1 4652 99 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 2 293 30 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 3 4895 31 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 4 4891 23 OXIDATIVE STRESS AND INFLAMMATORY MARKERS IN PREDIABETES AND DIABETES. PREDIABETES IS A STATE OF ELEVATED PLASMA GLUCOSE IN WHICH THE THRESHOLD FOR DIABETES HAS NOT YET BEEN REACHED AND CAN PREDISPOSE TO THE DEVELOPMENT OF TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. INSULIN RESISTANCE AND IMPAIRED BETA-CELL FUNCTION ARE OFTEN ALREADY PRESENT IN PREDIABETES. HYPERGLYCEMIA CAN UPREGULATE MARKERS OF CHRONIC INFLAMMATION AND CONTRIBUTE TO INCREASED REACTIVE OXYGEN SPECIES (ROS) GENERATION, WHICH ULTIMATELY CAUSE VASCULAR DYSFUNCTION. CONVERSELY, INCREASED OXIDATIVE STRESS AND INFLAMMATION CAN LEAD TO INSULIN RESISTANCE AND IMPAIRED INSULIN SECRETION. PROPER TREATMENT OF HYPERGLYCEMIA AND INHIBITION OF ROS OVERPRODUCTION IS CRUCIAL FOR DELAYING ONSET OF DIABETES AND FOR PREVENTION OF CARDIOVASCULAR COMPLICATIONS. THUS, IT IS IMPERATIVE TO DETERMINE THE MECHANISMS INVOLVED IN THE PROGRESSION FROM PREDIABETES TO DIABETES INCLUDING A CLARIFICATION OF HOW OLD AND NEW MEDICATIONS AFFECT OXIDATIVE AND IMMUNE MECHANISMS OF DIABETES. IN THIS REVIEW, WE DISCUSS THE RELATIONSHIP BETWEEN OXIDATIVE STRESS AND HYPERGLYCEMIA ALONG WITH LINKS BETWEEN INFLAMMATION AND PREDIABETES. ADDITIONALLY, THE EFFECTS OF HYPERGLYCEMIC MEMORY, MICROVESICLES, MICRO-RNA, AND EPIGENETIC REGULATION ON INFLAMMATION, OXIDATIVE STATE, AND GLYCEMIC CONTROL ARE HIGHLIGHTED. ADIPOSE TISSUE AND THEIR INFLUENCE ON CHRONIC INFLAMMATION ARE ALSO BRIEFLY REVIEWED. FINALLY, THE ROLE OF IMMUNE-TARGETED THERAPIES AND ANTI-DIABETIC MEDICATION ON GLYCEMIC CONTROL AND OXIDATIVE STRESS ARE DISCUSSED. 2019 5 6374 28 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 6 6205 33 THE INFLUENCE OF PLANT EXTRACTS AND PHYTOCONSTITUENTS ON ANTIOXIDANT ENZYMES ACTIVITY AND GENE EXPRESSION IN THE PREVENTION AND TREATMENT OF IMPAIRED GLUCOSE HOMEOSTASIS AND DIABETES COMPLICATIONS. DIABETES IS A COMPLEX METABOLIC DISORDER RESULTING EITHER FROM INSULIN RESISTANCE OR AN IMPAIRED INSULIN SECRETION. PROLONGED ELEVATED BLOOD GLUCOSE CONCENTRATION, THE KEY CLINICAL SIGN OF DIABETES, INITIATES AN ENHANCEMENT OF REACTIVE OXYGEN SPECIES DERIVED FROM GLUCOSE AUTOXIDATION AND GLYCOSYLATION OF PROTEINS. CONSEQUENTLY, CHRONIC OXIDATIVE STRESS OVERWHELMS CELLULAR ENDOGENOUS ANTIOXIDANT DEFENSES AND LEADS TO THE ACUTE AND LONG-STANDING STRUCTURAL AND FUNCTIONAL CHANGES OF MACROMOLECULES RESULTING IN IMPAIRED CELLULAR FUNCTIONING, CELL DEATH AND ORGAN DYSFUNCTION. THE OXIDATIVE STRESS PROVOKED CHAIN OF PATHOLOGICAL EVENTS OVER TIME CAUSE DIABETIC COMPLICATIONS SUCH AS NEPHROPATHY, PERIPHERAL NEUROPATHY, CARDIOMYOPATHY, RETINOPATHY, HYPERTENSION, AND LIVER DISEASE. UNDER DIABETIC CONDITIONS, ACCOMPANYING GENOME/EPIGENOME AND METABOLITE MARKERS ALTERATIONS MAY ALSO AFFECT GLUCOSE HOMEOSTASIS, PANCREATIC BETA-CELLS, MUSCLE, LIVER, AND ADIPOSE TISSUE. BY PROVIDING DEEPER GENETIC/EPIGENETIC INSIGHT OF DIRECT OR INDIRECT DIETARY EFFECTS, NUTRIGENOMICS OFFERS A PROMISING OPPORTUNITY TO IMPROVE THE QUALITY OF LIFE OF DIABETIC PATIENTS. NATURAL PLANT EXTRACTS, OR THEIR NATURALLY OCCURRING COMPOUNDS, WERE SHOWN TO BE VERY PROFICIENT IN THE PREVENTION AND TREATMENT OF DIFFERENT PATHOLOGIES ASSOCIATED WITH OXIDATIVE STRESS INCLUDING DIABETES AND ITS COMPLICATIONS. CONSIDERING THAT FOOD INTAKE IS ONE OF THE CRUCIAL COMPONENTS IN DIABETES' PREVALENCE, PROGRESSION AND COMPLICATIONS, THIS REVIEW SUMMARIZES THE EFFECT OF THE MAJOR PLANT SECONDARY METABOLITE AND PHYTOCONSTITUENTS ON THE ANTIOXIDANT ENZYMES ACTIVITY AND GENE EXPRESSION UNDER DIABETIC CONDITIONS. 2021 7 5391 30 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 8 4893 27 OXIDATIVE STRESS BIOMARKERS IN THE RELATIONSHIP BETWEEN TYPE 2 DIABETES AND AIR POLLUTION. THE INCIDENCE AND PREVALENCE OF TYPE 2 DIABETES HAVE INCREASED IN THE LAST DECADES AND ARE EXPECTED TO FURTHER GROW IN THE COMING YEARS. CHRONIC HYPERGLYCEMIA TRIGGERS FREE RADICAL GENERATION AND CAUSES INCREASED OXIDATIVE STRESS, AFFECTING A NUMBER OF MOLECULAR MECHANISMS AND CELLULAR PATHWAYS, INCLUDING THE GENERATION OF ADVANCED GLYCATION END PRODUCTS, PROINFLAMMATORY AND PROCOAGULANT EFFECTS, INDUCTION OF APOPTOSIS, VASCULAR SMOOTH-MUSCLE CELL PROLIFERATION, ENDOTHELIAL AND MITOCHONDRIAL DYSFUNCTION, REDUCTION OF NITRIC OXIDE RELEASE, AND ACTIVATION OF PROTEIN KINASE C. AMONG TYPE 2 DIABETES DETERMINANTS, MANY DATA HAVE DOCUMENTED THE ADVERSE EFFECTS OF ENVIRONMENTAL FACTORS (E.G., AIR POLLUTANTS) THROUGH MULTIPLE EXPOSURE-INDUCED MECHANISMS (E.G., SYSTEMIC INFLAMMATION AND OXIDATIVE STRESS, HYPERCOAGULABILITY, AND ENDOTHELIAL AND IMMUNE RESPONSES). THEREFORE, HERE WE DISCUSS THE ROLE OF AIR POLLUTION IN OXIDATIVE STRESS-RELATED DAMAGE TO GLYCEMIC METABOLISM HOMEOSTASIS, WITH A PARTICULAR FOCUS ON ITS IMPACT ON HEALTH. IN THIS CONTEXT, THE IMPROVEMENT OF NEW ADVANCED TOOLS (E.G., OMIC TECHNIQUES AND THE STUDY OF EPIGENETIC CHANGES) MAY PROVIDE A SUBSTANTIAL CONTRIBUTION, HELPING IN THE EVALUATION OF THE INDIVIDUAL IN HIS BIOLOGICAL TOTALITY, AND OFFER A COMPREHENSIVE ASSESSMENT OF THE MOLECULAR, CLINICAL, ENVIRONMENTAL, AND EPIDEMIOLOGICAL ASPECTS. 2021 9 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 10 4044 25 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 11 4896 30 OXIDATIVE STRESS IN AIRWAY DISEASES. AIRWAY OXIDATIVE STRESS IS BROADLY DEFINED AS AN IMBALANCE BETWEEN PROOXIDATIVE AND ANTIOXIDATIVE PROCESSES IN THE AIRWAY. GIVEN ITS DIRECT EXPOSURE TO THE ENVIRONMENT, THE LUNG HAS SEVERAL MECHANISMS TO PREVENT AN EXCESSIVE DEGREE OF OXIDATIVE STRESS. BOTH ENZYMATIC AND NONENZYMATIC SYSTEMS CAN BUFFER A WIDE RANGE OF REACTIVE OXIDATIVE SPECIES AND OTHER COMPOUNDS WITH OXIDATIVE POTENTIAL. IN DISEASES LIKE ASTHMA AND CHRONIC OBSTRUCTIVE LUNG DISEASE, AIRWAY OXIDATIVE STRESS CAN OCCUR FROM A NUMBER OF SOURCES, INCLUDING GREATER EXPOSURE TO ENVIRONMENTAL PROOXIDANTS, AIRWAY INFILTRATION OF INFLAMMATORY CELLS, METABOLIC DEREGULATION, AND REDUCED LEVELS OF ANTIOXIDANTS. AIRWAY OXIDATIVE STRESS HAS BEEN ASSOCIATED WITH WORSE DISEASE SEVERITY, REDUCED LUNG FUNCTION, AND EPIGENETIC CHANGES THAT CAN DIMINISH RESPONSE TO STEROIDS. ALTHOUGH OXIDATIVE STRESS HAS BEEN LINKED TO A WIDE RANGE OF ADVERSE BIOLOGICAL EFFECTS, IT HAS ALSO BEEN ASSOCIATED WITH ADAPTIVE RESPONSES AND WITH RESOLUTION OF INFLAMMATION. THEREFORE, MORE THAN BEING AN IMBALANCE WITH A PREDICTABLE THRESHOLD AFTER WHICH DISEASE OR INJURY ENSUES, OXIDATIVE STRESS IS A DYNAMIC AND CONTINUOUS PROCESS. THIS MIGHT EXPLAIN WHY SUPPLEMENTING ANTIOXIDANTS HAS LARGELY FAILED TO IMPROVE DISEASES SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, THE THERAPEUTIC POTENTIAL OF ANTIOXIDANTS COULD BE GREATLY IMPROVED BY TAKING AN APPROACH THAT CONSIDERS INDIVIDUAL AND ENVIRONMENTAL RISK FACTORS, INSTEAD OF TREATING OXIDATIVE AIRWAY STRESS BROADLY. 2013 12 5390 25 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 13 5826 24 STRESS SIGNAL NETWORK BETWEEN HYPOXIA AND ER STRESS IN CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS CHARACTERIZED BY AN IRREVERSIBLE DECREASE IN KIDNEY FUNCTION AND INDUCTION OF VARIOUS METABOLIC DYSFUNCTIONS. ACCUMULATED FINDINGS REVEAL THAT CHRONIC HYPOXIC STRESS AND ENDOPLASMIC RETICULUM (ER) STRESS ARE INVOLVED IN A RANGE OF PATHOGENIC CONDITIONS, INCLUDING THE PROGRESSION OF CKD. BECAUSE OF THE PRESENCE OF AN ARTERIOVENOUS OXYGEN SHUNT, THE KIDNEY IS THOUGHT TO BE SUSCEPTIBLE TO HYPOXIA. CHRONIC KIDNEY HYPOXIA IS INDUCED BY A NUMBER OF PATHOGENIC CONDITIONS, INCLUDING RENAL ISCHEMIA, REDUCED PERITUBULAR CAPILLARY, AND TUBULOINTERSTITIAL FIBROSIS. THE ER IS AN ORGANELLE WHICH HELPS MAINTAIN THE QUALITY OF PROTEINS THROUGH THE UNFOLDED PROTEIN RESPONSE (UPR) PATHWAY, AND ER DYSFUNCTION ASSOCIATED WITH MALADAPTIVE UPR ACTIVATION IS NAMED ER STRESS. ER STRESS IS REPORTED TO BE RELATED TO SOME OF THE EFFECTS OF PATHOGENESIS IN KIDNEY, PARTICULARLY IN THE PODOCYTE SLIT DIAPHRAGM AND TUBULOINTERSTITIUM. FURTHERMORE, CHRONIC HYPOXIA MEDIATES ER STRESS IN BLOOD VESSEL ENDOTHELIAL CELLS AND TUBULOINTERSTITIUM VIA SEVERAL MECHANISMS, INCLUDING OXIDATIVE STRESS, EPIGENETIC ALTERATION, LIPID METABOLISM, AND THE AKT PATHWAY. IN SUMMARY, A GROWING CONSENSUS CONSIDERS THAT THESE STRESSES INTERACT VIA COMPLICATED STRESS SIGNAL NETWORKS, WHICH LEADS TO THE EXACERBATION OF CKD (FIGURE 1). THIS STRESS SIGNAL NETWORK MIGHT BE A TARGET FOR INTERVENTIONS AIMED AT AMELIORATING CKD. 2017 14 4380 25 MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS IN RHEUMATOID ARTHRITIS. CONTROL OF EXCESSIVE MITOCHONDRIAL OXIDATIVE STRESS COULD PROVIDE NEW TARGETS FOR BOTH PREVENTIVE AND THERAPEUTIC INTERVENTIONS IN THE TREATMENT OF CHRONIC INFLAMMATION OR ANY PATHOLOGY THAT DEVELOPS UNDER AN INFLAMMATORY SCENARIO, SUCH AS RHEUMATOID ARTHRITIS (RA). INCREASING EVIDENCE HAS DEMONSTRATED THE ROLE OF MITOCHONDRIAL ALTERATIONS IN AUTOIMMUNE DISEASES MAINLY DUE TO THE INTERPLAY BETWEEN METABOLISM AND INNATE IMMUNITY, BUT ALSO IN THE MODULATION OF INFLAMMATORY RESPONSE OF RESIDENT CELLS, SUCH AS SYNOVIOCYTES. THUS, MITOCHONDRIAL DYSFUNCTION DERIVED FROM SEVERAL DANGER SIGNALS COULD ACTIVATE TRICARBOXYLIC ACID (TCA) DISRUPTION, THEREBY FAVORING A VICIOUS CYCLE OF OXIDATIVE/MITOCHONDRIAL STRESS. MITOCHONDRIAL DYSFUNCTION CAN ACT THROUGH MODULATING INNATE IMMUNITY VIA REDOX-SENSITIVE INFLAMMATORY PATHWAYS OR DIRECT ACTIVATION OF THE INFLAMMASOME. BESIDES, MITOCHONDRIA ALSO HAVE A CENTRAL ROLE IN REGULATING CELL DEATH, WHICH IS DEEPLY ALTERED IN RA. ADDITIONALLY, MULTIPLE EVIDENCE SUGGESTS THAT PATHOLOGICAL PROCESSES IN RA CAN BE SHAPED BY EPIGENETIC MECHANISMS AND THAT IN TURN, MITOCHONDRIA ARE INVOLVED IN EPIGENETIC REGULATION. FINALLY, WE WILL DISCUSS ABOUT THE INVOLVEMENT OF SOME DIETARY COMPONENTS IN THE ONSET AND PROGRESSION OF RA. 2022 15 6387 22 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 16 1254 26 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 17 4534 27 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 18 4898 24 OXIDATIVE STRESS INDUCED LUNG CANCER AND COPD: OPPORTUNITIES FOR EPIGENETIC THERAPY. REACTIVE OXYGEN SPECIES (ROS) FORM AS A NATURAL BY-PRODUCT OF THE NORMAL METABOLISM OF OXYGEN AND PLAY IMPORTANT ROLES WITHIN THE CELL. UNDER NORMAL CIRCUMSTANCES THE CELL IS ABLE TO MAINTAIN AN ADEQUATE HOMEOSTASIS BETWEEN THE FORMATION OF ROS AND ITS REMOVAL THROUGH PARTICULAR ENZYMATIC PATHWAYS OR VIA ANTIOXIDANTS. IF HOWEVER, THIS BALANCE IS DISTURBED A SITUATION CALLED OXIDATIVE STRESS OCCURS. CRITICALLY, OXIDATIVE STRESS PLAYS IMPORTANT ROLES IN THE PATHOGENESIS OF MANY DISEASES, INCLUDING CANCER. EPIGENETICS IS A PROCESS WHERE GENE EXPRESSION IS REGULATED BY HERITABLE MECHANISMS THAT DO NOT CAUSE ANY DIRECT CHANGES TO THE DNA SEQUENCE ITSELF, AND DISRUPTION OF EPIGENETIC MECHANISMS HAS IMPORTANT IMPLICATIONS IN DISEASE. EVIDENCE IS EMERGING THAT HISTONE DEACETYLASES (HDACS) PLAY DECISIVE ROLES IN REGULATING IMPORTANT CELLULAR OXIDATIVE STRESS PATHWAYS INCLUDING THOSE INVOLVED WITH SENSING OXIDATIVE STRESS AND THOSE INVOLVED WITH REGULATING THE CELLULAR RESPONSE TO OXIDATIVE STRESS. IN PARTICULAR ABERRANT REGULATION OF THESE PATHWAYS BY HDACS MAY PLAY CRITICAL ROLES IN CANCER PROGRESSION. IN THIS REVIEW WE DISCUSS THE CURRENT EVIDENCE LINKING EPIGENETICS AND OXIDATIVE STRESS AND CANCER, USING CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND NON-SMALL CELL LUNG CANCER TO ILLUSTRATE THE IMPORTANCE OF EPIGENETICS ON THESE PATHWAYS WITHIN THESE DISEASE SETTINGS. 2009 19 5943 26 TARGETING OXIDATIVE STRESS IN CANCER. IMPORTANCE OF THE FIELD: REACTIVE OXYGEN SPECIES (ROS) OCCUR AS NATURAL BY-PRODUCTS OF OXYGEN METABOLISM AND HAVE IMPORTANT CELLULAR FUNCTIONS. NORMALLY, THE CELL IS ABLE TO MAINTAIN AN ADEQUATE BALANCE BETWEEN THE FORMATION AND REMOVAL OF ROS EITHER VIA ANTI-OXIDANTS OR THROUGH THE USE SPECIFIC ENZYMATIC PATHWAYS. HOWEVER, IF THIS BALANCE IS DISTURBED, OXIDATIVE STRESS MAY OCCUR IN THE CELL, A SITUATION LINKED TO THE PATHOGENESIS OF MANY DISEASES, INCLUDING CANCER. AREAS COVERED IN THIS REVIEW: HDACS ARE IMPORTANT REGULATORS OF MANY OXIDATIVE STRESS PATHWAYS INCLUDING THOSE INVOLVED WITH BOTH SENSING AND COORDINATING THE CELLULAR RESPONSE TO OXIDATIVE STRESS. IN PARTICULAR ABERRANT REGULATION OF THESE PATHWAYS BY HISTONE DEACETYLASES MAY PLAY CRITICAL ROLES IN CANCER PROGRESSION. WHAT THE READER WILL GAIN: IN THIS REVIEW WE DISCUSS THE NOTION THAT TARGETING HDACS MAY BE A USEFUL THERAPEUTIC AVENUE IN THE TREATMENT OF OXIDATIVE STRESS IN CANCER, USING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), NSCLC AND HEPATOCELLULAR CARCINOMA (HCC) AS EXAMPLES TO ILLUSTRATE THIS POSSIBILITY. TAKE HOME MESSAGE: EPIGENETIC MECHANISMS MAY BE AN IMPORTANT NEW THERAPEUTIC AVENUE FOR TARGETING OXIDATIVE STRESS IN CANCER. 2010 20 4486 24 MOLECULAR, GENETIC AND EPIGENETIC PATHWAYS OF PEROXYNITRITE-INDUCED CELLULAR TOXICITY. OXIDATIVE STRESS PLAYS A KEY ROLE IN THE PATHOGENESIS OF CANCER AND MANY METABOLIC DISEASES; THEREFORE, AN EFFECTIVE ANTIOXIDANT THERAPY WOULD BE OF GREAT IMPORTANCE IN THESE CIRCUMSTANCES. NEVERTHELESS, CONVINCING RANDOMIZED CLINICAL TRIALS REVEALED THAT ANTIOXIDANT SUPPLEMENTATIONS WERE NOT ASSOCIATED WITH SIGNIFICANT REDUCTION IN INCIDENCE OF CANCER, CHRONIC DISEASES AND ALL-CAUSE MORTALITY. AS OXIDATION OF ESSENTIAL MOLECULES CONTINUES, IT TURNS TO NITRO-OXIDATIVE STRESS BECAUSE OF THE INVOLVEMENT OF NITRIC OXIDE IN PATHOGENESIS PROCESSES. PEROXYNITRITE DAMAGES VIA SEVERAL DISTINCTIVE MECHANISMS; FIRST, IT HAS DIRECT TOXIC EFFECTS ON ALL BIOMOLECULES AND CAUSES LIPID PEROXIDATION, PROTEIN OXIDATION AND DNA DAMAGE. THE SECOND MECHANISM INVOLVES THE INDUCTION OF SEVERAL TRANSCRIPTION FACTORS LEADING TO CYTOKINE-INDUCED CHRONIC INFLAMMATION. FINALLY, IT CAUSES EPIGENETIC PERTURBATIONS THAT EXAGGERATE NUCLEAR FACTOR KAPPA-B MEDIATED INFLAMMATORY GENE EXPRESSION. LESSONS-LEARNED FROM THE TREATMENT OF SEVERAL CHRONIC DISORDERS INCLUDING PULMONARY DISEASES SUGGEST THAT, CHRONIC INFLAMMATION AND GLUCOCORTICOID RESISTANCE ARE REGULATED BY PROLONGED PEROXYNITRITE PRODUCTION. 2009