1  5341 118 RADIATION-HORMESIS PHENOTYPES, THE RELATED MECHANISMS AND IMPLICATIONS FOR DISEASE PREVENTION AND THERAPY. HUMANS ARE CONTINUOUSLY EXPOSED TO IONIZING RADIATION THROUGHOUT LIFE FROM NATURAL SOURCES THAT INCLUDE COSMIC, SOLAR, AND TERRESTRIAL. MUCH HARSHER NATURAL RADIATION AND CHEMICAL ENVIRONMENTS EXISTED DURING OUR PLANET'S EARLY YEARS. MAMMALS SURVIVED THE HARSHER ENVIRONMENTS VIA EVOLUTIONARILY-CONSERVED GIFTS ? A CONTINUOUSLY EVOLVING SYSTEM OF STRESS-INDUCED NATURAL PROTECTIVE MEASURES (I.E., ACTIVATED NATURAL PROTECTION [ANP]). THE CURRENT PROTECTIVE SYSTEM IS DIFFERENTIALLY ACTIVATED BY STOCHASTIC (I.E., VARIABLE) LOW-RADIATION-DOSE THRESHOLDS AND WHEN OPTIMALLY ACTIVATED IN MAMMALS INCLUDES ANTIOXIDANTS, DNA DAMAGE REPAIR, P53-RELATED APOPTOSIS OF SEVERELY-DAMAGED CELLS, REACTIVE-OXYGEN-SPECIES (ROS)/REACTIVE-NITROGEN-SPECIES (RNS)- AND CYTOKINE-REGULATED AUXILIARY APOPTOSIS THAT SELECTIVELY REMOVES ABERRANT CELLS (E.G., PRECANCEROUS CELLS), SUPPRESSION OF DISEASE PROMOTING INFLAMMATION, AND IMMUNITY AGAINST CANCER CELLS. THE INTERCELLULAR-SIGNALING-BASED PROTECTIVE SYSTEM IS REGULATED AT LEAST IN PART VIA EPIGENETIC REPROGRAMMING OF ADAPTIVE-RESPONSE GENES. WHEN THE SYSTEM IS OPTIMALLY ACTIVATED, IT PROTECTS AGAINST CANCER AND SOME OTHER DISEASES, THEREBY LEADING TO HORMETIC PHENOTYPES (E.G., REDUCED DISEASE INCIDENCE TO BELOW THE BASELINE LEVEL; REDUCED PAIN FROM INFLAMMATION-RELATED PROBLEMS). HERE, SOME EXPRESSED RADIATION HORMESIS PHENOTYPES AND RELATED MECHANISMS ARE DISCUSSED ALONG WITH THEIR IMPLICATIONS FOR DISEASE PREVENTION AND THERAPY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  5343  61 RADIATION-STIMULATED EPIGENETIC REPROGRAMMING OF ADAPTIVE-RESPONSE GENES IN THE LUNG: AN EVOLUTIONARY GIFT FOR MOUNTING ADAPTIVE PROTECTION AGAINST LUNG CANCER. HUMANS ARE CONTINUOUSLY EXPOSED TO LOW-LEVEL IONIZING RADIATION FROM NATURAL SOURCES. HOWEVER, HARSHER RADIATION ENVIRONMENTS PERSISTED DURING OUR PLANET'S EARLY YEARS AND MAMMALS SURVIVED VIA AN EVOLUTIONARY GIFT--A SYSTEM OF RADIATION-INDUCED NATURAL PROTECTIVE MEASURES (ADAPTIVE PROTECTION). THIS SYSTEM INCLUDES ANTIOXIDANTS, DNA REPAIR, APOPTOSIS OF SEVERELY DAMAGED CELLS, EPIGENETICALLY REGULATED APOPTOSIS (EPIAPOPTOSIS) PATHWAYS THAT SELECTIVELY REMOVE PRECANCEROUS AND OTHER ABERRANT CELLS, AND IMMUNITY AGAINST CANCER. WE PROPOSE A NOVEL MODEL IN WHICH THE PROTECTIVE SYSTEM IS REGULATED AT LEAST IN PART VIA RADIATION-STRESS-STIMULATED EPIGENETIC REPROGRAMMING (EPIREPROGRAMMING) OF ADAPTIVE-RESPONSE GENES. HIGH-DOSE RADIATION CAN PROMOTE EPIGENETICALLY SILENCING OF ADAPTIVE-RESPONSE GENES (EPISILENCING), FOR EXAMPLE VIA PROMOTER-ASSOCIATED DNA AND/OR HISTONE METHYLATION AND/OR HISTONE DEACETYLATION. EVIDENCE IS PROVIDED FOR LOW LINEAR-ENERGY-TRANSFER (LET) RADIATION-ACTIVATED NATURAL PROTECTION (ANP) AGAINST HIGH-LET ALPHA-RADIATION-INDUCED LUNG CANCER IN PLUTONIUM-239 EXPOSED RATS AND RADON-PROGENY-EXPOSED HUMANS. USING A REVISED HORMETIC RELATIVE RISK MODEL FOR CANCER INDUCTION THAT ACCOUNTS FOR BOTH EPIGENETIC ACTIVATION (EPIACTIVATION) AND EPISILENCING OF GENES, WE DEMONSTRATE THAT, ON AVERAGE, >80% OF ALPHA-RADIATION-INDUCED RAT LUNG CANCERS WERE PREVENTED BY CHRONIC, LOW-RATE GAMMA-RAY ANP. INTERESTINGLY, LIFETIME EXPOSURE TO RESIDENTIAL RADON AT THE ENVIRONMENTAL PROTECTION AGENCY'S ACTION LEVEL OF 4 PCI L(-1) APPEARS TO BE ASSOCIATED WITH ON AVERAGE A > 60% REDUCTION IN LUNG CANCER CASES, RATHER THAN AN INCREASE. WE HAVE USED UNDERLINED ITALICS TO INDICATE NEWLY INTRODUCED TERMINOLOGY.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
3  1438  16 DIFFERENTIAL METHYLATION TESTS OF REGULATORY REGIONS. DIFFERENTIAL METHYLATION OF REGULATORY ELEMENTS IS CRITICAL IN EPIGENETIC RESEARCHES AND CAN BE STATISTICALLY TESTED. WE DEVELOPED A NEW STATISTICAL TEST, THE GENERALIZED INTEGRATED FUNCTIONAL TEST (GIFT), THAT TESTS FOR REGIONAL DIFFERENCES IN METHYLATION BASED ON THE METHYLATION PERCENT AT EACH CPG SITE WITHIN A GENOMIC REGION. THE GIFT USES ESTIMATED SUBJECT-SPECIFIC PROFILES WITH SMOOTHING METHODS, SPECIFICALLY WAVELET SMOOTHING, AND CALCULATES AN ANOVA-LIKE TEST TO COMPARE THE AVERAGE PROFILE OF GROUPS. IN THIS WAY, POSSIBLY CORRELATED CPG SITES WITHIN THE REGULATORY REGION ARE COMPARED ALL TOGETHER. SIMULATIONS AND ANALYSES OF DATA OBTAINED FROM PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA INDICATE THAT GIFT HAS GOOD STATISTICAL PROPERTIES AND IS ABLE TO IDENTIFY PROMISING GENOMIC REGIONS. FURTHER, GIFT IS LIKELY TO WORK WITH MULTIPLE DIFFERENT TYPES OF EXPERIMENTS SINCE DIFFERENT SMOOTHING METHODS CAN BE USED TO ESTIMATE THE PROFILES OF DATA WITHOUT NOISE. MATLAB CODE FOR GIFT AND SAMPLE DATA ARE AVAILABLE AT HTTP://WWW.AUGUSTA.EDU/MCG/BIOSTATEPI/PEOPLE/SOFTWARE/GIFT.HTML.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4  4932  22 PATERNAL ALCOHOL EXPOSURES PROGRAM INTERGENERATIONAL HORMETIC EFFECTS ON OFFSPRING FETOPLACENTAL GROWTH. HORMESIS REFERS TO GRADED ADAPTIVE RESPONSES TO HARMFUL ENVIRONMENTAL STIMULI WHERE LOW-LEVEL TOXICANT EXPOSURES STIMULATE TISSUE GROWTH AND RESPONSIVENESS WHILE, IN CONTRAST, HIGHER-LEVEL EXPOSURES INDUCE TOXICITY. ALTHOUGH THE INTERGENERATIONAL INHERITANCE OF PROGRAMMED HORMETIC GROWTH RESPONSES IS DESCRIBED IN PLANTS AND INSECTS, RESEARCHERS HAVE YET TO OBSERVE THIS PHENOMENON IN MAMMALS. USING A PHYSIOLOGICALLY RELEVANT MOUSE MODEL, WE DEMONSTRATE THAT CHRONIC PRECONCEPTION PATERNAL ALCOHOL EXPOSURES PROGRAM NONLINEAR, DOSE-DEPENDENT CHANGES IN OFFSPRING FETOPLACENTAL GROWTH. OUR STUDIES IDENTIFY AN INVERSE J-SHAPED CURVE WITH A THRESHOLD OF 2.4 G/KG PER DAY; BELOW THIS THRESHOLD, PATERNAL ETHANOL EXPOSURES INDUCE PROGRAMMED INCREASES IN PLACENTAL GROWTH, WHILE DOSES EXCEEDING THIS POINT YIELD COMPARATIVE DECREASES IN PLACENTAL GROWTH. IN MALE OFFSPRING, HIGHER PATERNAL EXPOSURES INDUCE DOSE-DEPENDENT INCREASES IN THE PLACENTAL LABYRINTH LAYER BUT DO NOT IMPACT FETAL GROWTH. IN CONTRAST, THE PLACENTAL HYPERTROPHY INDUCED BY LOW-LEVEL PATERNAL ETHANOL EXPOSURES ASSOCIATE WITH INCREASED OFFSPRING CROWN-RUMP LENGTH, PARTICULARLY IN MALE OFFSPRING. FINALLY, ALTERATIONS IN PLACENTAL PHYSIOLOGY CORRELATE WITH DISRUPTIONS IN BOTH MITOCHONDRIAL-ENCODED AND IMPRINTED GENE EXPRESSION. UNDERSTANDING THE INFLUENCE OF ETHANOL ON THE PATERNALLY-INHERITED EPIGENETIC PROGRAM AND DOWNSTREAM HORMETIC RESPONSES IN OFFSPRING GROWTH MAY HELP EXPLAIN THE ENORMOUS VARIATION OBSERVED IN FETAL ALCOHOL SPECTRUM DISORDER (FASD) PHENOTYPES AND INCIDENCE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5  3939  23 LNC-IL7R ALLEVIATES PM(2.5)-MEDIATED CELLULAR SENESCENCE AND APOPTOSIS THROUGH EZH2 RECRUITMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: LONG-TERM EXPOSURE TO PM(2.5) (PARTICULATE MATTER WITH AN AERODYNAMIC DIAMETER OF </= 2.5 MUM) IS ASSOCIATED WITH PULMONARY INJURY AND EMPHYSEMA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE INVESTIGATED MECHANISMS THROUGH WHICH THE LONG NONCODING RNA LNC-IL7R CONTRIBUTES TO CELLULAR DAMAGE BY INDUCING OXIDATIVE STRESS IN COPD PATIENTS EXPOSED TO PM(2.5). METHODS: ASSOCIATIONS OF SERUM LNC-IL7R LEVELS WITH LUNG FUNCTION, EMPHYSEMA, AND PREVIOUS PM(2.5) EXPOSURE IN COPD PATIENTS WERE ANALYZED. REACTIVE OXYGEN SPECIES AND LNC-IL7R LEVELS WERE MEASURED IN PM(2.5)-TREATED CELLS. THE LEVELS OF LNC-IL7R AND CELLULAR SENESCENCE-ASSOCIATED GENES, NAMELY P16(INK4A) AND P21(CIP1/WAF1), WERE DETERMINED THROUGH LUNG TISSUE SECTION STAINING. THE EFFECTS OF P16(INK4A) OR P21(CIP1/WAF1) REGULATION WERE EXAMINED BY PERFORMING LNC-IL7R OVEREXPRESSION AND KNOCKDOWN ASSAYS. THE FUNCTIONS OF LNC-IL7R-MEDIATED CELL PROLIFERATION, CELL CYCLE, SENESCENCE, COLONY FORMATION, AND APOPTOSIS WERE EXAMINED IN CELLS TREATED WITH PM(2.5). CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE CONDUCTED TO INVESTIGATE THE EPIGENETIC REGULATION OF P21(CIP1/WAF1). RESULTS: LNC-IL7R LEVELS DECREASED IN COPD PATIENTS AND WERE NEGATIVELY CORRELATED WITH EMPHYSEMA OR PM(2.5) EXPOSURE. LNC-IL7R LEVELS WERE UPREGULATED IN NORMAL LUNG EPITHELIAL CELLS BUT NOT IN COPD CELLS EXPOSED TO PM(2.5). LOWER LNC-IL7R EXPRESSION IN PM(2.5)-TREATED CELLS INDUCED P16(INK4A) AND P21(CIP1/WAF1) EXPRESSION BY INCREASING OXIDATIVE STRESS. HIGHER LNC-IL7R EXPRESSION PROTECTED AGAINST CELLULAR SENESCENCE AND APOPTOSIS, WHEREAS LOWER LNC-IL7R EXPRESSION AUGMENTED INJURY IN PM(2.5)-TREATED CELLS. LNC-IL7R AND THE ENHANCER OF ZESTE HOMOLOG 2 (EZH2) SYNERGISTICALLY SUPPRESSED P21(CIP1/WAF1) EXPRESSION THROUGH EPIGENETIC MODULATION. CONCLUSION: LNC-IL7R ATTENUATES PM(2.5)-MEDIATED P21(CIP1/WAF1) EXPRESSION THROUGH EZH2 RECRUITMENT, AND ITS DYSFUNCTION MAY AUGMENT CELLULAR INJURY IN COPD.	2022	
                                                                                                                                                                                                                                                                                              
6   708  22 BYSTANDER EFFECTS IN RADIATION-INDUCED GENOMIC INSTABILITY. EXPOSURE OF GM10115 HAMSTER-HUMAN HYBRID CELLS TO X-RAYS CAN RESULT IN THE INDUCTION OF CHROMOSOMAL INSTABILITY IN THE PROGENY OF SURVIVING CELLS. THIS INSTABILITY MANIFESTS AS THE DYNAMIC PRODUCTION OF NOVEL SUB-POPULATIONS OF CELLS WITH UNIQUE CYTOGENETIC REARRANGEMENTS INVOLVING THE "MARKER" HUMAN CHROMOSOME. WE HAVE USED THE COMET ASSAY TO INVESTIGATE WHETHER THERE WAS AN ELEVATED LEVEL OF ENDOGENOUS DNA BREAKS IN CHROMOSOMALLY UNSTABLE CLONES THAT COULD PROVIDE A SOURCE FOR THE CHROMOSOMAL REARRANGEMENTS AND THUS ACCOUNT FOR THE PERSISTENT INSTABILITY OBSERVED. OUR RESULTS INDICATE NO SIGNIFICANT DIFFERENCE IN COMET TAIL MEASUREMENT BETWEEN NON-IRRADIATED AND RADIATION-INDUCED CHROMOSOMALLY UNSTABLE CLONES. USING TWO-COLOR FLUORESCENCE IN SITU HYBRIDIZATION WE ALSO INVESTIGATED WHETHER RECOMBINATIONAL EVENTS INVOLVING THE INTERSTITIAL TELOMERE REPEAT-LIKE SEQUENCES IN GM10115 CELLS WERE INVOLVED AT FREQUENCIES HIGHER THAN RANDOM PROCESSES WOULD OTHERWISE PREDICT. NINE OF 11 CLONES DEMONSTRATED A SIGNIFICANTLY HIGHER THAN EXPECTED INVOLVEMENT OF THESE INTERSTITIAL TELOMERE REPEAT-LIKE SEQUENCES AT THE RECOMBINATION JUNCTION BETWEEN THE HUMAN AND HAMSTER CHROMOSOMES. SINCE ELEVATED LEVELS OF ENDOGENOUS BREAKS WERE NOT DETECTED IN UNSTABLE CLONES WE PROPOSE THAT EPIGENETIC OR BYSTANDER EFFECTS (BSES) LEAD TO THE ACTIVATION OF RECOMBINATIONAL PATHWAYS THAT PERPETUATE THE UNSTABLE PHENOTYPE. SPECIFICALLY, WE EXPAND UPON THE HYPOTHESIS THAT RADIATION INDUCES CONDITIONS AND/OR FACTORS THAT STIMULATE THE PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS). THESE REACTIVE INTERMEDIATES THEN CONTRIBUTE TO A CHRONIC PRO-OXIDANT ENVIRONMENT THAT CYCLES OVER MULTIPLE GENERATIONS, PROMOTING CHROMOSOMAL RECOMBINATION AND OTHER PHENOTYPES ASSOCIATED WITH GENOMIC INSTABILITY.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
7  2741  23 EXPOSURE TO IONIZING RADIATION DISRUPTS NORMAL EPIGENETIC AGING IN JAPANESE MEDAKA. ALTERATIONS TO THE EPIGENOME ARE A HALLMARK OF BIOLOGICAL AGING AND AGE-DEPENDENT PATTERNING OF THE DNA METHYLOME ("EPIGENETIC AGING") CAN BE MODELED TO PRODUCE EPIGENETIC AGE PREDICTORS. RATES OF EPIGENETIC AGING VARY AMONGST INDIVIDUALS AND CORRELATE TO THE ONSET OF AGE-RELATED DISEASE AND ALL-CAUSE MORTALITY. YET, THE ORIGINS OF EPIGENETIC-TO-CHRONOLOGICAL AGE DISCORDANCE ARE NOT EMPIRICALLY RESOLVED. HERE, WE INVESTIGATE THE RELATIONSHIP BETWEEN AGING, DNA METHYLATION, AND ENVIRONMENTAL EXPOSURES IN JAPANESE MEDAKA (ORYZIAS LATIPES). WE FIND AGE-ASSOCIATED DNA METHYLATION PATTERNING ENRICHED IN GENOMIC REGIONS OF LOW CPG DENSITY AND THAT, SIMILAR TO MAMMALS, MOST AGE-RELATED CHANGES OCCUR DURING EARLY LIFE. WE CONSTRUCT AN EPIGENETIC CLOCK CAPABLE OF PREDICTING CHRONOLOGICAL AGE WITH A MEAN ERROR OF 61.1 DAYS (~8.4% OF AVERAGE LIFESPAN). TO TEST THE ROLE OF ENVIRONMENTAL FACTORS IN DRIVING EPIGENETIC AGE VARIATION, WE EXPOSED MEDAKA TO CHRONIC, ENVIRONMENTALLY RELEVANT DOSES OF IONIZING RADIATION. BECAUSE MOST ORGANISMS SHARE AN EVOLUTIONARY HISTORY WITH IONIZING RADIATION, WE HYPOTHESIZED THAT EXPOSURE WOULD REVEAL FUNDAMENTAL INSIGHTS INTO ENVIRONMENT-BY-EPIGENETIC AGING INTERACTIONS. RADIATION EXPOSURE DISRUPTED EPIGENETIC AGING BY ACCELERATING AND DECELERATING NORMAL AGE-ASSOCIATED PATTERNING AND WAS MOST PRONOUNCED IN CYTOSINES THAT WERE MODERATELY ASSOCIATED WITH AGE. THESE FINDINGS EMPIRICALLY DEMONSTRATE THE ROLE OF DNA METHYLATION IN INTEGRATING ENVIRONMENTAL FACTORS INTO AGING TRAJECTORIES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8  6166  31 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	
                                                                                                                                                                                                                 
9  4018  33 LOW-DOSE IONIZING RADIATION: INDUCTION OF DIFFERENTIAL INTRACELLULAR SIGNALLING POSSIBLY AFFECTING INTERCELLULAR COMMUNICATION. GIVEN THE COMPLEXITY OF THE CARCINOGENIC PROCESS AND THE LACK OF ANY MECHANISTIC UNDERSTANDING OF HOW IONIZING RADIATION AT LOW-LEVEL EXPOSURES AFFECTS THE MULTISTAGE, MULTIMECHANISM PROCESSES OF CARCINOGENESIS, IT IS IMPERATIVE THAT CONCEPTS AND PARADIGMS BE REEXAMINED WHEN EXTRAPOLATING FROM HIGH DOSE TO LOW DOSE. ANY HEALTH EFFECT DIRECTLY LINKED TO LOW-DOSE RADIATION EXPOSURE MUST HAVE MOLECULAR/BIOCHEMICAL AND BIOLOGICAL BASES. ON THE OTHER HAND, DEMONSTRATING SOME MOLECULAR/BIOCHEMICAL OR CELLULAR EFFECT, USING SURROGATE SYSTEMS FOR THE HUMAN BEING, DOES NOT NECESSARILY IMPLY A CORRESPONDING HEALTH EFFECT. GIVEN THE GENERAL ACCEPTANCE OF AN EXTRAPOLATED LNT MODEL, OUR CURRENT UNDERSTANDING OF CARCINOGENESIS CRIES OUT FOR A RESOLUTION OF A REAL PROBLEM. HOW CAN A LOW-LEVEL ACUTE, OR EVEN A CHRONIC, EXPOSURE OF IONIZING RADIATION BRING ABOUT ALL THE DIFFERENT MECHANISMS (MUTAGENIC, CYTOTOXIC, AND EPIGENETIC) AND GENOTYPIC/PHENOTYPIC CHANGES NEEDED TO CONVERT NORMAL CELLS TO AN INVASIVE, MALIGNANT CELL, GIVEN ALL THE PROTECTIVE, REPAIR, AND SUPPRESSIVE SYSTEMS KNOWN TO EXIST IN THE HUMAN BODY? UNTIL RECENTLY, THE PREVAILING PARADIGM THAT IONIZING RADIATION BRINGS ABOUT CANCER PRIMARILY BY DNA DAMAGE AND ITS CONVERSION TO GENE AND CHROMOSOMAL MUTATIONS, DROVE OUR INTERPRETATION OF RADIATION CARCINOGENESIS. TODAY, OUR KNOWLEDGE INCLUDES THE FACTS BOTH THAT EPIGENETIC EVENTS PLAY A MAJOR ROLE IN CARCINOGENESIS AND THAT LOW-DOSE RADIATION CAN ALSO INDUCE EPIGENETIC EVENTS IN AND BETWEEN CELLS IN TISSUES. THIS CHALLENGES ANY SIMPLE EXTRAPOLATION OF THE LNT MODEL. ALTHOUGH A RECENT DELINEATION OF "HALLMARKS" OF THE CANCER PROCESS HAS HELPED TO FOCUS ON HOW IONIZING RADIATION MIGHT CONTRIBUTE TO THE INDUCTION OF CANCERS, SEVERAL OTHER HALLMARKS, PREVIOUSLY IGNORED--NAMELY, THE STEM CELLS IN TISSUES AS TARGETS FOR CARCINOGENESIS AND THE ROLE OF CELL-CELL COMMUNICATION PROCESSES IN MODULATING THE RADIATION EFFECTS ON THE TARGET CELL--MUST BE CONSIDERED, PARTICULARLY FOR THE ADAPTIVE RESPONSE, BYSTANDER EFFECTS, AND GENOMIC INSTABILITY PHENOMENA.	2005	
                                                                                                                                                                                                     
10  1863  27 EMERGENCE OF MUC1 IN MAMMALS FOR ADAPTATION OF BARRIER EPITHELIA. THE MUCIN 1 (MUC1) GENE WAS DISCOVERED BASED ON ITS OVEREXPRESSION IN HUMAN BREAST CANCERS. SUBSEQUENT WORK DEMONSTRATED THAT MUC1 IS ABERRANTLY EXPRESSED IN CANCERS ORIGINATING FROM OTHER DIVERSE ORGANS, INCLUDING SKIN AND IMMUNE CELLS. THESE FINDINGS SUPPORTED A ROLE FOR MUC1 IN THE ADAPTATION OF BARRIER TISSUES TO INFECTION AND ENVIRONMENTAL STRESS. OF FUNDAMENTAL IMPORTANCE FOR THIS EVOLUTIONARY ADAPTATION WAS INCLUSION OF A SEA DOMAIN, WHICH CATALYZES AUTOPROTEOLYSIS OF THE MUC1 PROTEIN AND FORMATION OF A NON-COVALENT HETERODIMERIC COMPLEX. THE RESULTING MUC1 HETERODIMER IS POISED AT THE APICAL CELL MEMBRANE TO RESPOND TO LOSS OF HOMEOSTASIS. DISRUPTION OF THE COMPLEX RELEASES THE MUC1 N-TERMINAL (MUC1-N) SUBUNIT INTO A PROTECTIVE MUCOUS GEL. CONVERSELY, THE TRANSMEMBRANE C-TERMINAL (MUC1-C) SUBUNIT ACTIVATES A PROGRAM OF LINEAGE PLASTICITY, EPIGENETIC REPROGRAMMING AND REPAIR. THIS MUC1-C-ACTIVATED PROGRAM APPARENTLY EVOLVED FOR BARRIER TISSUES TO MOUNT SELF-REGULATING PROLIFERATIVE, INFLAMMATORY AND REMODELING RESPONSES ASSOCIATED WITH WOUND HEALING. EMERGING EVIDENCE INDICATES THAT MUC1-C UNDERPINS INFLAMMATORY ADAPTATION OF TISSUE STEM CELLS AND IMMUNE CELLS IN THE BARRIER NICHE. THIS REVIEW FOCUSES ON HOW PROLONGED ACTIVATION OF MUC1-C BY CHRONIC INFLAMMATION IN THESE NICHES PROMOTES THE CANCER STEM CELL (CSC) STATE BY ESTABLISHING AUTO-INDUCTIVE NODES THAT DRIVE SELF-RENEWAL AND TUMORIGENICITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  1488  21 DNA DAMAGE RECOGNITION IN THE RAT ZYGOTE FOLLOWING CHRONIC PATERNAL CYCLOPHOSPHAMIDE EXPOSURE. THE DETRIMENTAL EFFECTS OF PRECONCEPTIONAL PATERNAL EXPOSURE TO THE ALKYLATING ANTICANCER AGENT, CYCLOPHOSPHAMIDE, INCLUDE ABERRANT EPIGENETIC PROGRAMMING, DYSREGULATED ZYGOTIC GENE ACTIVATION, AND ABNORMALITIES IN THE OFFSPRING THAT ARE TRANSMITTED TO THE NEXT GENERATION. THE ADVERSE DEVELOPMENTAL CONSEQUENCES OF GENOMIC INSTABILITIES TRANSMITTED VIA THE SPERMATOZOON EMPHASIZE THE NEED TO ELUCIDATE THE MECHANISMS BY WHICH THE EARLY EMBRYO RECOGNIZES DNA DAMAGE IN THE PATERNAL GENOME. LITTLE INFORMATION EXISTS ON DNA DAMAGE DETECTION IN THE ZYGOTE. WE ASSESSED THE IMPACT OF PATERNAL CYCLOPHOSPHAMIDE EXPOSURE ON PHOSPHORYLATED H2AX (GAMMAH2AX) AND POLY(ADP-RIBOSE) POLYMERASE-1(PARP-1), BIOMARKERS OF DNA DAMAGE, TO DETERMINE THE CAPACITY IN THE RAT ZYGOTE TO RECOGNIZE GENOMIC DAMAGE AND INITIATE A RESPONSE TO DNA LESIONS. AN AMPLIFIED BIPHASIC GAMMAH2AX RESPONSE WAS TRIGGERED IN THE PATERNAL PRONUCLEUS IN ZYGOTES SIRED BY DRUG-TREATED MALES; THE MATERNAL GENOME WAS NOT AFFECTED. PARP-1 IMMUNOREACTIVITY WAS SUBSTANTIALLY ELEVATED IN BOTH PARENTAL GENOMES, COINCIDENT WITH THE SECOND PHASE OF GAMMAH2AX INDUCTION IN EMBRYOS SIRED BY CYCLOPHOSPHAMIDE-EXPOSED SPERMATOZOA. THUS, PATERNAL EXPOSURE TO A DNA DAMAGING AGENT RAPIDLY ACTIVATES SIGNALS IMPLEMENTAL FOR DNA DAMAGE RECOGNITION IN THE ZYGOTE. INEFFICIENT REPAIR OF DNA LESIONS MAY LEAD TO PERSISTENT ALTERATIONS OF THE HISTONE CODE AND CHROMATIN INTEGRITY, RESULTING IN ABERRANT EMBRYOGENESIS. WE PROPOSE THAT THE RESPONSE OF THE EARLY EMBRYO TO DISTURBANCES IN SPERMATOZOAL GENOMIC INTEGRITY PLAYS A VITAL ROLE IN DETERMINING ITS OUTCOME.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12   930  24 CHRONIC IRRADIATION OF HUMAN CELLS REDUCES HISTONE LEVELS AND DEREGULATES GENE EXPRESSION. OVER THE PAST DECADES, THERE HAVE BEEN HUGE ADVANCES IN UNDERSTANDING CELLULAR RESPONSES TO IONISING RADIATION (IR) AND DNA DAMAGE. THESE STUDIES, HOWEVER, WERE MOSTLY EXECUTED WITH CELL LINES AND MICE USING SINGLE OR MULTIPLE ACUTE DOSES OF RADIATION. HENCE, RELATIVELY LITTLE IS KNOWN ABOUT HOW CONTINUOUS EXPOSURE TO LOW DOSE IONISING RADIATION AFFECTS NORMAL CELLS AND ORGANISMS, EVEN THOUGH OUR CELLS ARE CONSTANTLY EXPOSED TO LOW LEVELS OF RADIATION. WE ADDRESSED THIS ISSUE BY EXAMINING THE CONSEQUENCES OF EXPOSING HUMAN PRIMARY CELLS TO CONTINUOUS IONISING GAMMA-RADIATION DELIVERED AT 6-20 MGY/H. ALTHOUGH THESE DOSE RATES ARE ESTIMATED TO INFLICT FEWER THAN A SINGLE DNA DOUBLE-STRAND BREAK (DSB) PER HOUR PER CELL, THEY STILL CAUSED DOSE-DEPENDENT REDUCTIONS IN CELL PROLIFERATION AND INCREASED CELLULAR SENESCENCE. WE CONCOMITANTLY OBSERVED HISTONE PROTEIN LEVELS TO REDUCE BY UP TO 40%, WHICH IN CONTRAST TO PREVIOUS OBSERVATIONS, WAS NOT MAINLY DUE TO PROTEIN DEGRADATION BUT INSTEAD CORRELATED WITH REDUCED HISTONE GENE EXPRESSION. HISTONE REDUCTIONS WERE ACCOMPANIED BY ENLARGED NUCLEAR SIZE PARALLELED BY AN INCREASE IN GLOBAL TRANSCRIPTION, INCLUDING THAT OF PRO-INFLAMMATORY GENES. THUS, CHRONIC IRRADIATION, EVEN AT LOW DOSE-RATES, CAN INDUCE CELL SENESCENCE AND ALTER GENE EXPRESSION VIA A HITHERTO UNCHARACTERISED EPIGENETIC ROUTE. THESE FEATURES OF CHRONIC RADIATION REPRESENT A NEW ASPECT OF RADIATION BIOLOGY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13  5942  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14  4984  27 PATHWAYS OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI VIRULENCE AND INTERACTIONS WITH ANTIOXIDANT SYSTEMS, VITAMIN C AND PHYTOCHEMICALS. HELICOBACTER PYLORI IS A CLASS ONE CARCINOGEN WHICH CAUSES CHRONIC ATROPHIC GASTRITIS, GASTRIC INTESTINAL METAPLASIA, DYSPLASIA AND ADENOCARCINOMA. THE MECHANISMS BY WHICH H. PYLORI INTERACTS WITH OTHER RISK AND PROTECTIVE FACTORS, PARTICULARLY VITAMIN C IN GASTRIC CARCINOGENESIS ARE COMPLEX. GASTRIC CARCINOGENESIS INCLUDES METABOLIC, ENVIRONMENTAL, EPIGENETIC, GENOMIC, INFECTIVE, INFLAMMATORY AND ONCOGENIC PATHWAYS. THE MOLECULAR CLASSIFICATION OF GASTRIC CANCER SUBTYPES HAS REVOLUTIONIZED THE UNDERSTANDING OF GASTRIC CARCINOGENESIS. THIS INCLUDES THE TUMOUR MICROENVIRONMENT, GERMLINE MUTATIONS, AND THE ROLE OF HELICOBACTER PYLORI BACTERIA, EPSTEIN BARR VIRUS AND EPIGENETICS IN SOMATIC MUTATIONS. THERE IS EVIDENCE THAT ASCORBIC ACID, PHYTOCHEMICALS AND ENDOGENOUS ANTIOXIDANT SYSTEMS CAN MODIFY THE RISK OF GASTRIC CANCER. GASTRIC JUICE ASCORBATE LEVELS DEPEND ON DIETARY INTAKE OF ASCORBIC ACID BUT CAN ALSO BE DECREASED BY H. PYLORI INFECTION, H. PYLORI CAGA SECRETION, TOBACCO SMOKING, ACHLORHYDRIA AND CHRONIC ATROPHIC GASTRITIS. ASCORBIC ACID MAY BE PROTECTIVE AGAINST GASTRIC CANCER BY ITS ANTIOXIDANT EFFECT IN GASTRIC CYTOPROTECTION, REGENERATING ACTIVE VITAMIN E AND GLUTATHIONE, INHIBITING ENDOGENOUS N-NITROSATION, REDUCING TOXIC EFFECTS OF INGESTED NITROSODIMETHYLAMINES AND HETEROCYCLIC AMINES, AND PREVENTING H. PYLORI INFECTION. THE EFFECTIVENESS OF SUCH CYTOPROTECTION IS RELATED TO H. PYLORI STRAIN VIRULENCE, PARTICULARLY CAGA EXPRESSION. THE ROLE OF VITAMIN C IN EPIGENETIC REPROGRAMMING IN GASTRIC CANCER IS STILL EVOLVING. OTHER FACTORS IN CONJUNCTION WITH VITAMIN C ALSO PLAY A ROLE IN GASTRIC CARCINOGENESIS. ERADICATION OF H. PYLORI MAY LEAD TO RECOVERY OF VITAMIN C SECRETION BY GASTRIC EPITHELIUM AND ENABLE REGRESSION OF PREMALIGNANT GASTRIC LESIONS, THEREBY INTERRUPTING THE CORREA CASCADE OF GASTRIC CARCINOGENESIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                     
15  5628  19 SEMEN ABNORMALITIES, SPERM DNA DAMAGE AND GLOBAL HYPERMETHYLATION IN HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION. BACKGROUND: CYTOGENETIC STUDIES HAVE DEMONSTRATED THAT LOW LEVELS OF CHRONIC RADIATION EXPOSURE CAN POTENTIALLY INCREASE THE FREQUENCY OF CHROMOSOMAL ABERRATIONS AND ANEUPLOIDY IN SOMATIC CELLS. EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION BEAR AN INCREASED RISK OF HEMATOLOGICAL MALIGNANCIES. OBJECTIVES: TO FIND THE INFLUENCE OF OCCUPATIONAL RADIATION EXPOSURE ON SEMEN CHARACTERISTICS, INCLUDING GENETIC AND EPIGENETIC INTEGRITY OF SPERMATOZOA IN A CHRONICALLY EXPOSED POPULATION. METHODS: THIS CROSS SECTIONAL STUDY INCLUDED 134 MALE VOLUNTEERS OF WHICH 83 WERE OCCUPATIONALLY EXPOSED TO IONIZING RADIATION AND 51 WERE NON-EXPOSED CONTROL SUBJECTS. SEMEN CHARACTERISTICS, SPERM DNA FRAGMENTATION, ANEUPLOIDY AND INCIDENCE OF GLOBAL HYPERMETHYLATION IN THE SPERMATOZOA WERE DETERMINED AND COMPARED BETWEEN THE NON-EXPOSED AND THE EXPOSED GROUP. RESULTS: DIRECT COMPARISON OF THE SEMEN CHARACTERISTICS BETWEEN THE NON-EXPOSED AND THE EXPOSED POPULATION REVEALED SIGNIFICANT DIFFERENCES IN MOTILITY CHARACTERISTICS, VIABILITY, AND MORPHOLOGICAL ABNORMALITIES (P<0.05-0.0001). ALTHOUGH, THE LEVEL OF SPERM DNA FRAGMENTATION WAS SIGNIFICANTLY HIGHER IN THE EXPOSED GROUP AS COMPARED TO THE NON-EXPOSED GROUP (P<0.05-0.0001), THE INCIDENCE OF SPERM ANEUPLOIDY WAS NOT STATISTICALLY DIFFERENT BETWEEN THE TWO GROUPS. HOWEVER, A SIGNIFICANT NUMBER OF HYPERMETHYLATED SPERMATOZOA WERE OBSERVED IN THE EXPOSED GROUP IN COMPARISON TO NON-EXPOSED GROUP (P<0.05). CONCLUSIONS: WE PROVIDE THE FIRST EVIDENCE ON THE DETRIMENTAL EFFECTS OF OCCUPATIONAL RADIATION EXPOSURE ON FUNCTIONAL, GENETIC AND EPIGENETIC INTEGRITY OF SPERM IN HEALTH WORKERS. HOWEVER, FURTHER STUDIES ARE REQUIRED TO CONFIRM THE POTENTIAL DETRIMENTAL EFFECTS OF IONIZING RADIATION IN THESE SUBJECTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  4044  18 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  1399  23 DIET-INDUCED OBESITY MODULATES EPIGENETIC RESPONSES TO IONIZING RADIATION IN MICE. BOTH EXPOSURE TO IONIZING RADIATION AND OBESITY HAVE BEEN ASSOCIATED WITH VARIOUS PATHOLOGIES INCLUDING CANCER. THERE IS A CRUCIAL NEED IN BETTER UNDERSTANDING THE INTERACTIONS BETWEEN IONIZING RADIATION EFFECTS (ESPECIALLY AT LOW DOSES) AND OTHER RISK FACTORS, SUCH AS OBESITY. IN ORDER TO EVALUATE RADIATION RESPONSES IN OBESE ANIMALS, C3H AND C57BL/6J MICE FED A CONTROL NORMAL FAT OR A HIGH FAT (HF) DIET WERE EXPOSED TO FRACTIONATED DOSES OF X-RAYS (0.75 GY X4). BONE MARROW MICRONUCLEUS ASSAYS DID NOT SUGGEST A MODULATION OF RADIATION-INDUCED GENOTOXICITY BY HF DIET. USING MSP, WE OBSERVED THAT THE PROMOTERS OF P16 AND DAPK GENES WERE METHYLATED IN THE LIVERS OF C57BL/6J MICE FED A HF DIET (IRRADIATED AND NON-IRRADIATED); MGMT PROMOTER WAS METHYLATED IN IRRADIATED AND/OR HF DIET-FED MICE. IN ADDITION, METHYLATION PCR ARRAYS IDENTIFIED EP300 AND SOCS1 (WHOSE PROMOTERS EXHIBITED HIGHER METHYLATION LEVELS IN NON-IRRADIATED HF DIET-FED MICE) AS POTENTIAL TARGETS FOR FURTHER STUDIES. WE THEN COMPARED MICRORNA REGULATIONS AFTER RADIATION EXPOSURE IN THE LIVERS OF C57BL/6J MICE FED A NORMAL OR AN HF DIET, USING MICRORNA ARRAYS. INTERESTINGLY, RADIATION-TRIGGERED MICRORNA REGULATIONS OBSERVED IN NORMAL MICE WERE NOT OBSERVED IN OBESE MICE. MIR-466E WAS UPREGULATED IN NON-IRRADIATED OBESE MICE. IN VITRO FREE FATTY ACID (PALMITIC ACID, OLEIC ACID) ADMINISTRATION SENSITIZED AML12 MOUSE LIVER CELLS TO IONIZING RADIATION, BUT THE INHIBITION OF MIR-466E COUNTERACTED THIS RADIO-SENSITIZATION, SUGGESTING THAT THE MODULATION OF RADIATION RESPONSES BY DIET-INDUCED OBESITY MIGHT INVOLVE MIR-466E EXPRESSION. ALL TOGETHER, OUR RESULTS SUGGESTED THE EXISTENCE OF DIETARY EFFECTS ON RADIATION RESPONSES (ESPECIALLY EPIGENETIC REGULATIONS) IN MICE, POSSIBLY IN RELATIONSHIP WITH OBESITY-INDUCED CHRONIC OXIDATIVE STRESS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  5227  22 PRMT6 MEDIATES INFLAMMATION VIA ACTIVATION OF THE NF-KAPPAB/P65 PATHWAY ON A CIGARETTE SMOKE EXTRACT-INDUCED MURINE EMPHYSEMA MODEL. INTRODUCTION: SMOKE-DRIVEN LUNG INFLAMMATION IS CONSIDERED TO BE THE MAJOR PATHOPHYSIOLOGY MECHANISM OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA. PROTEIN ARGININE METHYLTRANSFERASE 6 (PRMT6) IS A KEY EPIGENETIC ENZYME, WHICH IS RELATED TO PROTECTING THE TRI-METHYLATION OF H3K4 (H3K4ME3). WE HYPOTHESIZED THAT PTMT6 PROTECTS LUNG INFLAMMATION THROUGH THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY. METHODS: MICE WERE INJECTED WITH CIGARETTE SMOKE EXTRACT (CSE) OR PBS TO ESTABLISH A MICE MODEL, INTRATRACHEALLY INSTILLED WITH OVEREXPRESSED PRMT6 OR NEGATIVE CONTROL VECTOR. MORPHOMETRY OF LUNG SLIDES AND LUNG FUNCTION WERE MEASURED. WE DETERMINED THE PROTEIN EXPRESSION OF PRMT6 AND ITS RELATED HISTONE TARGETS, THE ACTIVATION OF NF-KAPPAB PATHWAY, THE LEVEL OF TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) AND INTERLEUKIN-1BETA (IL-1BETA). RESULTS: AFTER PRMT6 OVEREXPRESSION, THE MORPHOMETRY INDEXES AND LUNG FUNCTION WERE IMPROVED. ALSO, THE EXPRESSION OF H3K4ME3 WAS DECREASED. OVEREXPRESSED PRMT6 COULD SUPPRESS CSE-INDUCED NF-KAPPAB ACTIVATION AND PRO-INFLAMMATION GENES EXPRESSION. CONCLUSIONS: THE OVEREXPRESSED PRMT6 COULD SERVE AS AN INFLAMMATION INHIBITOR, POTENTIALLY THROUGH BLOCKING THE NF-KAPPAB/P65 PATHWAY IN THE MURINE EMPHYSEMA MODEL.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  2940  27 GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL AND SENSITIVE COPD-DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5). EVEN THOUGH CLINICAL, EPIDEMIOLOGICAL AND TOXICOLOGICAL STUDIES HAVE PROGRESSIVELY PROVIDED A BETTER KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS, FURTHER IN VITRO STUDIES ON RELEVANT CELL SYSTEMS ARE STILL NEEDED. HENCE, AIMING OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS, PRIMARY HUMAN BRONCHIAL EPITHELIAL CELLS DERIVED FROM NORMAL SUBJECTS (NHBE) OR SENSITIVE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED PATIENTS (DHBE) WERE DIFFERENTIATED AT THE AIR-LIQUID INTERFACE. THEREAFTER, THEY WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) TO STUDY THE OCCURRENCE OF SOME RELEVANT GENETIC AND/OR EPIGENETIC ENDPOINTS. CONCENTRATION-, EXPOSURE- AND SEASON-DEPENDENT INCREASES OF OH-B[A]P METABOLITES IN NHBE, AND TO A LESSER EXTENT, COPD-DHBE CELLS WERE REPORTED; HOWEVER, THERE WERE MORE TETRA-OH-B[A]P AND 8-OHDG DNA ADDUCTS IN COPD-DHBE CELLS. NO INCREASE IN PRIMARY DNA STRAND BREAK NOR CHROMOSOMAL ABERRATION WAS OBSERVED IN REPEATEDLY EXPOSED CELLS. TELOMERE LENGTH AND TELOMERASE ACTIVITY WERE MODIFIED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN NHBE AND PARTICULARLY COPD-DHBE CELLS. THERE WERE A GLOBAL DNA HYPOMETHYLATION, A P16 GENE PROMOTER HYPERMETHYLATION, AND A DECREASING DNA METHYLTRANSFERASE ACTIVITY IN NHBE AND NOTABLY COPD-DHBE CELLS REPEATEDLY EXPOSED. CHANGES IN SITE-SPECIFIC METHYLATION, ACETYLATION, AND PHOSPHORYLATION OF HISTONE H3 (I.E., H3K4ME3, H3K9AC, H3K27AC, AND H3S10PH) AND RELATED ENZYME ACTIVITIES OCCURRED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN ALL THE REPEATEDLY EXPOSED CELLS. COLLECTIVELY, THESE RESULTS HIGHLIGHTED THE KEY ROLE PLAYED BY GENETIC AND EVEN EPIGENETIC EVENTS IN NHBE AND PARTICULARLY SENSITIVE COPD-DHBE CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) AND THEIR DIFFERENT RESPONSIVENESS. WHILE THESE SPECIFIC EPIGENETIC CHANGES HAVE BEEN ALREADY DESCRIBED IN COPD AND EVEN LUNG CANCER PHENOTYPES, OUR FINDINGS SUPPORTED THAT, TOGETHER WITH GENETIC EVENTS, THESE EPIGENETIC EVENTS COULD DRAMATICALLY CONTRIBUTE TO THE SHIFT FROM HEALTHY TO DISEASED PHENOTYPES FOLLOWING REPEATED EXPOSURE TO RELATIVELY LOW DOSES OF AIR POLLUTION-DERIVED PM(2.5).	2017	

20  3287  40 HIERARCHICAL AND CYBERNETIC NATURE OF BIOLOGIC SYSTEMS AND THEIR RELEVANCE TO HOMEOSTATIC ADAPTATION TO LOW-LEVEL EXPOSURES TO OXIDATIVE STRESS-INDUCING AGENTS. DURING EVOLUTION IN AN AEROBIC ENVIRONMENT, MULTICELLULAR ORGANISMS SURVIVED BY ADAPTIVE RESPONSES TO BOTH THE ENDOGENOUS OXIDATIVE METABOLISM IN THE CELLS OF THE ORGANISM AND THE CHEMICALS AND LOW-LEVEL RADIATION TO WHICH THEY HAD BEEN EXPOSED. THE DEFENSE REPERTOIRE EXISTS AT ALL LEVELS OF THE BIOLOGICAL HIERARCHY--FROM THE MOLECULAR AND BIOCHEMICAL LEVEL TO THE CELLULAR AND TISSUE LEVEL TO THE ORGAN AND ORGAN SYSTEM LEVEL. CELLS CONTAIN PREVENTIVE ANTIOXIDANTS TO SUPPRESS OXIDATIVE DAMAGE TO MEMBRANES. CELLS ALSO CONTAIN PROTEINS AND DNA; BUILT-IN REDUNDANCIES FOR DAMAGED MOLECULES AND ORGANELLES; TIGHTLY COUPLED REDOX SYSTEMS; POOLS OF REDUCTANTS; ANTIOXIDANTS; DNA REPAIR MECHANISMS AND SENSITIVE SENSOR MOLECULES SUCH AS NUCLEAR FACTOR KAPPA BETA; AND SIGNAL TRANSDUCTION MECHANISMS AFFECTING BOTH TRANSCRIPTION AND POST-TRANSLATIONAL MODIFICATION OF PROTEINS NEEDED TO COPE WITH OXIDATIVE STRESS. THE BIOLOGIC CONSEQUENCES OF THE LOW-LEVEL RADIATION THAT EXCEEDS THE BACKGROUND LEVEL OF OXIDATIVE DAMAGE COULD BE NECROSIS OR APOPTOSIS, CELL PROLIFERATION, OR CELL DIFFERENTIATION. THESE EFFECTS ARE TRIGGERED BY OXIDATIVE STRESS-INDUCED SIGNAL TRANSDUCTION MECHANISMS--AN EPIGENETIC, NOT GENOTOXIC, PROCESS. IF THE END POINTS OF CELL PROLIFERATION, DIFFERENTIATION, OR CELL DEATH ARE NOT SEEN AT FREQUENCIES ABOVE BACKGROUND LEVELS IN AN ORGANISM, IT IS UNLIKELY THAT LOW-LEVEL RADIATION WOULD PLAY A ROLE IN THE MULTISTEP PROCESSES OF CHRONIC DISEASES SUCH AS CANCER. THE MECHANISM LINKED TO HOMEOSTATIC REGULATION OF PROLIFERATION AND ADAPTIVE FUNCTIONS IN A MULTICELLULAR ORGANISM COULD PROVIDE PROTECTION OF ANY ONE CELL RECEIVING DEPOSITED ENERGY BY THE RADIATION TRACT THROUGH THE SHARING OF REDUCTANTS AND BY TRIGGERING APOPTOSIS OF TARGET STEM CELLS. EXAMPLES OF THE ROLE OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION IN THE ADAPTIVE RESPONSE OF CELLS AND THE BYSTANDER EFFECT ILLUSTRATE HOW THE INTERACTION OF CELLS CAN MODULATE THE EFFECT OF RADIATION ON THE SINGLE CELL.	1998