETIC MODIFICATIONS IN THE TREATMENT OF CARDIAC AND VASCULAR COMPLICATIONS ASSOCIATED WITH DM. WE ALSO DISCUSS AGONISTS THAT COULD POTENTIALLY REGULATE NRF2-ASSOCIATED EPIGENETIC MECHANISMS. THIS REVIEW PROVIDES A BETTER UNDERSTANDING OF STRATEGIES TO TARGET NRF2 TO PROTECT AGAINST DM-RELATED CARDIAC AND VASCULAR COMPLICATIONS. 2021 15 799 39 CELLULAR SIGNALING AND POTENTIAL NEW TREATMENT TARGETS IN DIABETIC RETINOPATHY. DYSFUNCTION AND DEATH OF MICROVASCULAR CELLS AND IMBALANCE BETWEEN THE PRODUCTION AND THE DEGRADATION OF EXTRACELLULAR MATRIX (ECM) PROTEINS ARE A CHARACTERISTIC FEATURE OF DIABETIC RETINOPATHY (DR). GLUCOSE-INDUCED BIOCHEMICAL ALTERATIONS IN THE VASCULAR ENDOTHELIAL CELLS MAY ACTIVATE A CASCADE OF SIGNALING PATHWAYS LEADING TO INCREASED PRODUCTION OF ECM PROTEINS AND CELLULAR DYSFUNCTION/DEATH. CHRONIC DIABETES LEADS TO THE ACTIVATION OF A NUMBER OF SIGNALING PROTEINS INCLUDING PROTEIN KINASE C, PROTEIN KINASE B, AND MITOGEN-ACTIVATED PROTEIN KINASES. THESE SIGNALING CASCADES ARE ACTIVATED IN RESPONSE TO HYPERGLYCEMIA-INDUCED OXIDATIVE STRESS, POLYOL PATHWAY, AND ADVANCED GLYCATION END PRODUCT FORMATION AMONG OTHERS. THE ABERRANT SIGNALING PATHWAYS ULTIMATELY LEAD TO ACTIVATION OF TRANSCRIPTION FACTORS SUCH AS NUCLEAR FACTOR-KAPPAB AND ACTIVATING PROTEIN-1. THE ACTIVITY OF THESE TRANSCRIPTION FACTORS IS ALSO REGULATED BY EPIGENETIC MECHANISMS THROUGH TRANSCRIPTIONAL COACTIVATOR P300. THESE COMPLEX SIGNALING PATHWAYS MAY BE INVOLVED IN GLUCOSE-INDUCED ALTERATIONS OF ENDOTHELIAL CELL PHENOTYPE LEADING TO THE PRODUCTION OF INCREASED ECM PROTEINS AND VASOACTIVE EFFECTOR MOLECULES CAUSING FUNCTIONAL AND STRUCTURAL CHANGES IN THE MICROVASCULATURE. UNDERSTANDING OF SUCH MECHANISTIC PATHWAYS WILL HELP TO DEVELOP FUTURE ADJUVANT THERAPIES FOR DIABETIC RETINOPATHY. 2007 16 4211 40 METFORMIN FOR CARDIOVASCULAR PROTECTION, INFLAMMATORY BOWEL DISEASE, OSTEOPOROSIS, PERIODONTITIS, POLYCYSTIC OVARIAN SYNDROME, NEURODEGENERATION, CANCER, INFLAMMATION AND SENESCENCE: WHAT IS NEXT? DIABETES IS ACCOMPANIED BY SEVERAL COMPLICATIONS. HIGHER PREVALENCE OF CANCERS, CARDIOVASCULAR DISEASES, CHRONIC KIDNEY DISEASE (CKD), OBESITY, OSTEOPOROSIS, AND NEURODEGENERATIVE DISEASES HAS BEEN REPORTED AMONG PATIENTS WITH DIABETES. METFORMIN IS THE OLDEST ORAL ANTIDIABETIC DRUG AND CAN IMPROVE COEXISTING COMPLICATIONS OF DIABETES. CLINICAL TRIALS AND OBSERVATIONAL STUDIES UNCOVERED THAT METFORMIN CAN REMARKABLY PREVENT OR ALLEVIATE CARDIOVASCULAR DISEASES, OBESITY, POLYCYSTIC OVARIAN SYNDROME (PCOS), OSTEOPOROSIS, CANCER, PERIODONTITIS, NEURONAL DAMAGE AND NEURODEGENERATIVE DISEASES, INFLAMMATION, INFLAMMATORY BOWEL DISEASE (IBD), TUBERCULOSIS, AND COVID-19. IN ADDITION, METFORMIN HAS BEEN PROPOSED AS AN ANTIAGING AGENT. NUMEROUS MECHANISMS WERE SHOWN TO BE INVOLVED IN THE PROTECTIVE EFFECTS OF METFORMIN. METFORMIN ACTIVATES THE LKB1/AMPK PATHWAY TO INTERACT WITH SEVERAL INTRACELLULAR SIGNALING PATHWAYS AND MOLECULAR MECHANISMS. THE DRUG MODIFIES THE BIOLOGIC FUNCTION OF NF-KAPPAB, PI3K/AKT/MTOR, SIRT1/PGC-1ALPHA, NLRP3, ERK, P38 MAPK, WNT/BETA-CATENIN, NRF2, JNK, AND OTHER MAJOR MOLECULES IN THE INTRACELLULAR SIGNALING NETWORK. IT ALSO REGULATES THE EXPRESSION OF NONCODING RNAS. THEREBY, METFORMIN CAN REGULATE METABOLISM, GROWTH, PROLIFERATION, INFLAMMATION, TUMORIGENESIS, AND SENESCENCE. ADDITIONALLY, METFORMIN MODULATES IMMUNE RESPONSE, AUTOPHAGY, MITOPHAGY, ENDOPLASMIC RETICULUM (ER) STRESS, AND APOPTOSIS AND EXERTS EPIGENETIC EFFECTS. FURTHERMORE, METFORMIN PROTECTS AGAINST OXIDATIVE STRESS AND GENOMIC INSTABILITY, PRESERVES TELOMERE LENGTH, AND PREVENTS STEM CELL EXHAUSTION. IN THIS REVIEW, THE PROTECTIVE EFFECTS OF METFORMIN ON EACH DISEASE WILL BE DISCUSSED USING THE RESULTS OF RECENT META-ANALYSES, CLINICAL TRIALS, AND OBSERVATIONAL STUDIES. THEREAFTER, IT WILL BE METICULOUSLY EXPLAINED HOW METFORMIN REPROGRAMS INTRACELLULAR SIGNALING PATHWAYS AND ALTERS MOLECULAR AND CELLULAR INTERACTIONS TO MODIFY THE CLINICAL PRESENTATIONS OF SEVERAL DISEASES. 2021 17 3701 33 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 18 4427 40 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 19 4044 31 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 1416 33 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