1 6387 86 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 2 633 31 BIOLOGICAL EFFECTS AND EPIDEMIOLOGICAL CONSEQUENCES OF ARSENIC EXPOSURE, AND REAGENTS THAT CAN AMELIORATE ARSENIC DAMAGE IN VIVO. THROUGH CONTAMINATED DIET, WATER, AND OTHER FORMS OF ENVIRONMENTAL EXPOSURE, ARSENIC AFFECTS HUMAN HEALTH. THERE ARE MANY U.S. AND WORLDWIDE "HOT SPOTS" WHERE THE ARSENIC LEVEL IN PUBLIC WATER EXCEEDS THE MAXIMUM EXPOSURE LIMIT. THE BIOLOGICAL EFFECTS OF CHRONIC ARSENIC EXPOSURE INCLUDE GENERATION OF REACTIVE OXYGEN SPECIES (ROS), LEADING TO OXIDATIVE STRESS AND DNA DAMAGE, EPIGENETIC DNA MODIFICATION, INDUCTION OF GENOMIC INSTABILITY, AND INFLAMMATION AND IMMUNOMODULATION, ALL OF WHICH CAN INITIATE CARCINOGENESIS. HIGH ARSENIC EXPOSURE IS EPIDEMIOLOGICALLY ASSOCIATED WITH SKIN, LUNG, BLADDER, LIVER, KIDNEY AND PANCREATIC CANCER, AND CARDIOVASCULAR, NEURONAL, AND OTHER DISEASES. THIS REVIEW BRIEFLY SUMMARIZES THE BIOLOGICAL EFFECTS OF ARSENIC EXPOSURE AND EPIDEMIOLOGICAL CANCER STUDIES WORLDWIDE, AND PROVIDES AN OVERVIEW FOR EMERGING RODENT-BASED STUDIES OF REAGENTS THAT CAN AMELIORATE THE EFFECTS OF ARSENIC EXPOSURE IN VIVO. THESE REAGENTS MAY BE TRANSLATED TO HUMAN POPULATIONS FOR DISEASE PREVENTION. WE PROPOSE THE IMPORTANCE OF DEVELOPING A BIOMARKER-BASED PRECISION PREVENTION APPROACH FOR THE HEALTH ISSUES ASSOCIATED WITH ARSENIC EXPOSURE THAT AFFECTS MILLIONS OF PEOPLE WORLDWIDE. 2017 3 3837 30 IONIZING RADIATION-INDUCED OXIDATIVE STRESS, EPIGENETIC CHANGES AND GENOMIC INSTABILITY: THE PIVOTAL ROLE OF MITOCHONDRIA. PURPOSE: TO REVIEW THE DATA CONCERNING THE ROLE OF ENDOGENOUSLY GENERATED REACTIVE OXYGEN SPECIES (ROS) IN THE NON-TARGETED IONIZING RADIATION (IR) EFFECTS AND IN DETERMINATION OF THE CELL POPULATION'S FATE, BOTH EARLY AFTER EXPOSURE AND AFTER MANY GENERATIONS. CONCLUSIONS: THE SHORT-TERM AS WELL AS CHRONIC OXIDATIVE STRESS RESPONSES MAINLY ARE PRODUCED DUE TO ROS GENERATION BY THE ELECTRON TRANSPORT CHAIN (ETC) OF THE MITOCHONDRIA AND BY THE CYTOPLASMIC NADPH OXIDASES. WHETHER THE INDUCTION OF THE OXIDATIVE STRESS AND ITS CONSEQUENCES OCCUR OR ARE HAMPERED IN A SINGLE CELL LARGELY DEPENDS ON THE INTERACTION BETWEEN THE NUCLEUS AND THE CELLULAR POPULATION OF SEVERAL HUNDRED OR THOUSANDS OF MITOCHONDRIA THAT ARE GENETICALLY HETEROGENEOUS. HIGH INTRA-MITOCHONDRIAL ROS LEVEL IS DAMAGING THE MITOCHONDRIAL (MT) DNA AND ITS MUTATIONS AFFECT THE EPIGENETIC CONTROL MECHANISMS OF THE NUCLEAR (N) DNA, BY DECREASING THE ACTIVITY OF METHYLTRANSFERASES AND THUS, CAUSING GLOBAL DNA HYPOMETHYLATION. THESE CHANGES ARE TRANSMITTED TO THE PROGENY OF THE IRRADIATED CELLS. THE CHRONIC OXIDATIVE STRESS IS THE MAIN CAUSE OF THE LATE POST-RADIATION EFFECTS, INCLUDING CANCER, AND THIS MAKES IT AN IMPORTANT ADVERSE EFFECT OF EXPOSURE TO IR AND A TARGET FOR RADIOLOGICAL PROTECTION. 2015 4 4898 36 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 5 4119 30 MECHANISMS OF CADMIUM CARCINOGENICITY IN THE GASTROINTESTINAL TRACT. CANCER, A SERIOUS PUBLIC HEALTH PROBLEM IN WORLDWIDE, RESULTS FROM AN EXCESSIVE AND UNCONTROLLED PROLIFERATION OF THE BODY CELLS WITHOUT OBVIOUS PHYSIOLOGICAL DEMANDS OF ORGANS. THE GASTROINTESTINAL TRACT, INCLUDING THE ESOPHAGUS, STOMACH AND INTESTINE, IS A UNIQUE ORGAN SYSTEM. IT HAS THE HIGHEST CANCER INCIDENCE AND CANCER- RELATED MORTALITY IN THE BODY AND IS INFLUENCEED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. AMONG THE VARIOUS CHEMICAL ELEMENTS RECOGNIZED IN THE NATURE, SOME OF THEM INCLUDING ZINC, IRON, COBALT, AND COPPER HAVE ESSENTIAL ROLES IN THE VARIOUS BIOCHEMICAL AND PHYSIOLOGICAL PROCESSES, BUT ONLY AT LOW LEVELS AND OTHERS SUCH AS CADMIUM, LEAD, MERCURY, ARSENIC, AND NICKEL ARE CONSIDERED AS THREATS FOR HUMAN HEALTH ESPECIALLY WITH CHRONIC EXPOSURE AT HIGH LEVELS. CADMIUM, AN ENVIRONMENT CONTAMINANT, CANNOT BE DESTROYED IN NATURE. THROUGH IMPAIRMENT OF VITAMIN D METABOLISM IN THE KIDNEY IT CAUSES NEPHROTOXICITY AND SUBSEQUENTLY BONE METABOLISM IMPAIRMENT AND FRAGILITY. THE MAJOR MECHANISMS INVOLVED IN CADMIUM CARCINOGENESIS COULD BE RELATED TO THE SUPPRESSION OF GENE EXPRESSION, INHIBITION OF DNA DAMAGE REPAIR, INHIBITION OF APOPTOSIS, AND INDUCTION OF OXIDATIVE STRESS. IN ADDITION, CADMIUM MAY ACT THROUGH ABERRANT DNA METHYLATION. CADMIUM AFFECTS MULTIPLE CELLULAR PROCESSES, INCLUDING SIGNAL TRANSDUCTION PATHWAYS, CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. DOWN-REGULATION OF METHYLTRANSFERASES ENZYMES AND REDUCTION OF DNA METHYLATION HAVE BEEN STATED AS EPIGENETIC EFFECTS OF CADMIUM. FURTHERMORE, INCREASING INTRACELLULAR FREE CALCIUM ION LEVELS INDUCES NEURONAL APOPTOSIS IN ADDITION TO OTHER DELETERIOUS INFLUENCE ON THE STABILITY OF THE GENOME. 2015 6 4897 29 OXIDATIVE STRESS IN ALCOHOL-RELATED LIVER DISEASE. ALCOHOL CONSUMPTION IS ONE OF THE LEADING CAUSES OF THE GLOBAL BURDEN OF DISEASE AND RESULTS IN HIGH HEALTHCARE AND ECONOMIC COSTS. HEAVY ALCOHOL MISUSE LEADS TO ALCOHOL-RELATED LIVER DISEASE, WHICH IS RESPONSIBLE FOR A SIGNIFICANT PROPORTION OF ALCOHOL-ATTRIBUTABLE DEATHS GLOBALLY. OTHER THAN REDUCING ALCOHOL CONSUMPTION, THERE ARE CURRENTLY NO EFFECTIVE TREATMENTS FOR ALCOHOL-RELATED LIVER DISEASE. OXIDATIVE STRESS REFERS TO AN IMBALANCE IN THE PRODUCTION AND ELIMINATION OF REACTIVE OXYGEN SPECIES AND ANTIOXIDANTS. IT PLAYS IMPORTANT ROLES IN SEVERAL ASPECTS OF ALCOHOL-RELATED LIVER DISEASE PATHOGENESIS. HERE, WE REVIEW HOW CHRONIC ALCOHOL USE RESULTS IN OXIDATIVE STRESS THROUGH INCREASED METABOLISM VIA THE CYTOCHROME P450 2E1 SYSTEM PRODUCING REACTIVE OXYGEN SPECIES, ACETALDEHYDE AND PROTEIN AND DNA ADDUCTS. THESE TRIGGER INFLAMMATORY SIGNALING PATHWAYS WITHIN THE LIVER LEADING TO EXPRESSION OF PRO-INFLAMMATORY MEDIATORS CAUSING HEPATOCYTE APOPTOSIS AND NECROSIS. REACTIVE OXYGEN SPECIES EXPOSURE ALSO RESULTS IN MITOCHONDRIAL STRESS WITHIN HEPATOCYTES CAUSING STRUCTURAL AND FUNCTIONAL DYSREGULATION OF MITOCHONDRIA AND UPREGULATING APOPTOTIC SIGNALING. THERE IS ALSO EVIDENCE THAT OXIDATIVE STRESS AS WELL AS THE DIRECT EFFECT OF ALCOHOL INFLUENCES EPIGENETIC REGULATION. INCREASED GLOBAL HISTONE METHYLATION AND ACETYLATION AND SPECIFIC HISTONE ACETYLATION INHIBITS ANTIOXIDANT RESPONSES AND PROMOTES EXPRESSION OF KEY PRO-INFLAMMATORY GENES. THIS REVIEW HIGHLIGHTS ASPECTS OF THE ROLE OF OXIDATIVE STRESS IN DISEASE PATHOGENESIS THAT WARRANT FURTHER STUDY INCLUDING MITOCHONDRIAL STRESS AND EPIGENETIC REGULATION. IMPROVED UNDERSTANDING OF THESE PROCESSES MAY IDENTIFY NOVEL TARGETS FOR THERAPY. 2020 7 3210 32 HEALTH EFFECTS ASSOCIATED WITH PRE- AND PERINATAL EXPOSURE TO ARSENIC. INORGANIC ARSENIC IS A WELL-ESTABLISHED HUMAN CARCINOGEN, ABLE TO INDUCE GENETIC AND EPIGENETIC ALTERATIONS. MORE THAN 200 MILLION PEOPLE WORLDWIDE ARE EXPOSED TO ARSENIC CONCENTRATIONS IN DRINKING WATER EXCEEDING THE RECOMMENDED WHO THRESHOLD (10MUG/L). ADDITIONALLY, CHRONIC EXPOSURE TO LEVELS BELOW THIS THRESHOLD IS KNOWN TO RESULT IN LONG-TERM HEALTH EFFECTS IN HUMANS. THE ARSENIC-RELATED HEALTH EFFECTS IN HUMANS ARE ASSOCIATED WITH ITS BIOTRANSFORMATION PROCESS, WHEREBY THE RESULTING METABOLITES CAN INDUCE MOLECULAR DAMAGE THAT ACCUMULATES OVER TIME. THE EFFECTS DERIVED FROM THESE ALTERATIONS INCLUDE GENOMIC INSTABILITY ASSOCIATED WITH OXIDATIVE DAMAGE, ALTERATION OF GENE EXPRESSION (INCLUDING CODING AND NON-CODING RNAS), GLOBAL AND LOCALIZED EPIGENETIC REPROGRAMMING, AND HISTONE POSTTRANSLATIONAL MODIFICATIONS. THESE ALTERATIONS DIRECTLY AFFECT MOLECULAR PATHWAYS INVOLVED IN THE ONSET AND PROGRESSION OF MANY CONDITIONS THAT CAN ARISE EVEN DECADES AFTER THE EXPOSURE OCCURS. IMPORTANTLY, ARSENIC METABOLITES GENERATED DURING ITS BIOTRANSFORMATION CAN ALSO PASS THROUGH THE PLACENTAL BARRIER, RESULTING IN FETAL EXPOSURE TO THIS CARCINOGEN AT SIMILAR LEVELS TO THOSE OF THE MOTHER. AS SUCH, MORE IMMEDIATE EFFECTS OF THE ARSENIC-INDUCED MOLECULAR DAMAGE CAN BE OBSERVED AS DETRIMENTAL EFFECTS ON FETAL DEVELOPMENT, PREGNANCY, AND BIRTH OUTCOMES. IN THIS REVIEW, WE FOCUS ON THE GENETIC AND EPIGENETIC DAMAGE ASSOCIATED WITH EXPOSURE TO LOW LEVELS OF ARSENIC, PARTICULARLY THOSE AFFECTING EARLY DEVELOPMENTAL STAGES. WE ALSO PRESENT HOW THESE ALTERATIONS OCCURRING DURING EARLY LIFE CAN IMPACT THE DEVELOPMENT OF CERTAIN DISEASES IN ADULT LIFE. 2021 8 480 32 ARSENIC-INDUCED CARCINOGENESIS: THE IMPACT OF MIRNA DYSREGULATION. ARSENIC IS A TOXIC METALLOID WIDELY PRESENT IN THE EARTH'S CRUST, AND IS A PROVEN HUMAN CARCINOGEN. CHRONIC ARSENIC EXPOSURE MAINLY THROUGH DRINKING WATER CAUSES SKIN, LUNG, AND URINARY BLADDER CANCERS, AND IS ASSOCIATED WITH LIVER, PROSTATE, AND KIDNEY CANCERS, CARDIOVASCULAR AND NEUROLOGICAL DISORDERS, AND DIABETES. SEVERAL MODES OF ACTION HAVE BEEN SUGGESTED IN ARSENIC CARCINOGENESIS. HOWEVER, THE MOLECULAR ETIOLOGY OF ARSENIC-INDUCED CANCER REMAINS UNCLEAR. RECENT EVIDENCE CLEARLY INDICATES THAT GENE EXPRESSION MODIFICATIONS INDUCED BY ARSENIC MAY INVOLVE EPIGENETIC ALTERATIONS, INCLUDING MIRNA DYSREGULATION. MANY MIRNAS HAVE BEEN IMPLICATED IN DIFFERENT HUMAN CANCERS AS A CONSEQUENCE OF LOSSES AND OR GAINS OF MIRNA FUNCTION THAT CONTRIBUTE TO CANCER DEVELOPMENT. PROGRESS IN IDENTIFYING MIRNA DYSREGULATION INDUCED BY ARSENIC HAS BEEN MADE USING DIFFERENT APPROACHES AND MODELS. THE PRESENT REVIEW DISCUSSES THE RECENT DATA REGARDING DYSREGULATED EXPRESSION OF MIRNA IN ARSENIC-INDUCED MALIGNANT TRANSFORMATION IN VITRO, GAPS IN CURRENT UNDERSTANDING AND DEFICIENCIES IN CURRENT MODELS FOR ARSENIC-INDUCED CARCINOGENESIS, AND FUTURE DIRECTIONS OF RESEARCH THAT WOULD IMPROVE OUR KNOWLEDGE REGARDING THE MECHANISMS INVOLVED IN ARSENIC-INDUCED CARCINOGENESIS. 2018 9 474 21 ARSENIC BIOTRANSFORMATION AS A CANCER PROMOTING FACTOR BY INDUCING DNA DAMAGE AND DISRUPTION OF REPAIR MECHANISMS. CHRONIC EXPOSURE TO ARSENIC IN DRINKING WATER POSES A MAJOR GLOBAL HEALTH CONCERN. POPULATIONS EXPOSED TO HIGH CONCENTRATIONS OF ARSENIC-CONTAMINATED DRINKING WATER SUFFER SERIOUS HEALTH CONSEQUENCES, INCLUDING ALARMING CANCER INCIDENCE AND DEATH RATES. ARSENIC IS BIOTRANSFORMED THROUGH SEQUENTIAL ADDITION OF METHYL GROUPS, ACQUIRED FROM S-ADENOSYLMETHIONINE (SAM). METABOLISM OF ARSENIC GENERATES A VARIETY OF GENOTOXIC AND CYTOTOXIC SPECIES, DAMAGING DNA DIRECTLY AND INDIRECTLY, THROUGH THE GENERATION OF REACTIVE OXIDATIVE SPECIES AND INDUCTION OF DNA ADDUCTS, STRAND BREAKS AND CROSS LINKS, AND INHIBITION OF THE DNA REPAIR PROCESS ITSELF. SINCE SAM IS THE METHYL GROUP DONOR USED BY DNA METHYLTRANSFERASES TO MAINTAIN NORMAL EPIGENETIC PATTERNS IN ALL HUMAN CELLS, ARSENIC IS ALSO POSTULATED TO AFFECT MAINTENANCE OF NORMAL DNA METHYLATION PATTERNS, CHROMATIN STRUCTURE, AND GENOMIC STABILITY. THE BIOLOGICAL PROCESSES UNDERLYING THE CANCER PROMOTING FACTORS OF ARSENIC METABOLISM, RELATED TO DNA DAMAGE AND REPAIR, WILL BE DISCUSSED HERE. 2011 10 860 37 CHROMATIN MODIFICATIONS DURING REPAIR OF ENVIRONMENTAL EXPOSURE-INDUCED DNA DAMAGE: A POTENTIAL MECHANISM FOR STABLE EPIGENETIC ALTERATIONS. EXPOSURES TO ENVIRONMENTAL TOXICANTS AND TOXINS CAUSE EPIGENETIC CHANGES THAT LIKELY PLAY A ROLE IN THE DEVELOPMENT OF DISEASES ASSOCIATED WITH EXPOSURE. THE MECHANISM BEHIND THESE EXPOSURE-INDUCED EPIGENETIC CHANGES IS CURRENTLY UNKNOWN. ONE COMMONALITY BETWEEN MOST ENVIRONMENTAL EXPOSURES IS THAT THEY CAUSE DNA DAMAGE EITHER DIRECTLY OR THROUGH CAUSING AN INCREASE IN REACTIVE OXYGEN SPECIES, WHICH CAN DAMAGE DNA. LIKE TRANSCRIPTION, DNA DAMAGE REPAIR MUST OCCUR IN THE CONTEXT OF CHROMATIN REQUIRING BOTH HISTONE MODIFICATIONS AND ATP-DEPENDENT CHROMATIN REMODELING. THESE CHROMATIN CHANGES AID IN DNA DAMAGE ACCESSIBILITY AND SIGNALING. SEVERAL PROTEINS AND COMPLEXES INVOLVED IN EPIGENETIC SILENCING DURING BOTH DEVELOPMENT AND CANCER HAVE BEEN FOUND TO BE LOCALIZED TO SITES OF DNA DAMAGE. THE CHROMATIN-BASED RESPONSE TO DNA DAMAGE IS CONSIDERED A TRANSIENT EVENT, WITH CHROMATIN BEING RESTORED TO NORMAL AS DNA DAMAGE REPAIR IS COMPLETED. HOWEVER, IN INDIVIDUALS CHRONICALLY EXPOSED TO ENVIRONMENTAL TOXICANTS OR WITH CHRONIC INFLAMMATORY DISEASE, REPEATED DNA DAMAGE-INDUCED CHROMATIN REARRANGEMENT MAY ULTIMATELY LEAD TO PERMANENT EPIGENETIC ALTERATIONS. UNDERSTANDING THE MECHANISM BEHIND EXPOSURE-INDUCED EPIGENETIC CHANGES WILL ALLOW US TO DEVELOP STRATEGIES TO PREVENT OR REVERSE THESE CHANGES. THIS REVIEW FOCUSES ON EPIGENETIC CHANGES AND DNA DAMAGE INDUCED BY ENVIRONMENTAL EXPOSURES, THE CHROMATIN CHANGES THAT OCCUR AROUND SITES OF DNA DAMAGE, AND HOW THESE TRANSIENT CHROMATIN CHANGES MAY LEAD TO HERITABLE EPIGENETIC ALTERATIONS AT SITES OF CHRONIC EXPOSURE. 2014 11 5942 40 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 12 4840 27 ONCOGENOMIC DISRUPTIONS IN ARSENIC-INDUCED CARCINOGENESIS. CHRONIC EXPOSURE TO ARSENIC AFFECTS MORE THAN 200 MILLION PEOPLE WORLDWIDE, AND HAS BEEN ASSOCIATED WITH MANY ADVERSE HEALTH EFFECTS, INCLUDING CANCER IN SEVERAL ORGANS. THERE IS ACCUMULATING EVIDENCE THAT ARSENIC BIOTRANSFORMATION, A STEP IN THE ELIMINATION OF ARSENIC FROM THE HUMAN BODY, CAN INDUCE CHANGES AT A GENETIC AND EPIGENETIC LEVEL, LEADING TO CARCINOGENESIS. AT THE GENETIC LEVEL, ARSENIC INTERFERES WITH KEY CELLULAR PROCESSES SUCH AS DNA DAMAGE-REPAIR AND CHROMOSOMAL STRUCTURE, LEADING TO GENOMIC INSTABILITY. AT THE EPIGENETIC LEVEL, ARSENIC PLACES A HIGH DEMAND ON THE CELLULAR METHYL POOL, LEADING TO GLOBAL HYPOMETHYLATION AND HYPERMETHYLATION OF SPECIFIC GENE PROMOTERS. THESE ARSENIC-ASSOCIATED DNA ALTERATIONS RESULT IN THE DEREGULATION OF BOTH ONCOGENIC AND TUMOUR-SUPPRESSIVE GENES. FURTHERMORE, RECENT REPORTS HAVE IMPLICATED ABERRANT EXPRESSION OF NON-CODING RNAS AND THE CONSEQUENTIAL DISRUPTION OF SIGNALING PATHWAYS IN THE CONTEXT OF ARSENIC-INDUCED CARCINOGENESIS. THIS ARTICLE PROVIDES AN OVERVIEW OF THE ONCOGENOMIC ANOMALIES ASSOCIATED WITH ARSENIC EXPOSURE AND CONVEYS THE IMPORTANCE OF NON-CODING RNAS IN THE ARSENIC-INDUCED CARCINOGENIC PROCESS. 2017 13 6865 27 [OXIDATIVE STRESS IN PROSTATE HYPERTROPHY AND CARCINOGENESIS]. AGING, SIGNIFICANT IMPAIRMENT OF THE OXIDATION/REDUCTION BALANCE, INFECTION, AND INFLAMMATION ARE RECOGNIZED RISK FACTORS OF BENIGN HYPERPLASIA AND PROSTATE CANCER. CHRONIC SYMPTOMATIC AND ASYMPTOMATIC PROSTATE INFLAMMATORY PROCESSES GENERATE SIGNIFICANTLY ELEVATED LEVELS OF REACTIVE OXYGEN AND NITROGEN SPECIES, AND HALOGENATED COMPOUNDS. PROSTATE CANCER PATIENTS SHOWED SIGNIFICANTLY HIGHER LIPID PEROXIDATION AND LOWER ANTIOXIDANT LEVELS IN PERIPHERAL BLOOD THAN HEALTHY CONTROLS, WHEREAS PATIENTS WITH PROSTATE HYPERPLASIA DID NOT SHOW SUCH SYMPTOMS. OXIDATIVE/NITROSATIVE/HALOGENATIVE STRESS CAUSES DNA MODIFICATIONS LEADING TO GENOME INSTABILITY THAT MAY INITIATE CARCINOGENESIS; HOWEVER, IT WAS SHOWN THAT OXIDATIVE DAMAGE ALONE IS NOT SUFFICIENT TO INITIATE THIS PROCESS. PEROXIDATION PRODUCTS INDUCED BY REACTIVE OXYGEN AND NITROGEN SPECIES SEEM TO TAKE PART IN EPIGENETIC MECHANISMS REGULATING GENOME ACTIVITY. ONE OF THE MOST COMMON CHANGES OCCURRING IN MORE THAN 90% OF ALL ANALYZED PROSTATE CANCERS IS THE SILENCING OF GSTP1 GENE ACTIVITY. THE GENE ENCODES GLUTATHIONE TRANSFERASE, AN ENZYME PARTICIPATING IN DETOXIFICATION PROCESSES. PROSTATE HYPERPLASIA IS OFTEN ACCOMPANIED BY CHRONIC INFLAMMATION AND SUCH A RELATIONSHIP WAS NOT OBSERVED IN PROSTATE CANCER. THE PARTICIPATION OF INFECTION AND INFLAMMATION IN THE DEVELOPMENT OF HYPERPLASIA IS UNQUESTIONABLE AND THESE FACTORS PROBABLY ALSO TAKE PART IN INITIATING THE EARLY STAGES OF PROSTATE CARCINOGENESIS. THUS IT SEEMS THAT THERAPEUTIC STRATEGIES THAT PREVENT GENOME OXIDATIVE DAMAGE IN SITUATIONS INVOLVING OXIDATIVE/NITROSATIVE/HALOGENATIVE STRESS, I.E. USE OF ANTIOXIDANTS, PLANT STEROIDS, ANTIBIOTICS, AND NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, COULD HELP PREVENT CARCINOGENESIS. 2009 14 2655 37 EPIMUTAGENESIS: A PROSPECTIVE MECHANISM TO REMEDIATE ARSENIC-INDUCED TOXICITY. ARSENIC TOXICITY IS A GLOBAL ISSUE, ADDRESSED BY THE WORLD HEALTH ORGANIZATION AS ONE OF THE MAJOR NATURAL CALAMITIES FACED BY HUMANS. MORE THAN 137 MILLION INDIVIDUALS IN 70 NATIONS ARE AFFECTED BY ARSENIC MAINLY THROUGH DRINKING WATER AND ALSO THROUGH DIET. CHRONIC ARSENIC EXPOSURE LEADS TO VARIOUS TYPES OF PATHO-PHYSIOLOGICAL END POINTS IN HUMANS INCLUDING CANCERS. ARSENIC, A XENOBIOTIC SUBSTANCE, IS BIOTRANSFORMED IN THE BODY TO ITS METHYLATED SPECIES BY USING THE PHYSIOLOGICAL S-ADENOSYL METHIONINE (SAM). SAM DICTATES METHYLATION STATUS OF THE GENOME AND ARSENIC METABOLISM LEADS TO DEPLETION OF SAM LEADING TO AN EPIGENETIC DISEQUILIBRIUM. SINCE EPIGENETICS IS ONE OF THE MAJOR PHENOMENON AT THE INTERFACE BETWEEN THE ENVIRONMENT AND HUMAN HEALTH IMPACT, ITS DISEQUILIBRIUM BY ARSENIC INFLICTS UPON THE CHROMATIN COMPACTION, GENE EXPRESSION, GENOMIC STABILITY AND A HOST OF BIOMOLECULAR INTERACTIONS, THE INTERACTOME WITHIN THE CELL. SINCE ARSENIC IS NOT MUTAGENIC BUT IS CARCINOGENIC IN NATURE, ARSENIC INDUCED EPIMUTAGENESIS HAS COME TO THE FOREFRONT SINCE IT DETERMINES THE TRANSCRIPTIONAL AND GENOMIC INTEGRITY OF THE CELL. ARSENIC TOXICITY BRINGS FORTH SEVERAL PATHOPHYSIOLOGICAL MANIFESTATIONS LIKE DERMATOLOGICAL NON-CANCEROUS, PRE-CANCEROUS AND CANCEROUS LESIONS, PERIPHERAL NEUROPATHY, DNA DAMAGE, RESPIRATORY DISORDERS AND CANCERS OF SEVERAL INTERNAL ORGANS. RECENTLY, SEVERAL DISEASES OF SIMILAR MANIFESTATIONS HAVE BEEN EXPLAINED WITH THE RELEVANT EPIGENETIC PERSPECTIVES REGARDING THE POSSIBLE MOLECULAR MECHANISM FOR THEIR ONSET. HENCE, IN THE CURRENT REVIEW, WE COMPREHENSIVELY TRY TO INTERCALATE THE INFORMATION ON ARSENIC-INDUCED EPIGENETIC ALTERATIONS OF DNA, HISTONES AND MICRORNA SO AS TO UNDERSTAND WHETHER THE ARSENIC-INDUCED TOXIC MANIFESTATIONS ARE BROUGHT ABOUT BY THE EPIGENETIC CHANGES. WE HIGHLIGHT THE NEED TO UNDERSTAND THE ASPECT OF EPIMUTAGENESIS AND SUBSEQUENT ALTERATIONS IN THE CELLULAR INTERACTOME DUE TO ARSENIC-INDUCED MOLECULAR CHANGES, WHICH MAY BE UTILIZED TO DEVELOP PUTATIVE THERAPEUTIC STRATEGIES TARGETING BOTH OXIDATIVE POTENTIAL AND EPIMUTAGENESIS IN HUMANS. 2015 15 5943 29 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 16 712 32 CADMIUM AND ITS EPIGENETIC EFFECTS. CADMIUM (CD) IS A TOXIC, NONESSENTIAL TRANSITION METAL AND CONTRIBUTES A HEALTH RISK TO HUMANS, INCLUDING VARIOUS CANCERS AND CARDIOVASCULAR DISEASES; HOWEVER, UNDERLYING MOLECULAR MECHANISMS REMAIN LARGELY UNKNOWN. CELLS TRANSMIT INFORMATION TO THE NEXT GENERATION VIA TWO DISTINCT WAYS: GENETIC AND EPIGENETIC. CHEMICAL MODIFICATIONS TO DNA OR HISTONE THAT ALTERS THE STRUCTURE OF CHROMATIN WITHOUT CHANGE OF DNA NUCLEOTIDE SEQUENCE ARE KNOWN AS EPIGENETICS. THESE HERITABLE EPIGENETIC CHANGES INCLUDE DNA METHYLATION, POST-TRANSLATIONAL MODIFICATIONS OF HISTONE TAILS (ACETYLATION, METHYLATION, PHOSPHORYLATION, ETC), AND HIGHER ORDER PACKAGING OF DNA AROUND NUCLEOSOMES. APART FROM DNA METHYLTRANSFERASES, HISTONE MODIFICATION ENZYMES SUCH AS HISTONE ACETYLTRANSFERASE, HISTONE DEACETYLASE, AND METHYLTRANSFERASE, AND MICRORNAS (MIRNAS) ALL INVOLVE IN THESE EPIGENETIC CHANGES. RECENT STUDIES INDICATE THAT CD IS ABLE TO INDUCE VARIOUS EPIGENETIC CHANGES IN PLANT AND MAMMALIAN CELLS IN VITRO AND IN VIVO. SINCE ABERRANT EPIGENETICS PLAYS A CRITICAL ROLE IN THE DEVELOPMENT OF VARIOUS CANCERS AND CHRONIC DISEASES, CD MAY CAUSE THE ABOVE-MENTIONED PATHOGENIC RISKS VIA EPIGENETIC MECHANISMS. HERE WE REVIEW THE IN VITRO AND IN VIVO EVIDENCE OF EPIGENETIC EFFECTS OF CD. THE AVAILABLE FINDINGS INDICATE THAT EPIGENETICS OCCURRED IN ASSOCIATION WITH CD INDUCTION OF MALIGNANT TRANSFORMATION OF CELLS AND PATHOLOGICAL PROLIFERATION OF TISSUES, SUGGESTING THAT EPIGENETIC EFFECTS MAY PLAY A ROLE IN CD TOXIC, PARTICULARLY CARCINOGENIC EFFECTS. THE FUTURE OF ENVIRONMENTAL EPIGENOMIC RESEARCH ON CD SHOULD INCLUDE THE ROLE OF EPIGENETICS IN DETERMINING LONG-TERM AND LATE-ONSET HEALTH EFFECTS FOLLOWING CD EXPOSURE. 2012 17 5557 31 ROLE OF GENOMIC INSTABILITY IN ARSENIC-INDUCED CARCINOGENICITY. A REVIEW. EXPOSURE TO CHRONIC ARSENIC TOXICITY IS ASSOCIATED WITH CANCER. ALTHOUGH UNSTABLE GENOME IS A CHARACTERISTIC FEATURE OF CANCER CELLS, THE MECHANISMS LEADING TO GENOMIC INSTABILITY IN ARSENIC-INDUCED CARCINOGENESIS ARE POORLY UNDERSTOOD. WHILE THERE ARE EXCELLENT REVIEWS RELATING TO GENOMIC INSTABILITY IN GENERAL, THERE IS NO COMPREHENSIVE REVIEW PRESENTING THE MECHANISMS INVOLVED IN ARSENIC-INDUCED GENOMIC INSTABILITY. THIS REVIEW WAS UNDERTAKEN TO PRESENT THE CURRENT STATE OF RESEARCH IN THIS AREA AND TO HIGHLIGHT THE MAJOR MECHANISMS THAT MAY INVOLVED IN ARSENIC-INDUCED GENOMIC INSTABILITY LEADING TO CANCER. GENOMIC INSTABILITY IS BROADLY CLASSIFIED INTO CHROMOSOMAL INSTABILITY (CIN), PRIMARILY ASSOCIATED WITH MITOTIC ERRORS; AND MICROSATELLITE INSTABILITY (MIN), ASSOCIATED WITH DNA LEVEL INSTABILITY. ARSENIC-INDUCED GENOMIC INSTABILITY IS ESSENTIALLY MULTI-FACTORIAL IN NATURE AND INVOLVES MOLECULAR CROSS-TALK ACROSS SEVERAL CELLULAR PATHWAYS, AND IS MODULATED BY A NUMBER OF ENDOGENOUS AND EXOGENOUS FACTORS. ARSENIC AND ITS METABOLITES GENERATE OXIDATIVE STRESS, WHICH IN TURN INDUCES GENOMIC INSTABILITY THROUGH DNA DAMAGE, IRREVERSIBLE DNA REPAIR, TELOMERE DYSFUNCTION, MITOTIC ARREST AND APOPTOSIS. IN ADDITION TO GENETIC ALTERATION; EPIGENETIC REGULATION THROUGH PROMOTER METHYLATION AND MIRNA EXPRESSION ALTERS GENE EXPRESSION PROFILING LEADING TO GENOME MORE VULNERABLE AND UNSTABLE TOWARDS CANCER RISK. MOREOVER, MUTATIONS OR SILENCING OF PRO-APOPTOTIC GENES CAN LEAD TO GENOMIC INSTABILITY BY ALLOWING SURVIVAL OF DAMAGED CELLS THAT WOULD OTHERWISE DIE. ALTHOUGH A LARGE BODY OF INFORMATION IS NOW GENERATED REGARDING ARSENIC-INDUCED CARCINOGENESIS; FURTHER STUDIES EXPLORING GENOME-WIDE ASSOCIATION, ROLE OF ENVIRONMENT AND DIET ARE NEEDED FOR A BETTER UNDERSTANDING OF THE ARSENIC-INDUCED GENOMIC INSTABILITY. 2013 18 6183 38 THE IMPACT OF ENVIRONMENTAL FACTORS IN INFLUENCING EPIGENETICS RELATED TO OXIDATIVE STATES IN THE CARDIOVASCULAR SYSTEM. OXIDATIVE STATES EXERT A SIGNIFICANT INFLUENCE ON A WIDE RANGE OF BIOLOGICAL AND MOLECULAR PROCESSES AND FUNCTIONS. WHEN THEIR BALANCE IS SHIFTED TOWARDS ENHANCED AMOUNTS OF FREE RADICALS, PATHOLOGICAL PHENOMENA CAN OCCUR, AS THE GENERATION OF REACTIVE OXYGEN SPECIES (ROS) IN TISSUE MICROENVIRONMENT OR IN THE SYSTEMIC CIRCULATION CAN BE DETRIMENTAL. EPIDEMIC CHRONIC DISEASES OF WESTERN SOCIETIES, SUCH AS CARDIOVASCULAR DISEASE, OBESITY, AND DIABETES CORRELATE WITH THE IMBALANCE OF REDOX HOMEOSTASIS. CURRENT ADVANCES IN OUR UNDERSTANDING OF EPIGENETICS HAVE REVEALED A PARALLEL SCENARIO SHOWING THE INFLUENCE OF OXIDATIVE STRESS AS A MAJOR REGULATOR OF EPIGENETIC GENE REGULATION VIA MODIFICATION OF DNA METHYLATION, HISTONES, AND MICRORNAS. THIS HAS PROVIDED BOTH THE BIOLOGICAL LINK AND A POTENTIAL MOLECULAR EXPLANATION BETWEEN OXIDATIVE STRESS AND CARDIOVASCULAR/METABOLIC PHENOMENA. ACCORDINGLY, IN THIS REVIEW, WE WILL PROVIDE CURRENT INSIGHTS ON THE PHYSIOLOGICAL AND PATHOLOGICAL IMPACT OF CHANGES IN OXIDATIVE STATES ON CARDIOVASCULAR DISORDERS, BY SPECIFICALLY FOCUSING ON THE INFLUENCE OF EPIGENETIC REGULATION. A SPECIAL EMPHASIS WILL HIGHLIGHT THE EFFECT ON EPIGENETIC REGULATION OF HUMAN'S CURRENT LIFE HABITS, EXTERNAL AND ENVIRONMENTAL FACTORS, INCLUDING FOOD INTAKE, TOBACCO, AIR POLLUTION, AND ANTIOXIDANT-BASED APPROACHES. ADDITIONALLY, THE STRATEGY TO QUANTIFY OXIDATIVE STATES IN HUMANS IN ORDER TO DETERMINE WHICH BIOLOGICAL MARKER COULD BEST MATCH A SUBJECT'S PROFILE WILL BE DISCUSSED. 2017 19 318 35 ALCOHOL-INDUCED EPIGENETIC CHANGES IN CANCER. CHRONIC, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH SERIOUS NEGATIVE HEALTH EFFECTS, INCLUDING THE DEVELOPMENT OF SEVERAL CANCER TYPES. ONE OF THE PATHWAYS AFFECTED BY ALCOHOL TOXICITY IS THE ONE-CARBON METABOLISM. THE ALCOHOL-INDUCED IMPAIRMENT OF THIS METABOLIC PATHWAY RESULTS IN EPIGENETIC CHANGES ASSOCIATED WITH CANCER DEVELOPMENT. THESE EPIGENETIC CHANGES ARE INDUCED BY FOLATE DEFICIENCY AND BY PRODUCTS OF THE ETHANOL METABOLISM. THE CHANGES INDUCED BY LONG-TERM HEAVY ETHANOL CONSUMPTION RESULT IN ELEVATIONS OF HOMOCYSTEINE AND S-ADENOSYL-HOMOCYSTEINE (SAH) AND REDUCTIONS IN S-ADENOSYLMETHIONINE (SAM) AND ANTIOXIDANT GLUTATHIONE (GSH) LEVELS, LEADING TO ABNORMAL PROMOTER GENE HYPERMETHYLATION, GLOBAL HYPOMETHYLATION, AND METABOLIC INSUFFICIENCY OF ANTIOXIDANT DEFENSE MECHANISMS. IN ADDITION, REACTIVE OXYGEN SPECIES (ROS) GENERATED DURING THE ETHANOL METABOLISM INDUCE ALTERATIONS IN DNA METHYLATION PATTERNS THAT PLAY A CRITICAL ROLE IN CANCER DEVELOPMENT. SPECIFIC EPIGENETIC CHANGES IN ESOPHAGEAL, HEPATIC, AND COLORECTAL CANCERS HAVE BEEN DETECTED IN BLOOD SAMPLES AND PROPOSED TO BE USED CLINICALLY AS EPIGENETIC BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS OF THESE CANCERS. ALSO, GENETIC VARIANTS OF GENES INVOLVED IN ONE-CARBON METABOLISM AND ETHANOL METABOLISM WERE FOUND TO MODULATE THE RELATIONSHIP BETWEEN ALCOHOL-INDUCED EPIGENETIC CHANGES AND CANCER RISK. FURTHERMORE, ALCOHOL METABOLISM PRODUCTS HAVE BEEN ASSOCIATED WITH AN INCREASE IN NADH LEVELS, WHICH LEAD TO HISTONE MODIFICATIONS AND CHANGES IN GENE EXPRESSION THAT IN TURN INFLUENCE CANCER SUSCEPTIBILITY. CHRONIC EXCESSIVE USE OF ALCOHOL ALSO AFFECTS SELECTED MEMBERS OF THE FAMILY OF MICRORNAS, AND AS MIRNAS COULD ACT AS EPIGENETIC REGULATORS, THIS MAY PLAY AN IMPORTANT ROLE IN CARCINOGENESIS. IN CONCLUSION, TARGETING ALCOHOL-INDUCED EPIGENETIC CHANGES IN SEVERAL CANCER TYPES COULD MAKE AVAILABLE CLINICAL TOOLS FOR THE DIAGNOSIS, PROGNOSIS, AND TREATMENT OF THESE CANCERS, WITH AN IMPORTANT ROLE IN PRECISION MEDICINE. 2018 20 2950 19 GENETIC AND EPIGENETIC DAMAGE INDUCED BY REACTIVE NITROGEN SPECIES: IMPLICATIONS IN CARCINOGENESIS. CHRONIC INFECTION AND INFLAMMATION ARE RECOGNIZED RISK FACTORS FOR HUMAN CANCER AT VARIOUS SITES. INFECTION AND INFLAMMATION CAN ACTIVATE AND INDUCE A VARIETY OF OXIDANT-GENERATING ENZYMES, INCLUDING NADPH OXIDASE AND INDUCIBLE NITRIC OXIDE SYNTHASE. REACTIVE OXYGEN AND NITROGEN SPECIES PRODUCED BY SUCH ENZYMES REACT WITH EACH OTHER TO GENERATE NEW AND MORE POTENT REACTIVE SPECIES. THESE OXIDANTS NOT ONLY CAN DAMAGE DNA AND INDUCE MUTATIONS, BUT ALSO CAN ACTIVATE ONCOGENE PRODUCTS AND/OR INACTIVATE TUMOR-SUPPRESSOR PROTEINS, THUS CONTRIBUTING TO MOST PROCESSES OF CARCINOGENESIS. APPROPRIATE TREATMENT OF INFLAMMATION SHOULD BE FURTHER EXPLORED FOR CHEMOPREVENTION OF HUMAN CANCERS, ESPECIALLY THOSE ASSOCIATED WITH CHRONIC INFLAMMATION. 2003