1 5052 132 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 2 5391 34 REDOX-RELATED BIOMARKERS IN HUMAN CARDIOVASCULAR DISEASE - CLASSICAL FOOTPRINTS AND BEYOND. GLOBAL EPIDEMIOLOGICAL STUDIES SHOW THAT CHRONIC NON-COMMUNICABLE DISEASES SUCH AS ATHEROSCLEROSIS AND METABOLIC DISORDERS REPRESENT THE LEADING CAUSE OF PREMATURE MORTALITY AND MORBIDITY. CARDIOVASCULAR DISEASE SUCH AS ISCHEMIC HEART DISEASE IS A MAJOR CONTRIBUTOR TO THE GLOBAL BURDEN OF DISEASE AND THE SOCIOECONOMIC HEALTH COSTS. CLINICAL AND EPIDEMIOLOGICAL DATA SHOW AN ASSOCIATION OF TYPICAL OXIDATIVE STRESS MARKERS SUCH AS LIPID PEROXIDATION PRODUCTS, 3-NITROTYROSINE OR OXIDIZED DNA/RNA BASES WITH ALL MAJOR CARDIOVASCULAR DISEASES. THIS SUPPORTS THE CONCEPT THAT THE FORMATION OF REACTIVE OXYGEN AND NITROGEN SPECIES BY VARIOUS SOURCES (NADPH OXIDASES, XANTHINE OXIDASE AND MITOCHONDRIAL RESPIRATORY CHAIN) REPRESENTS A HALLMARK OF THE LEADING CARDIOVASCULAR COMORBIDITIES SUCH AS HYPERLIPIDEMIA, HYPERTENSION AND DIABETES. THESE REACTIVE OXYGEN AND NITROGEN SPECIES CAN LEAD TO OXIDATIVE DAMAGE BUT ALSO ADVERSE REDOX SIGNALING AT THE LEVEL OF KINASES, CALCIUM HANDLING, INFLAMMATION, EPIGENETIC CONTROL, CIRCADIAN CLOCK AND PROTEASOMAL SYSTEM. THE IN VIVO FOOTPRINTS OF THESE ADVERSE PROCESSES (REDOX BIOMARKERS) ARE DISCUSSED IN THE PRESENT REVIEW WITH FOCUS ON THEIR CLINICAL RELEVANCE, WHEREAS THE DETAILS OF THEIR MECHANISMS OF FORMATION AND TECHNICAL ASPECTS OF THEIR DETECTION ARE ONLY BRIEFLY MENTIONED. THE MAJOR CATEGORIES OF REDOX BIOMARKERS ARE SUMMARIZED AND EXPLAINED ON THE BASIS OF SUITABLE EXAMPLES. ALSO THE POTENTIAL PROGNOSTIC VALUE OF REDOX BIOMARKERS IS CRITICALLY DISCUSSED TO UNDERSTAND WHAT KIND OF INFORMATION THEY CAN PROVIDE BUT ALSO WHAT THEY CANNOT ACHIEVE. 2021 3 4652 26 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 4 6166 32 THE GLUTATHIONE SYSTEM: A NEW DRUG TARGET IN NEUROIMMUNE DISORDERS. GLUTATHIONE (GSH) HAS A CRUCIAL ROLE IN CELLULAR SIGNALING AND ANTIOXIDANT DEFENSES EITHER BY REACTING DIRECTLY WITH REACTIVE OXYGEN OR NITROGEN SPECIES OR BY ACTING AS AN ESSENTIAL COFACTOR FOR GSH S-TRANSFERASES AND GLUTATHIONE PEROXIDASES. GSH ACTING IN CONCERT WITH ITS DEPENDENT ENZYMES, KNOWN AS THE GLUTATHIONE SYSTEM, IS RESPONSIBLE FOR THE DETOXIFICATION OF REACTIVE OXYGEN AND NITROGEN SPECIES (ROS/RNS) AND ELECTROPHILES PRODUCED BY XENOBIOTICS. ADEQUATE LEVELS OF GSH ARE ESSENTIAL FOR THE OPTIMAL FUNCTIONING OF THE IMMUNE SYSTEM IN GENERAL AND T CELL ACTIVATION AND DIFFERENTIATION IN PARTICULAR. GSH IS A UBIQUITOUS REGULATOR OF THE CELL CYCLE PER SE. GSH ALSO HAS CRUCIAL FUNCTIONS IN THE BRAIN AS AN ANTIOXIDANT, NEUROMODULATOR, NEUROTRANSMITTER, AND ENABLER OF NEURON SURVIVAL. DEPLETION OF GSH LEADS TO EXACERBATION OF DAMAGE BY OXIDATIVE AND NITROSATIVE STRESS; HYPERNITROSYLATION; INCREASED LEVELS OF PROINFLAMMATORY MEDIATORS AND INFLAMMATORY POTENTIAL; DYSFUNCTIONS OF INTRACELLULAR SIGNALING NETWORKS, E.G., P53, NUCLEAR FACTOR-KAPPAB, AND JANUS KINASES; DECREASED CELL PROLIFERATION AND DNA SYNTHESIS; INACTIVATION OF COMPLEX I OF THE ELECTRON TRANSPORT CHAIN; ACTIVATION OF CYTOCHROME C AND THE APOPTOTIC MACHINERY; BLOCKADE OF THE METHIONINE CYCLE; AND COMPROMISED EPIGENETIC REGULATION OF GENE EXPRESSION. AS SUCH, GSH DEPLETION HAS MARKED CONSEQUENCES FOR THE HOMEOSTATIC CONTROL OF THE IMMUNE SYSTEM, OXIDATIVE AND NITROSATIVE STRESS (O&NS) PATHWAYS, REGULATION OF ENERGY PRODUCTION, AND MITOCHONDRIAL SURVIVAL AS WELL. GSH DEPLETION AND CONCOMITANT INCREASE IN O&NS AND MITOCHONDRIAL DYSFUNCTIONS PLAY A ROLE IN THE PATHOPHYSIOLOGY OF DIVERSE NEUROIMMUNE DISORDERS, INCLUDING DEPRESSION, MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME AND PARKINSON'S DISEASE, SUGGESTING THAT DEPLETED GSH IS AN INTEGRAL PART OF THESE DISEASES. THERAPEUTICAL INTERVENTIONS THAT AIM TO INCREASE GSH CONCENTRATIONS IN VIVO INCLUDE N-ACETYL CYSTEINE; NRF-2 ACTIVATION VIA HYPERBARIC OXYGEN THERAPY; DIMETHYL FUMARATE; PHYTOCHEMICALS, INCLUDING CURCUMIN, RESVERATROL, AND CINNAMON; AND FOLATE SUPPLEMENTATION. 2014 5 6387 30 THE ROLE OF REACTIVE OXYGEN SPECIES IN ARSENIC TOXICITY. ARSENIC POISONING IS A GLOBAL HEALTH PROBLEM. CHRONIC EXPOSURE TO ARSENIC HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF A WIDE RANGE OF DISEASES AND HEALTH PROBLEMS IN HUMANS. ARSENIC EXPOSURE INDUCES THE GENERATION OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS), WHICH MEDIATE MULTIPLE CHANGES TO CELL BEHAVIOR BY ALTERING SIGNALING PATHWAYS AND EPIGENETIC MODIFICATIONS, OR CAUSE DIRECT OXIDATIVE DAMAGE TO MOLECULES. ANTIOXIDANTS WITH THE POTENTIAL TO REDUCE ROS LEVELS HAVE BEEN SHOWN TO AMELIORATE ARSENIC-INDUCED LESIONS. HOWEVER, EMERGING EVIDENCE SUGGESTS THAT CONSTRUCTIVE ACTIVATION OF ANTIOXIDATIVE PATHWAYS AND DECREASED ROS LEVELS CONTRIBUTE TO CHRONIC ARSENIC TOXICITY IN SOME CASES. THIS REVIEW DETAILS THE PATHWAYS INVOLVED IN ARSENIC-INDUCED REDOX IMBALANCE, AS WELL AS CURRENT STUDIES ON PROPHYLAXIS AND TREATMENT STRATEGIES USING ANTIOXIDANTS. 2020 6 616 38 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 7 4044 23 MACROPHAGES IN OXIDATIVE STRESS AND MODELS TO EVALUATE THE ANTIOXIDANT FUNCTION OF DIETARY NATURAL COMPOUNDS. ANTIOXIDANT TESTING OF NATURAL PRODUCTS HAS ATTRACTED INCREASING INTEREST IN RECENT YEARS, MAINLY DUE TO THE FACT THAT AN ANTIOXIDANT-RICH DIET MIGHT PROVIDE HEALTH BENEFITS. ACTIVATED MACROPHAGES ARE A MAJOR SOURCE OF REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES, AND PEROXYNITRITE GENERATED THROUGH THE SO-CALLED RESPIRATORY BURST. CONSTITUTIVELY RELEASED PROINFLAMMATORY CYTOKINE, ESPECIALLY TUMOR NECROSIS FACTOR-ALPHA, TRIGGERS NUCLEAR FACTOR-KAPPAB, AND ACTIVATOR PROTEIN-1 TRANSLOCATION LEADING TO THE OVER PRODUCTION OF REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN SPECIES IN MACROPHAGES. ACTIVATION OF TRANSCRIPTION FACTORS IN THE LONG-LIVED TISSUE-RESIDENT MACROPHAGES AND/OR MONOCYTE-DERIVED MACROPHAGES, TRIGGER EPIGENETIC MODIFICATIONS LEADING TO THE PATHOGENESIS OF CHRONIC DISEASES. NUTRACEUTICALS INCLUDING LIPID RAFT STRUCTURE DISRUPTION AGENT, CHOLESTEROL DEPLETION AGENT, FARNESYLTRANSFERASE INHIBITOR, NUCLEAR FACTOR-KAPPAB BLOCKER (ALPHA,BETA-UNSATURATED CARBONYL COMPOUNDS), GLUCOCORTICOID RECEPTOR AGONIST, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST HAVE LONG BEEN USED TO INACTIVE MACROPHAGE. THE INHIBITION EFFECTS ON THE FORMATION OF NITRIC OXIDE, SUPEROXIDE, AND NITRITE PEROXIDE MAY BE RESPONSIBLE FOR THE ANTI-INFLAMMATORY FUNCTIONALITIES. ACTIVATED MACROPHAGE MODELS COULD BE USED TO IDENTIFY THE ACTIVE COMPONENTS FOR FUNCTIONAL DIETS DEVELOPMENT THROUGH A MULTIPLE TARGETS STRATEGY. 2017 8 5942 35 TARGETING OF CELLULAR REDOX METABOLISM FOR MITIGATION OF RADIATION INJURY. ACCIDENTAL EXPOSURE TO IONIZING RADIATION IS A SERIOUS CONCERN TO HUMAN LIFE. STUDIES ON THE MITIGATION OF SIDE EFFECTS FOLLOWING EXPOSURE TO ACCIDENTAL RADIATION EVENTS ARE ONGOING. RECENT STUDIES HAVE SHOWN THAT RADIATION CAN ACTIVATE SEVERAL SIGNALING PATHWAYS, LEADING TO CHANGES IN THE METABOLISM OF FREE RADICALS INCLUDING REACTIVE OXYGEN SPECIES (ROS) AND NITRIC OXIDE (NO). CELLULAR AND MOLECULAR MECHANISMS SHOW THAT RADIATION CAN CAUSE DISRUPTION OF NORMAL REDUCTION/OXIDATION (REDOX) SYSTEM. MITOCHONDRIA MALFUNCTION FOLLOWING EXPOSURE TO RADIATION AND MUTATIONS IN MITOCHONDRIA DNA (MTDNA) HAVE A KEY ROLE IN CHRONIC OXIDATIVE STRESS. FURTHERMORE, EXPOSURE TO RADIATION LEADS TO INFILTRATION OF INFLAMMATORY CELLS SUCH AS MACROPHAGES, LYMPHOCYTES AND MAST CELLS, WHICH ARE IMPORTANT SOURCES OF ROS AND NO. THESE CELLS GENERATE FREE RADICALS VIA UPREGULATION OF SOME PRO-OXIDANT ENZYMES SUCH AS NADPH OXIDASES, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) AND CYCLOOXYGENASE-2 (COX-2). EPIGENETIC CHANGES ALSO HAVE A KEY ROLE IN A SIMILAR WAY. OTHER MEDIATORS SUCH AS MAMMALIAN TARGET OF RAPAMYCIN (MTOR) AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR), WHICH ARE INVOLVED IN THE NORMAL METABOLISM OF CELLS HAVE ALSO BEEN SHOWN TO REGULATE CELL DEATH FOLLOWING EXPOSURE TO RADIATION. THESE MECHANISMS ARE TISSUE SPECIFIC. INHIBITION OR ACTIVATION OF EACH OF THESE TARGETS CAN BE SUGGESTED FOR MITIGATION OF RADIATION INJURY IN A SPECIFIC TISSUE. IN THE CURRENT PAPER, WE REVIEW THE CELLULAR AND MOLECULAR CHANGES IN THE METABOLISM OF CELLS AND ROS/NO FOLLOWING EXPOSURE TO RADIATION. FURTHERMORE, THE POSSIBLE STRATEGIES FOR MITIGATION OF RADIATION INJURY THROUGH MODULATION OF CELLULAR METABOLISM IN IRRADIATED ORGANS WILL BE DISCUSSED. 2020 9 5409 29 REGULATION OF ACETYLATION STATES BY NUTRIENTS IN THE INHIBITION OF VASCULAR INFLAMMATION AND ATHEROSCLEROSIS. ATHEROSCLEROSIS (AS) IS A CHRONIC METABOLIC DISORDER AND PRIMARY CAUSE OF CARDIOVASCULAR DISEASES, RESULTING IN SUBSTANTIAL MORBIDITY AND MORTALITY WORLDWIDE. INITIATED BY ENDOTHELIAL CELL STIMULATION, AS IS CHARACTERIZED BY ARTERIAL INFLAMMATION, LIPID DEPOSITION, FOAM CELL FORMATION, AND PLAQUE DEVELOPMENT. NUTRIENTS SUCH AS CAROTENOIDS, POLYPHENOLS, AND VITAMINS CAN PREVENT THE ATHEROSCLEROTIC PROCESS BY MODULATING INFLAMMATION AND METABOLIC DISORDERS THROUGH THE REGULATION OF GENE ACETYLATION STATES MEDIATED WITH HISTONE DEACETYLASES (HDACS). NUTRIENTS CAN REGULATE AS-RELATED EPIGENETIC STATES VIA SIRTUINS (SIRTS) ACTIVATION, SPECIFICALLY SIRT1 AND SIRT3. NUTRIENT-DRIVEN ALTERATIONS IN THE REDOX STATE AND GENE MODULATION IN AS PROGRESSION ARE LINKED TO THEIR PROTEIN DEACETYLATING, ANTI-INFLAMMATORY, AND ANTIOXIDANT PROPERTIES. NUTRIENTS CAN ALSO INHIBIT ADVANCED OXIDATION PROTEIN PRODUCT FORMATION, REDUCING ARTERIAL INTIMA-MEDIA THICKNESS EPIGENETICALLY. NONETHELESS, KNOWLEDGE GAPS REMAIN WHEN IT COMES TO UNDERSTANDING EFFECTIVE AS PREVENTION THROUGH EPIGENETIC REGULATION BY NUTRIENTS. THIS WORK REVIEWS AND CONFIRMS THE UNDERLYING MECHANISMS BY WHICH NUTRIENTS PREVENT ARTERIAL INFLAMMATION AND AS, FOCUSING ON THE EPIGENETIC PATHWAYS THAT MODIFY HISTONES AND NON-HISTONE PROTEINS BY REGULATING REDOX AND ACETYLATION STATES THROUGH HDACS SUCH AS SIRTS. THESE FINDINGS MAY SERVE AS A FOUNDATION FOR DEVELOPING POTENTIAL THERAPEUTIC AGENTS TO PREVENT AS AND CARDIOVASCULAR DISEASES BY EMPLOYING NUTRIENTS BASED ON EPIGENETIC REGULATION. 2023 10 4534 29 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 11 293 31 AGING HALLMARKS AND THE ROLE OF OXIDATIVE STRESS. AGING IS A COMPLEX BIOLOGICAL PROCESS ACCOMPANIED BY A PROGRESSIVE DECLINE IN THE PHYSICAL FUNCTION OF THE ORGANISM AND AN INCREASED RISK OF AGE-RELATED CHRONIC DISEASES SUCH AS CARDIOVASCULAR DISEASES, CANCER, AND NEURODEGENERATIVE DISEASES. STUDIES HAVE ESTABLISHED THAT THERE EXIST NINE HALLMARKS OF THE AGING PROCESS, INCLUDING (I) TELOMERE SHORTENING, (II) GENOMIC INSTABILITY, (III) EPIGENETIC MODIFICATIONS, (IV) MITOCHONDRIAL DYSFUNCTION, (V) LOSS OF PROTEOSTASIS, (VI) DYSREGULATED NUTRIENT SENSING, (VII) STEM CELL EXHAUSTION, (VIII) CELLULAR SENESCENCE, AND (IX) ALTERED CELLULAR COMMUNICATION. ALL THESE ALTERATIONS HAVE BEEN LINKED TO SUSTAINED SYSTEMIC INFLAMMATION, AND THESE MECHANISMS CONTRIBUTE TO THE AGING PROCESS IN TIMING NOT CLEARLY DETERMINED YET. NEVERTHELESS, MITOCHONDRIAL DYSFUNCTION IS ONE OF THE MOST IMPORTANT MECHANISMS CONTRIBUTING TO THE AGING PROCESS. MITOCHONDRIA IS THE PRIMARY ENDOGENOUS SOURCE OF REACTIVE OXYGEN SPECIES (ROS). DURING THE AGING PROCESS, THERE IS A DECLINE IN ATP PRODUCTION AND ELEVATED ROS PRODUCTION TOGETHER WITH A DECLINE IN THE ANTIOXIDANT DEFENSE. ELEVATED ROS LEVELS CAN CAUSE OXIDATIVE STRESS AND SEVERE DAMAGE TO THE CELL, ORGANELLE MEMBRANES, DNA, LIPIDS, AND PROTEINS. THIS DAMAGE CONTRIBUTES TO THE AGING PHENOTYPE. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES IN THE MECHANISMS OF AGING WITH AN EMPHASIS ON MITOCHONDRIAL DYSFUNCTION AND ROS PRODUCTION. 2023 12 5381 36 RECONSIDERING THE ROLE OF MITOCHONDRIA IN AGING. BACKGROUND: MITOCHONDRIAL DYSFUNCTION HAS LONG BEEN CONSIDERED A MAJOR CONTRIBUTOR TO AGING AND AGE-RELATED DISEASES. HARMAN'S MITOCHONDRIAL FREE RADICAL THEORY OF AGING POSTULATED THAT SOMATIC MITOCHONDRIAL DNA MUTATIONS THAT ACCUMULATE OVER THE LIFE SPAN CAUSE EXCESSIVE PRODUCTION OF REACTIVE OXYGEN SPECIES THAT DAMAGE MACROMOLECULES AND IMPAIR CELL AND TISSUE FUNCTION. INDEED, STUDIES HAVE SHOWN THAT MAXIMAL OXIDATIVE CAPACITY DECLINES WITH AGE WHILE REACTIVE OXYGEN SPECIES PRODUCTION INCREASES. HARMAN'S HYPOTHESIS HAS BEEN SERIOUSLY CHALLENGED BY RECENT STUDIES SHOWING THAT REACTIVE OXYGEN SPECIES EVOKE METABOLIC HEALTH AND LONGEVITY, PERHAPS THROUGH HORMETIC MECHANISMS THAT INCLUDE AUTOPHAGY. THE PURPOSE OF THIS REVIEW IS TO SCAN THE EVER-GROWING LITERATURE ON MITOCHONDRIA FROM THE PERSPECTIVE OF AGING RESEARCH AND TRY TO IDENTIFY PRIORITY QUESTIONS THAT SHOULD BE ADDRESSED IN FUTURE RESEARCH. METHODS: A SYSTEMATIC SEARCH OF PEER-REVIEWED STUDIES WAS PERFORMED USING PUBMED. SEARCH TERMS INCLUDED (I) MITOCHONDRIA OR MITOCHONDRIAL; (II) AGING, AGEING, OLDER ADULTS OR ELDERLY; AND (III) REACTIVE OXYGEN SPECIES, MITOCHONDRIA DYNAMICS, MITOCHONDRIAL PROTEOSTASIS, CYTOSOL, MITOCHONDRIAL-ASSOCIATED MEMBRANES, REDOX HOMEOSTASIS, ELECTRON TRANSPORT CHAIN, ELECTRON TRANSPORT CHAIN EFFICIENCY, EPIGENETIC REGULATION, DNA HETEROPLASMY. RESULTS: THE IMPORTANCE OF MITOCHONDRIAL BIOLOGY AS A TRAIT D'UNION BETWEEN THE BASIC BIOLOGY OF AGING AND THE PATHOGENESIS OF AGE-RELATED DISEASES IS STRONGER THAN EVER, ALTHOUGH THE EMPHASIS HAS MOVED FROM REACTIVE OXYGEN SPECIES PRODUCTION TO OTHER ASPECTS OF MITOCHONDRIAL PHYSIOLOGY, INCLUDING MITOCHONDRIAL BIOGENESIS AND TURNOVER, ENERGY SENSING, APOPTOSIS, SENESCENCE, AND CALCIUM DYNAMICS. CONCLUSIONS: MITOCHONDRIA COULD PLAY A KEY ROLE IN THE PATHOPHYSIOLOGY OF AGING OR IN THE EARLIER STAGES OF SOME EVENTS THAT LEAD TO THE AGING PHENOTYPE. THEREFORE, MITOCHONDRIA WILL INCREASINGLY BE TARGETED TO PREVENT AND TREAT CHRONIC DISEASES AND TO PROMOTE HEALTHY AGING. 2015 13 5390 26 REDOX-FIBROSIS: IMPACT OF TGFBETA1 ON ROS GENERATORS, MEDIATORS AND FUNCTIONAL CONSEQUENCES. FIBROSIS IS ONE OF THE MOST PREVALENT FEATURES OF AGE-RELATED DISEASES LIKE OBESITY, DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, CHRONIC KIDNEY DISEASE, OR CARDIOMYOPATHY AND AFFECTS MILLIONS OF PEOPLE IN ALL COUNTRIES. ALTHOUGH THE UNDERSTANDING ABOUT THE PATHOPHYSIOLOGY OF FIBROSIS HAS IMPROVED A LOT DURING THE RECENT YEARS, A NUMBER OF MECHANISMS STILL REMAIN UNKNOWN. ALTHOUGH TGF-BETA1 SIGNALING, LOSS OF METABOLIC HOMEOSTASIS AND CHRONIC LOW-GRADE INFLAMMATION APPEAR TO PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF FIBROSIS, RECENT EVIDENCE INDICATES THAT OXIDATIVE STRESS AND THE ANTIOXIDANT SYSTEM MAY ALSO BE CRUCIAL FOR FIBROSIS DEVELOPMENT AND PERSISTENCE. THESE FINDINGS POINT TO A CONCEPT OF A REDOX-FIBROSIS WHERE THE CELLULAR OXIDANT AND ANTIOXIDANT SYSTEM COULD BE POTENTIAL THERAPEUTIC TARGETS. THE CURRENT REVIEW AIMS TO SUMMARIZE THE EXISTING LINKS BETWEEN TGF-BETA1 SIGNALING, GENERATION AND ACTION OF REACTIVE OXYGEN SPECIES, EXPRESSION OF ANTIOXIDATIVE ENZYMES, AND FUNCTIONAL CONSEQUENCES INCLUDING EPIGENETIC REDOX-MEDIATED RESPONSES DURING FIBROSIS. 2015 14 5580 31 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 15 6403 30 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 16 6374 36 THE ROLE OF MITOCHONDRIA IN MYOCARDIAL DAMAGE CAUSED BY ENERGY METABOLISM DISORDERS: FROM MECHANISMS TO THERAPEUTICS. MYOCARDIAL DAMAGE IS THE MOST SERIOUS PATHOLOGICAL CONSEQUENCE OF CARDIOVASCULAR DISEASES AND AN IMPORTANT REASON FOR THEIR HIGH MORTALITY. IN RECENT YEARS, BECAUSE OF THE HIGH PREVALENCE OF SYSTEMIC ENERGY METABOLISM DISORDERS (E.G., OBESITY, DIABETES MELLITUS, AND METABOLIC SYNDROME), COMPLICATIONS OF MYOCARDIAL DAMAGE CAUSED BY THESE DISORDERS HAVE ATTRACTED WIDESPREAD ATTENTION. ENERGY METABOLISM DISORDERS ARE INDEPENDENT OF TRADITIONAL INJURY-RELATED RISK FACTORS, SUCH AS ISCHEMIA, HYPOXIA, TRAUMA, AND INFECTION. AN IMBALANCE OF MYOCARDIAL METABOLIC FLEXIBILITY AND MYOCARDIAL ENERGY DEPLETION ARE USUALLY THE INITIAL CHANGES OF MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS, AND ABNORMAL MORPHOLOGY AND FUNCTIONAL DESTRUCTION OF THE MITOCHONDRIA ARE THEIR IMPORTANT FEATURES. SPECIFICALLY, MITOCHONDRIA ARE THE CENTERS OF ENERGY METABOLISM, AND RECENT EVIDENCE HAS SHOWN THAT DECREASED MITOCHONDRIAL FUNCTION, CAUSED BY AN IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL, MAY PLAY A KEY ROLE IN MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS. UNDER CHRONIC ENERGY STRESS, MITOCHONDRIA UNDERGO PATHOLOGICAL FISSION, WHILE MITOPHAGY, MITOCHONDRIAL FUSION, AND BIOGENESIS ARE INHIBITED, AND MITOCHONDRIAL PROTEIN BALANCE AND TRANSFER ARE DISTURBED, RESULTING IN THE ACCUMULATION OF NONFUNCTIONAL AND DAMAGED MITOCHONDRIA. CONSEQUENTLY, DAMAGED MITOCHONDRIA LEAD TO MYOCARDIAL ENERGY DEPLETION AND THE ACCUMULATION OF LARGE AMOUNTS OF REACTIVE OXYGEN SPECIES, FURTHER AGGRAVATING THE IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL AND FORMING A VICIOUS CYCLE. IN ADDITION, IMPAIRED MITOCHONDRIA COORDINATE CALCIUM HOMEOSTASIS IMBALANCE, AND EPIGENETIC ALTERATIONS PARTICIPATE IN THE PATHOGENESIS OF MYOCARDIAL DAMAGE. THESE PATHOLOGICAL CHANGES INDUCE RAPID PROGRESSION OF MYOCARDIAL DAMAGE, EVENTUALLY LEADING TO HEART FAILURE OR SUDDEN CARDIAC DEATH. TO INTERVENE MORE SPECIFICALLY IN THE MYOCARDIAL DAMAGE CAUSED BY METABOLIC DISORDERS, WE NEED TO UNDERSTAND THE SPECIFIC ROLE OF MITOCHONDRIA IN THIS CONTEXT IN DETAIL. ACCORDINGLY, PROMISING THERAPEUTIC STRATEGIES HAVE BEEN PROPOSED. WE ALSO SUMMARIZE THE EXISTING THERAPEUTIC STRATEGIES TO PROVIDE A REFERENCE FOR CLINICAL TREATMENT AND DEVELOPING NEW THERAPIES. 2023 17 4895 35 OXIDATIVE STRESS DRIVERS AND MODULATORS IN OBESITY AND CARDIOVASCULAR DISEASE: FROM BIOMARKERS TO THERAPEUTIC APPROACH. THIS REVIEW ARTICLE IS INTENDED TO DESCRIBE HOW OXIDATIVE STRESS REGULATES CARDIOVASCULAR DISEASE DEVELOPMENT AND PROGRESSION. EPIGENETIC MECHANISMS RELATED TO OXIDATIVE STRESS, AS WELL AS MORE RELIABLE BIOMARKERS OF OXIDATIVE STRESS, ARE EMERGING OVER THE LAST YEARS AS POTENTIALLY USEFUL TOOLS TO DESIGN THERAPEUTIC APPROACHES AIMED AT MODULATING ENHANCED OXIDATIVE STRESS "IN VIVO", THEREBY MITIGATING THE CONSEQUENT ATHEROSCLEROTIC BURDEN. AS A PARADIGM, WE DESCRIBE THE CASE OF OBESITY, IN WHICH THE INTERTWINING AMONG OXIDATIVE STRESS, DUE TO CALORIC OVERLOAD, CHRONIC LOW-GRADE INFLAMMATION INDUCED BY ADIPOSE TISSUE DYSFUNCTION, AND PLATELET ACTIVATION REPRESENTS A VICIOUS CYCLE FAVORING THE PROGRESSION OF ATHEROTHROMBOSIS. OXIDATIVE STRESS IS A MAJOR PLAYER IN THE PATHOBIOLOGY OF CARDIOVASCULAR DISEASE (CVD). REACTIVE OXYGEN SPECIES (ROS)- DEPENDENT SIGNALING PATHWAYS PROMPT TRANSCRIPTIONAL AND EPIGENETIC DYSREGULATION, INDUCING CHRONIC LOW-GRADE INFLAMMATION, PLATELET ACTIVATION AND ENDOTHELIAL DYSFUNCTION. IN ADDITION, SEVERAL OXIDATIVE BIOMARKERS HAVE BEEN PROPOSED WITH THE POTENTIAL TO IMPROVE CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING CVD. THESE INCLUDE ROS-GENERATING AND/OR QUENCHING MOLECULES, AND ROS-MODIFIED COMPOUNDS, SUCH AS F2-ISOPROSTANES. THERE IS ALSO INCREASING EVIDENCE THAT NONCODING MICRO- RNA (MI-RNA) ARE CRITICALLY INVOLVED IN POST- TRANSCRIPTIONAL REGULATION OF CELL FUNCTIONS, INCLUDING ROS GENERATION, INFLAMMATION, REGULATION OF CELL PROLIFERATION, ADIPOCYTE DIFFERENTIATION, ANGIOGENESIS AND APOPTOSIS. THESE MOLECULES HAVE PROMISING TRANSLATIONAL POTENTIAL AS BOTH MARKERS OF DISEASE AND SITE OF TARGETED INTERVENTIONS. FINALLY, OXIDATIVE STRESS IS A CRITICAL TARGET OF SEVERAL CARDIOPROTECTIVE DRUGS AND NUTRACEUTICALS, INCLUDING ANTIDIABETIC AGENTS, STATINS, RENIN-ANGIOTENSIN SYSTEM BLOCKERS, POLYPHENOLS AND OTHER ANTIOXIDANTS. FURTHER UNDERSTANDING OF ROS-GENERATING MECHANISMS, THEIR BIOLOGICAL ROLE AS WELL AS POTENTIAL THERAPEUTIC IMPLICATIONS WOULD TRANSLATE INTO CONSISTENT BENEFITS FOR EFFECTIVE CV PREVENTION. 2015 18 6436 27 THERAPEUTIC ACTIONS OF TEA PHENOLIC COMPOUNDS AGAINST OXIDATIVE STRESS AND INFLAMMATION AS CENTRAL MEDIATORS IN THE DEVELOPMENT AND PROGRESSION OF HEALTH PROBLEMS: A REVIEW FOCUSING ON MICRORNA REGULATION. MANY HEALTH PROBLEMS INCLUDING CHRONIC DISEASES ARE CLOSELY ASSOCIATED WITH OXIDATIVE STRESS AND INFLAMMATION. TEA HAS ABUNDANT PHENOLIC COMPOUNDS WITH VARIOUS HEALTH BENEFITS INCLUDING ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES. THIS REVIEW FOCUSES ON THE PRESENT UNDERSTANDING OF THE IMPACT OF TEA PHENOLIC COMPOUNDS ON THE EXPRESSION OF MIRNAS, AND ELUCIDATES THE BIOCHEMICAL AND MOLECULAR MECHANISMS UNDERLYING THE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL PROTECTIVE ACTIONS OF TEA PHENOLIC COMPOUNDS AGAINST OXIDATIVE STRESS- AND/OR INFLAMMATION-MEDIATED DISEASES. CLINICAL STUDIES SHOWED THAT DRINKING TEA OR TAKING CATECHIN SUPPLEMENT ON A DAILY BASIS PROMOTED THE ENDOGENOUS ANTIOXIDANT DEFENSE SYSTEM OF THE BODY WHILE INHIBITING INFLAMMATORY FACTORS. THE REGULATION OF CHRONIC DISEASES BASED ON EPIGENETIC MECHANISMS, AND THE EPIGENETIC-BASED THERAPIES INVOLVING DIFFERENT TEA PHENOLIC COMPOUNDS, HAVE BEEN INSUFFICIENTLY STUDIED. THE MOLECULAR MECHANISMS AND APPLICATION STRATEGIES OF MIR-27 AND MIR-34 INVOLVED IN OXIDATIVE STRESS RESPONSE AND MIR-126 AND MIR-146 INVOLVED IN INFLAMMATION PROCESS WERE PRELIMINARILY INVESTIGATED. SOME EMERGING EVIDENCE SUGGESTS THAT TEA PHENOLIC COMPOUNDS MAY PROMOTE EPIGENETIC CHANGES, INVOLVING NON-CODING RNA REGULATION, DNA METHYLATION, HISTONE MODIFICATION, UBIQUITIN AND SUMO MODIFICATIONS. HOWEVER, EPIGENETIC MECHANISMS AND EPIGENETIC-BASED DISEASE THERAPIES INVOLVING PHENOLIC COMPOUNDS FROM DIFFERENT TEAS, AND THE POTENTIAL CROSS-TALKS AMONG THE EPIGENETIC EVENTS, REMAIN UNDERSTUDIED. 2023 19 4396 23 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 20 6441 23 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