1 4894 243 OXIDATIVE STRESS CAUSED BY ACUTE AND CHRONIC EXPOSITION TO ALTITUDE. IN THIS ARTICLE, CURRENT VIEWS ON CELLULAR AND MOLECULAR BIOLOGY (BIOCHEMICAL) MECHANISMS ARE DISCUSSED UNDER THE ASPECT OF ALTITUDE EXPOSITION. THE ANDEAN, TIBETAN, AND ETHIOPIAN PATTERNS OF ADAPTATION TO HIGH-ALTITUDE HYPOXIA ARE KNOWN [BEAL ET AL. (2002) PROC NATL ACAD SCI USA 99: 17215-17218]. THE PHYLOGENETIC TREE OF THE HUMAN SPECIES SUGGESTS THAT THERE ARE GENETIC DIFFERENCES IN ADAPTATION PATTERNS TO CHRONIC HYPOXIC HYPOXIA. FIVE DEFENSE MECHANISMS ARE WELL ESTABLISHED FOR LOWLANDERS WHO ARE EXPOSED TO ACUTE HYPOXIC HYPOXIA. CONSEQUENCES OF THE CELLULAR DECREASE IN ATP ARE THE FORMATION OF HYPOXANTHINE AND XANTHINE, WHICH ARE THE SUBSTRATES FOR THE MASSIVE FORMATION OF SUPEROXIDE ANION RADICALS AND HYDROGEN PEROXIDE VIA THE OXIDASE ACTIVITY OF THE XANTHINE OXIDOREDUCTASE REACTION. UNDER SEVERE HYPOXIA, ABOUT 51 % OF THE TOTAL INHALED OXYGEN IS USED TO FORM SUPEROXIDE ANION RADICALS IN RAT LIVER [GERBER ET AL. (1989) ADV EXP MED BIOL 253B, PLENUM PRESS, NEW YORK, 497-504]. THE REACTIVITY AND SELECTIVITY OF THE SUPEROXIDE ANION RADICAL ARE MODIFIED BY SPECIFIC INTERACTIONS AND ELECTRON EXCHANGE. IT IS COMMONLY ACCEPTED THAT THE SUPEROXIDE ANION RADICAL IN AQUEOUS SOLUTIONS HAS A LIFETIME IN THE MILLISECOND RANGE. HOWEVER, ELECTRON SPIN RESONANCE SPECTROSCOPY STUDIES IN A KO2/H2O/IRON ION SYSTEM REVEALED FOR THE FIRST TIME A STABILIZATION OF A PART OF THE INITIALLY ADDED SUPEROXIDE ANION RADICALS LASTING UP TO HOURS AT ROOM TEMPERATURE [FOLDES-PAPP (1992) GEN PHYSIOL BIOPHYS 11: 3-38]. SUPEROXIDE ANION RADICALS ADSORBED ON AN OXIDIC IRON HYDRATE PHASE IN AQUEOUS SYSTEMS MIGHT FUNCTION AS A STRONG OXIDANT SIMILAR TO THAT SPECIES WHICH HAS BEEN SUGGESTED TO BE A COMPLEX BETWEEN OXYGEN AND DIFFERENT VALENCE STATES OF IRON IN THE INITIATION OF LIPID PEROXIDATION BY FERROUS IRON. THERE WERE SERIOUS DOUBTS ABOUT THE IDENTITY OF ALKOXY RADICALS. FOR THE FIRST TIME, ALKOXY RADICALS WERE DIRECTLY DEMONSTRATED IN SOLUTION BY ELECTRON SPIN RESONANCE SPECTROSCOPY [FOLDES-PAPP ET AL. (1991) ADV SYNTH CATAL 333: 293-301]. THE REDOX STATUS IN MAMMALIAN CELLS IS MAINLY DETERMINED BY THE ANTIOXIDANT GLUTATHIONE, WHICH IS A KEY PLAYER IN MAINTAINING THE INTRACELLULAR REDOX EQUILIBRIUM AND IN THE METABOLIC REGULATION OF THE CELLULAR DEFENSE AGAINST OXIDATIVE STRESS. AS REACTIVE OXYGEN SPECIES OCCUPY AN ESSENTIAL ROLE IN MEMBRANE DAMAGE, THE IDEA OF MEMBRANE-BOUND ENZYMATIC DEFENSE MECHANISMS GETS A NEW DIMENSION [FOLDES-PAPP ET AL. (1981) ACTA BIOL MED GER 40: 1129-1132; FOLDES-PAPP AND MARETZKI (1982) ACTA BIOL MED GER 41: 1003-1008]. THE STEADY-STATE BETWEEN ANTIOXIDANTS AND PRO-OXIDANTS AFFECTS THE GENE EXPRESSION VIA HYPOXIA-INDUCED TRANSCRIPTION ACTIVITIES. THE TRANSCRIPTION FACTOR HYPOXIA-INDUCIBLE FACTOR 1 (HIF-1) IS A GLOBAL REGULATOR OF OXYGEN HOMEOSTASIS. AS DISCUSSED IN THIS ARTICLE, HYPOXIA OR 'OXIDATIVE STRESS' IS ACCOMPANIED BY APPROPRIATE MOLECULAR ADAPTATION MECHANISMS AT THE ENZYMATIC OR EPIGENETIC LEVEL (ENZYMATIC AND NON-ENZYMATIC RADICAL INHIBITORS, POSTTRANSLATIONAL MODIFICATIONS) AND AT THE GENETIC LEVEL (TRANSCRIPTION, TRANSLATION).	2005	

2 6484  30 TOXICOLOGIC PROFILE OF ACRYLONITRILE. ACRYLONITRILE IS A MONOMER USED EXTENSIVELY AS A RAW MATERIAL IN THE MANUFACTURING OF ACRYLIC FIBERS, PLASTICS, SYNTHETIC RUBBERS, AND ACRYLAMIDE. IT HAS BEEN CLASSIFIED AS A PROBABLE HUMAN CARCINOGEN ACCORDING TO THE RESULTS OF NUMEROUS CHRONIC RAT BIOASSAYS. THE PRESENT REPORT SUMMARIZES THE TOXICITY DATA ON ACRYLONITRILE AND REVIEWS AVAILABLE DATA CONCERNING THE MECHANISM (GENETIC VERSUS EPIGENETIC) BY WHICH ACRYLONITRILE IS CARCINOGENIC IN RATS. FROM THE EVALUATION OF THE RELEVANT TOXICITY DATA, IT CAN BE CONCLUDED THAT ACRYLONITRILE IS INDEED CARCINOGENIC TO RATS AFTER EITHER ORAL OR INHALATIONAL EXPOSURE. HOWEVER, INFORMATION ON OTHER MAMMALIAN SPECIES IS LACKING, AND, MOREOVER, THE EXACT MECHANISM OF THE CARCINOGENIC PROCESS IS UNCLEAR. THEREFORE, IT IS RECOMMENDED TO CONDUCT AN ADDITIONAL LONG-TERM INHALATION CARCINOGENICITY STUDY WITH ACRYLONITRILE IN MICE, AS WELL AS STUDIES INTO THE MECHANISM BY WHICH ACRYLONITRILE INDUCES (BRAIN) TUMORS IN RATS (GENETIC VERSUS EPIGENETIC).	1998	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
3 1109  32 COMMERCIAL PROCESSED SOY-BASED FOOD PRODUCT CONTAINS GLYCATED AND GLYCOXIDATED LUNASIN PROTEOFORMS. NUTRACEUTICALS HAVE BEEN PROPOSED TO EXERT POSITIVE EFFECTS ON HUMAN HEALTH AND CONFER PROTECTION AGAINST MANY CHRONIC DISEASES. A MAJOR BIOACTIVE COMPONENT OF SOY-BASED FOODS IS LUNASIN PEPTIDE, WHICH HAS POTENTIAL TO EXERT A MAJOR IMPACT ON THE HEALTH OF HUMAN CONSUMERS WORLDWIDE, BUT THE BIOCHEMICAL FEATURES OF DIETARY LUNASIN STILL REMAIN POORLY CHARACTERIZED. IN THIS STUDY, LUNASIN WAS PURIFIED FROM A SOY-BASED FOOD PRODUCT VIA STRONG ANION EXCHANGE SOLID PHASE EXTRACTION AND THEN SUBJECTED TO TOP-DOWN MASS SPECTROMETRY ANALYSIS THAT REVEALED IN DETAIL THE MOLECULAR DIVERSITY OF LUNASIN IN PROCESSED SOYBEAN FOODS. WE DETECTED MULTIPLE GLYCATED PROTEOFORMS TOGETHER WITH POTENTIALLY TOXIC ADVANCED GLYCATION END PRODUCTS (AGES) DERIVED FROM LUNASIN. IN BOTH CASES, MODIFICATION SITES WERE LYS24 AND LYS29 LOCATED AT THE HELICAL REGION THAT SHOWS STRUCTURAL HOMOLOGY WITH A CONSERVED REGION OF CHROMATIN-BINDING PROTEINS. THE IDENTIFIED POST-TRANSLATIONAL MODIFICATIONS MAY HAVE AN IMPORTANT REPERCUSSION ON LUNASIN EPIGENETIC REGULATORY CAPACITY. TAKING TOGETHER, OUR RESULTS DEMONSTRATE THE IMPORTANCE OF PROPER CHEMICAL CHARACTERIZATION OF COMMERCIAL PROCESSED FOOD PRODUCTS TO ASSESS THEIR IMPACT ON CONSUMER'S HEALTH AND RISK OF CHRONIC DISEASES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  452  28 APPLICATION OF THE KEY CHARACTERISTICS OF CARCINOGENS TO PER AND POLYFLUOROALKYL SUBSTANCES. PER- AND POLYFLUOROALKYL SUBSTANCES (PFAS) CONSTITUTE A LARGE CLASS OF ENVIRONMENTALLY PERSISTENT CHEMICALS USED IN INDUSTRIAL AND CONSUMER PRODUCTS. HUMAN EXPOSURE TO PFAS IS EXTENSIVE, AND PFAS CONTAMINATION HAS BEEN REPORTED IN DRINKING WATER AND FOOD SUPPLIES AS WELL AS IN THE SERUM OF NEARLY ALL PEOPLE. THE MOST WELL-STUDIED MEMBER OF THE PFAS CLASS, PERFLUOROOCTANOIC ACID (PFOA), INDUCES TUMORS IN ANIMAL BIOASSAYS AND HAS BEEN ASSOCIATED WITH ELEVATED RISK OF CANCER IN HUMAN POPULATIONS. GENX, ONE OF THE PFOA REPLACEMENT CHEMICALS, INDUCES TUMORS IN ANIMAL BIOASSAYS AS WELL. USING THE KEY CHARACTERISTICS OF CARCINOGENS FRAMEWORK FOR CANCER HAZARD IDENTIFICATION, WE CONSIDERED THE EXISTING EPIDEMIOLOGICAL, TOXICOLOGICAL AND MECHANISTIC DATA FOR 26 DIFFERENT PFAS. WE FOUND STRONG EVIDENCE THAT MULTIPLE PFAS INDUCE OXIDATIVE STRESS, ARE IMMUNOSUPPRESSIVE, AND MODULATE RECEPTOR-MEDIATED EFFECTS. WE ALSO FOUND SUGGESTIVE EVIDENCE INDICATING THAT SOME PFAS CAN INDUCE EPIGENETIC ALTERATIONS AND INFLUENCE CELL PROLIFERATION. EXPERIMENTAL DATA INDICATE THAT PFAS ARE NOT GENOTOXIC AND GENERALLY DO NOT UNDERGO METABOLIC ACTIVATION. DATA ARE CURRENTLY INSUFFICIENT TO ASSESS WHETHER ANY PFAS PROMOTE CHRONIC INFLAMMATION, CELLULAR IMMORTALIZATION OR ALTER DNA REPAIR. WHILE MORE RESEARCH IS NEEDED TO ADDRESS DATA GAPS, EVIDENCE EXISTS THAT SEVERAL PFAS EXHIBIT ONE OR MORE OF THE KEY CHARACTERISTICS OF CARCINOGENS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5 2818  20 FIBROSIS UNDER ARREST. APPROXIMATELY 5% OF PEOPLE THAT ARE HOSPITALIZED FOR ANY REASON DEVELOP ACUTE KIDNEY FAILURE, WHICH, IN SOME CASES, PROGRESSES TO A CHRONIC CONDITION RESULTING IN FIBROSIS OF THE KIDNEY AND PERMANENT CHANGES IN THE ORGAN'S FUNCTION. TWO NEW STUDIES SUGGEST THAT CELL CYCLE ARREST OF EPITHELIAL CELLS AND EPIGENETIC MODIFICATIONS HAVE KEY ROLES IN THE SWITCH TO CHRONIC DISEASE (PAGES 535-543 AND 544-550).	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6 4834  34 ON THE INTERPLAY BETWEEN THE MEDICINE OF HILDEGARD OF BINGEN AND MODERN MEDICINE: THE ROLE OF ESTROGEN RECEPTOR AS AN EXAMPLE OF BIODYNAMIC INTERFACE FOR STUDYING THE CHRONIC DISEASE'S COMPLEXITY. INTRODUCTION: HILDEGARD OF BINGEN (1098-1179) INTERPRETED THE ORIGINS OF CHRONIC DISEASE HIGHLIGHTING AND ANTICIPATING, ALTHOUGH ONLY IN A LIMITED FASHION, THE IMPORTANCE THAT COMPLEX INTERACTIONS AMONG NUMEROUS GENETIC, INTERNAL MILIEU AND EXTERNAL ENVIRONMENTAL FACTORS HAVE IN DETERMINING THE DISEASE PHENOTYPE. TODAY, WE RECOGNIZE THOSE FACTORS, CAPABLE OF MEDIATING THE TRANSMISSION OF MESSAGES BETWEEN HUMAN BODY AND ENVIRONMENT AND VICE VERSA, AS BIODYNAMIC INTERFACES. AIM: WE ANALYZED, IN THE LIGHT OF MODERN SCIENTIFIC EVIDENCE, HILDEGARD OF BINGEN'S MEDICAL APPROACH AND HER ORIGINAL HUMORAL THEORY IN ORDER TO IDENTIFY POSSIBLE INSIGHTS INCLUDED IN HER MEDICINE THAT COULD BE REFERRED TO IN THE CONTEXT OF MODERN EVIDENCE-BASED MEDICINE. IN PARTICULAR, THE ABBESS'S HUMORAL THEORY SUGGESTS THE IDENTIFICATION OF BIODYNAMIC INTERFACES WITH SEX HORMONES AND THEIR RECEPTORS. FINDINGS: WE FOUND THAT THE HILDEGARDIAN HOLISTIC VISION OF THE ORGANISM-ENVIRONMENT RELATIONSHIP CAN ACTUALLY REPRESENT A VISIONARY APPROACH TO MODERN ENDOCRINOLOGY AND THAT SEX HORMONES, IN PARTICULAR ESTROGENS, COULD REPRESENT AN EXAMPLE OF A BIODYNAMIC INTERFACE. ESTROGEN RECEPTORS ARE FOUND IN REGIONS OF THE BRAIN INVOLVED IN EMOTIONAL AND COGNITIVE REGULATION, CONTROLLING THE MOLECULAR MECHANISM OF BRAIN FUNCTION. ESTROGEN RECEPTORS ARE INVOLVED IN THE REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IN THE EPIGENETIC REGULATION OF RESPONSES TO PHYSIOLOGICAL, SOCIAL, AND HORMONAL STIMULI. FURTHERMORE, ESTROGEN AFFECTS GENE METHYLATION ON ITS OWN AND RELATED RECEPTOR PROMOTERS IN DISCRETE REGIONS OF THE DEVELOPING BRAIN. THIS SCENARIO WAS STRIKINGLY PERCEIVED BY THE ABBESS IN THE XIITH CENTURY, AND DEPICTED AS A COMPLEX INTERPLAY AMONG DIFFERENT HUMORS AND FLEGMATA THAT SHE RECOGNIZED TO BE SEX SPECIFIC AND ENVIRONMENTALLY REGULATED. VIEWPOINT: CONSIDERING THE FUNCTION PLAYED BY HORMONES, ANALYZED THROUGH THE LAST SCIENTIFIC EVIDENCE, AND SCIENTIFIC LITERATURE ON BIODYNAMIC INTERFACES, WE COULD SUGGEST HILDEGARDIAN INSIGHTS AND THEORIES AS THE FIRST ATTEMPT TO DESCRIBE THE MODERN HOLISTIC, SEX-BASED MEDICINE. CONCLUSION: HILDEGARD ANTICIPATED A CONCEPT OF PATHOGENESIS THAT SEES A CENTRAL ROLE FOR ENDOCRINOLOGY IN SEX-SPECIFIC DISEASE. FURTHERMORE, ESTROGENS AND ESTROGEN RECEPTORS COULD REPRESENT A GOOD EXAMPLE OF MOLECULAR INTERFACES CAPABLE OF MODULATING THE INTERACTION BETWEEN THE ORGANISM INTERNAL MILIEU AND THE ENVIRONMENTAL FACTORS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7 5046  43 PHARMACOLOGICAL AND DIETARY ANTIOXIDANT THERAPIES FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE PROGRESSION AND EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE INTIMATELY ASSOCIATED WITH TOBACCO SMOKE/BIOMASS FUEL-INDUCED OXIDATIVE AND ALDEHYDE/CARBONYL STRESS. ALTERATIONS IN REDOX SIGNALING PROINFLAMMATORY KINASES AND TRANSCRIPTION FACTORS, STEROID RESISTANCE, UNFOLDED PROTEIN RESPONSE, MUCUS HYPERSECRETION, EXTRACELLULAR MATRIX REMODELING, AUTOPHAGY/APOPTOSIS, EPIGENETIC CHANGES, CELLULAR SENESCENCE/AGING, ENDOTHELIAL DYSFUNCTION, AUTOIMMUNITY, AND SKELETAL MUSCLE DYSFUNCTION ARE SOME OF THE PATHOLOGICAL HALLMARKS OF COPD. IN LIGHT OF THE ABOVE IT WOULD BE PRUDENT TO TARGET SYSTEMIC AND LOCAL OXIDATIVE STRESS WITH AGENTS THAT CAN MODULATE THE ANTIOXIDANTS/ REDOX SYSTEM OR BY BOOSTING THE ENDOGENOUS LEVELS OF ANTIOXIDANTS FOR THE TREATMENT AND MANAGEMENT OF COPD. IDENTIFICATION OF VARIOUS ANTIOXIDANT AGENTS, SUCH AS THIOL MOLECULES (GLUTATHIONE AND MUCOLYTIC DRUGS, SUCH AS N-ACETYL-L-CYSTEINE, N-ACYSTELYN, ERDOSTEINE, FUDOSTEINE, ERGOTHIONEINE, AND CARBOCYSTEINE LYSINE SALT), DIETARY NATURAL PRODUCT-DERIVED POLYPHENOLS AND OTHER COMPOUNDS (CURCUMIN, RESVERATROL, GREEN TEA CATECHINS, QUERCETIN SULFORAPHANE, LYCOPENE, ACAI, ALPHA-LIPOIC ACID, TOCOTRIENOLS, AND APOCYNIN) HAVE MADE IT POSSIBLE TO MODULATE VARIOUS BIOCHEMICAL ASPECTS OF COPD. VARIOUS RESEARCHES AND CLINICAL TRIALS HAVE REVEALED THAT THESE ANTIOXIDANTS CAN DETOXIFY FREE RADICALS AND OXIDANTS, CONTROL EXPRESSION OF REDOX AND GLUTATHIONE BIOSYNTHESIS GENES, CHROMATIN REMODELING, AND ULTIMATELY INFLAMMATORY GENE EXPRESSION. IN ADDITION, MODULATION OF CIGARETTE SMOKE-INDUCED OXIDATIVE STRESS AND RELATED CELLULAR CHANGES HAVE ALSO BEEN REPORTED TO BE EFFECTED BY SYNTHETIC MOLECULES. THIS INCLUDES SPECIFIC SPIN TRAPS LIKE ALPHA-PHENYL-N-TERT-BUTYL NITRONE, A CATALYTIC ANTIOXIDANT (ECSOD MIMETIC), PORPHYRINS (AEOL 10150 AND AEOL 10113), AND A SUPEROXIDE DISMUTASE MIMETIC M40419, LIPID PEROXIDATION AND PROTEIN CARBONYLATION BLOCKERS/INHIBITORS, SUCH AS EDARAVONE AND LAZAROIDS/TIRILAZAD, MYELOPEROXIDASE INHIBITORS, AS WELL AS SPECIALIZED PRO-RESOLVING MEDIATORS/INFLAMMATORY RESOLVING LIPID MEDIATORS, OMEGA-3 FATTY ACIDS, VITAMIN D, AND HYDROGEN SULFIDE. ACCORDING TO VARIOUS STUDIES IT APPEARS THAT THE ADMINISTRATION OF MULTIPLE ANTIOXIDANTS COULD BE A MORE EFFECTIVE MODE USED IN THE TREATMENT OF COPD. IN THIS REVIEW, VARIOUS PHARMACOLOGICAL AND DIETARY APPROACHES TO ENHANCE LUNG ANTIOXIDANT LEVELS AND BENEFICIAL EFFECTS OF ANTIOXIDANT THERAPEUTICS IN TREATING OR INTERVENING THE PROGRESSION OF COPD HAVE BEEN DISCUSSED.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8 3465  47 HYPOTHESIS: REGULATION OF NEUROPLASTICITY MAY INVOLVE I-MOTIF AND G-QUADRUPLEX DNA FORMATION MODULATED BY EPIGENETIC MECHANISMS. RECENT STUDIES DEMONSTRATED THE EXISTENCE IN VIVO OF VARIOUS FUNCTIONAL DNA STRUCTURES THAT DIFFER FROM THE DOUBLE HELIX. THE G-QUADRUPLEX (G4) AND INTERCALATED MOTIF (I-MOTIF OR IM) DNA STRUCTURES ARE FORMED AS KNOTS WHERE, CORRESPONDINGLY, GUANINES OR CYTOSINES ON THE SAME STRAND OF DNA BIND TO EACH OTHER. THERE ARE GROUNDS TO BELIEVE THAT G4 AND IM SEQUENCES PLAY A SIGNIFICANT ROLE IN REGULATING GENE EXPRESSION CONSIDERING THEIR TENDENCY TO BE FOUND IN OR NEAR REGULATORY SITES (SUCH AS PROMOTERS, ENHANCERS, AND TELOMERES) AS WELL AS THE CORRELATION BETWEEN THE PREVALENCE OF G4 OR IM CONFORMATIONS AND SPECIFIC PHASES OF CELL CYCLE. NOTABLY, G4 AND IM CAPABLE SEQUENCES TEND TO BE FOUND ON THE OPPOSITE STRANDS OF THE SAME DNA SITE WITH AT MOST ONE OF THE TWO STRUCTURES FORMED AT ANY GIVEN TIME. THE RECENT EVIDENCE THAT K(+), MG(2+) CONCENTRATIONS DIRECTLY AFFECT IM FORMATION (AND LIKELY G4 FORMATION INDIRECTLY) LEAD US TO BELIEVE THAT THESE STRUCTURES MAY PLAY A MAJOR ROLE IN SYNAPTIC PLASTICITY OF NEURONS, AND, THEREFORE, IN A VARIETY OF CENTRAL NERVOUS SYSTEM (CNS) FUNCTIONS INCLUDING MEMORY, LEARNING, HABITUAL BEHAVIORS, PAIN PERCEPTION AND OTHERS. FURTHERMORE, EPIGENETIC MECHANISMS, WHICH HAVE AN IMPORTANT ROLE IN SYNAPTIC PLASTICITY AND MEMORY FORMATION, WERE ALSO SHOWN TO INFLUENCE FORMATION AND STABILITY OF G4S AND IMS. OUR HYPOTHESIS IS THAT NON-CANONICAL DNA AND RNA STRUCTURES COULD BE AN INTEGRAL PART OF NEUROPLASTICITY CONTROL VIA GENE EXPRESSION REGULATION AT THE LEVEL OF TRANSCRIPTION, TRANSLATION AND SPLICING. WE PROPOSE THAT THE REGULATORY ACTIVITY OF DNA IM AND G4 STRUCTURES IS MODULATED BY DNA METHYLATION/DEMETHYLATION OF THE IM AND/OR G4 SEQUENCES, WHICH FACILITATES THE SWITCH BETWEEN CANONICAL AND NON-CANONICAL CONFORMATION. OTHER NEURONAL MECHANISMS INTERACTING WITH THE FORMATION AND REGULATORY ACTIVITY OF NON-CANONICAL DNA AND RNA STRUCTURES, PARTICULARLY G4, IM AND TRIPLEXES, MAY INVOLVE MICRORNAS AS WELL AS ION AND PROTON FLUXES. WE ARE PROPOSING EXPERIMENTS IN ACUTE BRAIN SLICES AND IN VIVO TO TEST OUR HYPOTHESIS. THE PROPOSED STUDIES WOULD PROVIDE NEW INSIGHTS INTO FUNDAMENTAL NEURONAL MECHANISMS IN HEALTH AND DISEASE AND POTENTIALLY OPEN NEW AVENUES FOR TREATING MENTAL HEALTH DISORDERS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9 5809  30 STRAWBERRY AND HUMAN HEALTH: EFFECTS BEYOND ANTIOXIDANT ACTIVITY. THE USEFULNESS OF A DIET RICH IN VEGETABLES AND FRUITS ON HUMAN HEALTH HAS BEEN WIDELY RECOGNIZED: A HIGH INTAKE OF ANTIOXIDANT AND BIOACTIVE COMPOUNDS MAY IN FACT PLAY A CRUCIAL ROLE IN THE PREVENTION OF SEVERAL DISEASES, SUCH AS CANCER, CARDIOVASCULAR, NEURODEGENERATIVE, AND OTHER CHRONIC PATHOLOGIES. THE STRAWBERRY (FRAGARIA X ANANASSA DUCH.) POSSESSES A REMARKABLE NUTRITIONAL COMPOSITION IN TERMS OF MICRONUTRIENTS, SUCH AS MINERALS, VITAMIN C, AND FOLATES, AND NON-NUTRIENT ELEMENTS, SUCH AS PHENOLIC COMPOUNDS, THAT ARE ESSENTIAL FOR HUMAN HEALTH. ALTHOUGH STRAWBERRY PHENOLICS ARE KNOWN MAINLY FOR THEIR ANTI-INFLAMMATORY AND ANTIOXIDANT ACTIONS, RECENT STUDIES HAVE DEMONSTRATED THAT THEIR BIOLOGICAL ACTIVITIES ALSO SPREAD TO OTHER PATHWAYS INVOLVED IN CELLULAR METABOLISM AND CELLULAR SURVIVAL. THIS PAPER HAS THE MAIN OBJECTIVE OF REVIEWING CURRENT INFORMATION ABOUT THE POTENTIAL MECHANISMS INVOLVED IN THE EFFECTS ELICITED BY STRAWBERRY POLYPHENOLS ON HUMAN HEALTH, DEVOTING SPECIAL ATTENTION TO THE LATEST FINDINGS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10 5153  26 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  491  36 ASSESSING THE IMPACT OF POLYETHYLENE NANO/MICROPLASTIC EXPOSURE ON HUMAN VAGINAL KERATINOCYTES. THE GLOBAL RISE OF SINGLE-USE THROW-AWAY PLASTIC PRODUCTS HAS ELICITED A MASSIVE INCREASE IN THE NANO/MICROPLASTICS (N/MPLS) EXPOSURE BURDEN IN HUMANS. RECENTLY, IT HAS BEEN DEMONSTRATED THAT DISPOSABLE PERIOD PRODUCTS MAY RELEASE N/MPLS WITH USAGE, WHICH REPRESENTS A POTENTIAL THREAT TO WOMEN'S HEALTH WHICH HAS NOT BEEN SCIENTIFICALLY ADDRESSED YET. BY USING POLYETHYL ENE (PE) PARTICLES (200 NM TO 9 MUM), WE SHOWED THAT ACUTE EXPOSURE TO A HIGH CONCENTRATION OF N/MPLS INDUCED CELL TOXICITY IN VAGINAL KERATINOCYTES AFTER EFFECTIVE CELLULAR UPTAKE, AS VIABILITY AND APOPTOSIS DATA SUGGEST, ALONG WITH TRANSMISSION ELECTRON MICROSCOPY (TEM) OBSERVATIONS. THE INTERNALISED N/MPLS ALTERED THE EXPRESSION OF JUNCTIONAL AND ADHERENCE PROTEINS AND THE ORGANISATION OF THE ACTIN CORTEX, INFLUENCING THE LEVEL OF GENES INVOLVED IN OXIDATIVE STRESS SIGNALLING PATHWAYS AND THAT OF MIRNAS RELATED TO EPITHELIAL BARRIER FUNCTION. WHEN THE EXPOSURE TO PE N/MPLS WAS DISCONTINUED OR BECAME CHRONIC, CELLS WERE ABLE TO RECOVER FROM THE NEGATIVE EFFECTS ON VIABILITY AND DIFFERENTIATION/PROLIFERATION GENE EXPRESSION IN A FEW DAYS. HOWEVER, IN ALL CASES, PE N/MPL EXPOSURE PROMPTED A SUSTAINED ALTERATION OF DNA METHYLTRANSFERASE AND DNA DEMETHYLASE EXPRESSION, WHICH MIGHT IMPACT EPIGENETIC REGULATION PROCESSES, LEADING TO ACCELERATED CELL AGEING AND INFLAMMATION, OR THE OCCURRENCE OF MALIGNANT TRANSFORMATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12 3074  26 GENOME-WIDE DNA METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INORGANIC NANOPARTICLES IN HUMAN KIDNEY CELLS AFTER CHRONIC EXPOSURE. THE UNIQUE PHYSICOCHEMICAL PROPERTIES MAKE INORGANIC NANOPARTICLES (INPS) AN EXCITING TOOL IN DIAGNOSIS AND DISEASE MANAGEMENT. HOWEVER, AS INPS ARE RELATIVELY DIFFICULT TO FULLY DEGRADE AND EXCRETE, THEIR UNINTENDED ACCUMULATION IN THE TISSUE MIGHT RESULT IN ADVERSE HEALTH EFFECTS. HEREIN, WE PROVIDE A METHYLOME-TRANSCRIPTOME FRAMEWORK FOR CHRONIC EFFECTS OF INPS, COMMONLY USED IN BIOMEDICAL APPLICATIONS, IN HUMAN KIDNEY TH-1 CELLS. RENAL CLEARANCE IS ONE OF THE MOST IMPORTANT ROUTES OF NANOPARTICLE EXCRETION; THEREFORE, A DETAILED EVALUATION OF NANOPARTICLE-MEDIATED NEPHROTOXICITY IS AN IMPORTANT TASK. INTEGRATED ANALYSIS OF METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INPS (PEG-AUNPS, FE(3)O(4)NPS, SIO(2)NPS, AND TIO(2)NPS) REVEALED SIGNIFICANTLY DEREGULATED GENES WITH FUNCTIONAL CLASSIFICATION IN IMMUNE RESPONSE, DNA DAMAGE, AND CANCER-RELATED PATHWAYS. ALTHOUGH MOST DEREGULATED GENES WERE UNIQUE TO INDIVIDUAL INPS, A RELATIVELY HIGH PROPORTION OF THEM ENCODED THE TRANSCRIPTION FACTORS. INTERESTINGLY, FOS HYPERMETHYLATION INVERSELY CORRELATING WITH GENE EXPRESSION WAS ASSOCIATED WITH ALL INPS EXPOSURES. OUR STUDY EMPHASIZES THE NEED FOR A MORE COMPREHENSIVE INVESTIGATION OF INPS' BIOLOGICAL SAFETY, ESPECIALLY AFTER CHRONIC EXPOSURE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13 6351  37 THE ROLE OF EPIGENOMICS IN MAPPING POTENTIAL PRECURSORS FOR FOOT AND ANKLE TENDINOPATHY: A SYSTEMATIC REVIEW. TENDINOPATHY OF THE FOOT AND ANKLE IS A COMMON CLINICAL PROBLEM FOR WHICH THE EXACT ETIOLOGY IS POORLY UNDERSTOOD. THE FIELD OF EPIGENETICS HAS BEEN A RECENT FOCUS OF THIS INVESTIGATION. THE PURPOSE OF THIS ARTICLE WAS TO REVIEW THE GENOMIC ADVANCES IN FOOT AND ANKLE TENDINOPATHY THAT COULD POTENTIALLY BE USED TO STRATIFY DISEASE RISK AND CREATE PREVENTATIVE OR THERAPEUTIC AGENTS. A MULTI-DATABASE SEARCH OF PUBMED, COCHRANE, GOOGLE SCHOLAR, AND CLINICALTRIALS.GOV FROM JANUARY 1, 2000 TO JULY 1, 2022 WAS PERFORMED. A TOTAL OF 18 ARTICLES MET INCLUSION AND EXCLUSION CRITERIA FOR THIS REVIEW. THE MAJORITY OF SUCH RESEARCH UTILIZED CASE-CONTROL CANDIDATE GENE ASSOCIATION TO IDENTIFY DIFFERENT GENETIC RISK FACTORS ASSOCIATED WITH CHRONIC TENDINOPATHY. POLYMORPHISMS IN COLLAGEN GENES COL5A1, COL27A1, AND COL1A1 WERE NOTED AT A SIGNIFICANTLY HIGHER FREQUENCY IN ACHILLES TENDINOPATHY VERSUS CONTROL GROUPS. OTHER ALLELIC VARIATIONS THAT WERE OBSERVED AT AN INCREASED INCIDENCE IN ACHILLES TENDINOPATHY WERE TNC AND CASP8. THE EXTRACELLULAR MATRIX (ECM) DEMONSTRATED MACROSCOPIC CHANGES IN ACHILLES TENDINOPATHY, INCLUDING AN INCREASE IN AGGRECAN AND BIGLYCAN MRNA EXPRESSION, AND INCREASED EXPRESSION OF MULTIPLE MATRIX METALLOPROTEINASES. CYTOKINE EXPRESSION WAS ALSO INFLUENCED IN PATHOLOGY AND ABERRANTLY DEMONSTRATED DYNAMIC RESPONSE TO MECHANICAL LOAD. THE PATHOLOGIC ACCUMULATION OF ECM PROTEINS AND CYTOKINE EXPRESSION ALTERS THE ADAPTIVE RESPONSE NORMAL TENDON HAS TO PHYSIOLOGIC STRESS, FURTHER PROPAGATING THE RISK FOR TENDINOPATHY. BY IDENTIFYING AND UNDERSTANDING THE EPIGENETIC MEDIATORS THAT LEAD TO TENDINOPATHY, THERAPEUTIC AGENTS CAN BE DEVELOPED TO TARGET THE EXACT UNDERLYING ETIOLOGY AND MINIMIZE SIDE EFFECTS.LEVEL OF EVIDENCE: LEVEL IV: SYSTEMATIC REVIEW OF LEVEL II-IV STUDIES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14 3899  25 LATE NEUROLOGICAL CONSEQUENCES OF ZIKA VIRUS INFECTION: RISK FACTORS AND PHARMACEUTICAL APPROACHES. ZIKA VIRUS (ZIKV) INFECTION WAS HISTORICALLY CONSIDERED A DISEASE WITH MILD SYMPTOMS AND NO MAJOR CONSEQUENCES TO HUMAN HEALTH. HOWEVER, SEVERAL LONG-TERM, LATE ONSET, AND CHRONIC NEUROLOGICAL COMPLICATIONS, BOTH IN CONGENITALLY-EXPOSED BABIES AND IN ADULT PATIENTS, HAVE BEEN REPORTED AFTER ZIKV INFECTION, ESPECIALLY AFTER THE 2015 EPIDEMICS IN THE AMERICAN CONTINENT. THE DEVELOPMENT OR SEVERITY OF THESE CONDITIONS CANNOT BE FULLY PREDICTED, BUT IT IS POSSIBLE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO DETERMINE ZIKV INFECTION OUTCOMES. THIS REINFORCES THE IMPORTANCE THAT INDIVIDUALS EXPOSED TO ZIKV ARE SUBMITTED TO LONG-TERM CLINICAL SURVEILLANCE AND HIGHLIGHTS THE URGENT NEED FOR THE DEVELOPMENT OF THERAPEUTIC APPROACHES TO REDUCE OR ELIMINATE THE NEUROLOGICAL BURDEN OF INFECTION. HERE, WE REVIEW THE EPIDEMIOLOGY OF ZIKV-ASSOCIATED NEUROLOGICAL COMPLICATIONS AND THE ROLE OF FACTORS THAT MAY INFLUENCE DISEASE OUTCOME. MOREOVER, WE DISCUSS EXPERIMENTAL AND CLINICAL EVIDENCE OF DRUGS THAT HAVE SHOWN PROMISING RESULTS IN VITRO OR IN VITRO AGAINST VIRAL REPLICATION AND AND/OR ZIKV-INDUCED NEUROTOXICITY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  227  26 ADAPTATION OF AN OUTBREAKING INSECT DEFOLIATOR TO CHRONIC NUTRITIONAL STRESS. DURING INSECT OUTBREAKS, THE HIGH NUMBER OF INDIVIDUALS FEEDING ON ITS HOST PLANT CAUSES A DEPLETION OF THE FOOD SOURCE. REDUCED AVAILABILITY AND DECREASED QUALITY OF NUTRIENTS NEGATIVELY INFLUENCE LIFE-HISTORY TRAITS OF INSECTS DRIVING THEM TO DEVELOP ADAPTIVE STRATEGIES TO PERSIST IN THE ENVIRONMENT. IN A LABORATORY EXPERIMENT WITH THREE REPETITIONS, WE TESTED THE EFFECT OF CHRONIC NUTRITIONAL STRESS ON SPRUCE BUDWORM PERFORMANCE DURING THREE GENERATIONS TO DETERMINE THE ADAPTIVE STRATEGIES EMPLOYED BY THE INSECT TO DEAL WITH A SELECTION PRESSURE PRODUCED BY LOW-QUALITY DIET. OUR RESULTS SHOW THAT ALL TESTED LIFE-HISTORY TRAITS (MORTALITY, DEVELOPMENTAL TIME, PUPAL MASS, GROWTH RATE AND FEMALE FECUNDITY) BUT FEMALE FERTILITY WERE NEGATIVELY INFLUENCED BY THE LOW-QUALITY DIET SIMULATING FOOD DEPLETION DURING OUTBREAK CONDITIONS. HOWEVER, ESPECIALLY FEMALES IN THE THIRD GENERATION UNDER CHRONIC NUTRITIONAL STRESS SHOW AN ADAPTIVE RESPONSE IN LIFE-HISTORY TRAITS WHEN COMPARED TO THOSE REARED ONLY ONE GENERATION ON LOW-QUALITY DIET. LARVAL DEVELOPMENTAL TIME SIGNIFICANTLY DECREASED AND PUPAL MASS, GROWTH RATE AND FECUNDITY SIGNIFICANTLY INCREASED. THE STUDY DEMONSTRATES THE CAPACITY OF SPRUCE BUDWORM TO REACT TO CHRONIC NUTRITIONAL STRESS WITH ADAPTATIONS THAT MAY BE CAUSED BY EPIGENETIC PARENTAL EFFECTS. THIS INFORMATION CAN HELP TO UNDERSTAND THE COURSE OF AN OUTBREAK ESPECIALLY AT PEAK DENSITIES AND DURING THE COLLAPSE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16 2597  33 EPIGENETICS OF SUBCELLULAR STRUCTURE FUNCTIONING IN THE ORIGIN OF RISK OR RESILIENCE TO COMORBIDITY OF NEUROPSYCHIATRIC AND CARDIOMETABOLIC DISORDERS. MECHANISMS CONTROLLING MITOCHONDRIAL FUNCTION, PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM (ER) AND NUCLEAR PROCESSES SUCH AS TELOMERE LENGTH AND DNA REPAIR MAY BE SUBJECT TO EPIGENETIC CUES THAT RELATE THE GENOMIC EXPRESSION AND ENVIRONMENTAL EXPOSURES IN EARLY STAGES OF LIFE. THEY MAY ALSO BE INVOLVED IN THE COMORBID APPEARANCE OF CARDIOMETABOLIC (CMD) AND NEUROPSYCHIATRIC DISORDERS (NPD) DURING ADULTHOOD. MITOCHONDRIAL FUNCTION AND PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM ARE ASSOCIATED WITH OXIDATIVE STRESS AND ELEVATED INTRACELLULAR CALCIUM LEVELS AND MAY ALSO UNDERLIE THE VULNERABILITY FOR COMORBID CMD AND NPD. MITOCHONDRIA PROVIDE KEY METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+), ATP, ALPHA-KETOGLUTARATE AND ACETYL COENZYME A THAT ARE REQUIRED FOR MANY TRANSCRIPTIONAL AND EPIGENETIC PROCESSES. THEY ARE ALSO A SOURCE OF FREE RADICALS. ON THE OTHER HAND, EPIGENETIC MARKERS IN NUCLEAR DNA DETERMINE MITOCHONDRIAL BIOGENESIS. THE ER IS THE SUBCELLULAR ORGANELLE IN WHICH SECRETORY PROTEINS ARE FOLDED. MANY ENVIRONMENTAL FACTORS STOP THE ABILITY OF CELLS TO PROPERLY FOLD PROTEINS AND MODIFY POST-TRANSLATIONALLY SECRETORY AND TRANSMEMBRANE PROTEINS LEADING TO ENDOPLASMIC RETICULUM STRESS AND OXIDATIVE STRESS. ER FUNCTIONING MAY BE EPIGENETICALLY DETERMINED. CHRONIC ER STRESS IS EMERGING AS A KEY CONTRIBUTOR TO A GROWING LIST OF HUMAN DISEASES, INCLUDING CMD AND NPD. TELOMERE LOSS CAUSES CHROMOSOMAL FUSION, ACTIVATION OF THE CONTROL OF DNA DAMAGE-RESPONSES, UNSTABLE GENOME AND ALTERED STEM CELL FUNCTION, WHICH MAY UNDERLIE THE COMORBIDITY OF CMD AND NPD. THE LENGTH OF TELOMERES IS RELATED TO OXIDATIVE STRESS AND MAY BE EPIGENETICALLY PROGRAMMED. PATHWAYS INVOLVED IN DNA REPAIR MAY BE EPIGENETICALLY PROGRAMMED AND MAY CONTRIBUTE TO DISEASES. IN THIS PAPER, WE DESCRIBE SUBCELLULAR MECHANISMS THAT ARE DETERMINED BY EPIGENETIC MARKERS AND THEIR POSSIBLE RELATION TO THE DEVELOPMENT OF INCREASED SUSCEPTIBILITY TO DEVELOP CMD AND NPD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17 4019  30 LOW-DOSE OR LOW-DOSE-RATE IONIZING RADIATION-INDUCED BIOEFFECTS IN ANIMAL MODELS. ANIMAL EXPERIMENTAL STUDIES INDICATE THAT ACUTE OR CHRONIC LOW-DOSE IONIZING RADIATION (LDIR) (</=100 MSV) OR LOW-DOSE-RATE IONIZING RADIATION (LDRIR) (<6 MSV/H) EXPOSURES MAY BE HARMFUL. IT INDUCES GENETIC AND EPIGENETIC CHANGES AND IS ASSOCIATED WITH A RANGE OF PHYSIOLOGICAL DISTURBANCES THAT INCLUDES ALTERED IMMUNE SYSTEM, ABNORMAL BRAIN DEVELOPMENT WITH RESULTANT COGNITIVE IMPAIRMENT, CATARACTOGENESIS, ABNORMAL EMBRYONIC DEVELOPMENT, CIRCULATORY DISEASES, WEIGHT GAIN, PREMATURE MENOPAUSE IN FEMALE ANIMALS, TUMORIGENESIS AND SHORTENED LIFESPAN. PATERNAL OR PRENATAL LDIR/LDRIR EXPOSURE IS ASSOCIATED WITH REDUCED FERTILITY AND NUMBER OF LIVE FETUSES, AND TRANSGENERATIONAL GENOMIC ABERRATIONS. ON THE OTHER HAND, IN SOME EXPERIMENTAL STUDIES, LDIR/LDRIR EXPOSURE HAS ALSO BEEN REPORTED TO BRING ABOUT BENEFICIAL EFFECTS SUCH AS REDUCTION IN TUMORIGENESIS, PROLONGED LIFESPAN AND ENHANCED FERTILITY. THE DIFFERENCES IN REPORTED EFFECTS OF LDIR/LDRIR EXPOSURE ARE DEPENDENT ON ANIMAL GENETIC BACKGROUND (SUSCEPTIBILITY), AGE (PRENATAL OR POSTNATAL DAYS), SEX, NATURE OF RADIATION EXPOSURE (I.E. ACUTE, FRACTIONATED OR CHRONIC RADIATION EXPOSURE), TYPE OF RADIATION, COMBINATION OF RADIATION WITH OTHER TOXIC AGENTS (SUCH AS SMOKING, PESTICIDES OR OTHER CHEMICAL TOXINS) OR ANIMAL EXPERIMENTAL DESIGNS. IN THIS REVIEW PAPER, WE AIMED TO UPDATE RADIATION RESEARCHERS AND RADIOLOGISTS ON THE CURRENT PROGRESS ACHIEVED IN UNDERSTANDING THE LDIR/LDRIR-INDUCED BIONEGATIVE AND BIOPOSITIVE EFFECTS REPORTED IN THE VARIOUS ANIMAL MODELS. THE ROLES PLAYED BY A VARIETY OF MOLECULES THAT ARE IMPLICATED IN LDIR/LDRIR-INDUCED HEALTH EFFECTS WILL BE ELABORATED. THE REVIEW WILL HELP IN FUTURE INVESTIGATIONS OF LDIR/LDRIR-INDUCED HEALTH EFFECTS BY PROVIDING CLUES FOR DESIGNING IMPROVED ANIMAL RESEARCH MODELS IN ORDER TO CLARIFY THE CURRENT CONTROVERSIAL/CONTRADICTORY FINDINGS FROM EXISTING STUDIES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18  238  33 ADENOSINE KINASE: A KEY REGULATOR OF PURINERGIC PHYSIOLOGY. ADENOSINE (ADO) IS AN ESSENTIAL BIOMOLECULE FOR LIFE THAT PROVIDES CRITICAL REGULATION OF ENERGY UTILIZATION AND HOMEOSTASIS. ADENOSINE KINASE (ADK) IS AN EVOLUTIONARY ANCIENT RIBOKINASE DERIVED FROM BACTERIAL SUGAR KINASES THAT IS WIDELY EXPRESSED IN ALL FORMS OF LIFE, TISSUES AND ORGAN SYSTEMS THAT TIGHTLY REGULATES INTRACELLULAR AND EXTRACELLULAR ADO CONCENTRATIONS. THE FACILE ABILITY OF ADK TO ALTER ADO AVAILABILITY PROVIDES A "SITE AND EVENT" SPECIFICITY TO THE ENDOGENOUS PROTECTIVE EFFECTS OF ADO IN SITUATIONS OF CELLULAR STRESS. IN ADDITION TO MODULATING THE ABILITY OF ADO TO ACTIVATE ITS COGNATE RECEPTORS (P1 RECEPTORS), NUCLEAR ADK ISOFORM ACTIVITY HAS BEEN LINKED TO EPIGENETIC MECHANISMS BASED ON TRANSMETHYLATION PATHWAYS. PREVIOUS DRUG DISCOVERY RESEARCH HAS TARGETED ADK INHIBITION AS A THERAPEUTIC APPROACH TO MANAGE EPILEPSY, PAIN, AND INFLAMMATION. THESE EFFORTS GENERATED MULTIPLE CLASSES OF HIGHLY POTENT AND SELECTIVE INHIBITORS. HOWEVER, CLINICAL DEVELOPMENT OF EARLY ADK INHIBITORS WAS STOPPED DUE TO APPARENT MECHANISTIC TOXICITY AND THE LACK OF SUITABLE TRANSLATIONAL MARKERS. NEW INSIGHTS REGARDING THE POTENTIAL ROLE OF THE NUCLEAR ADK ISOFORM (ADK-LONG) IN THE EPIGENETIC MODULATION OF MALADAPTIVE DNA METHYLATION OFFERS THE POSSIBILITY OF IDENTIFYING NOVEL ADK-ISOFORM SELECTIVE INHIBITORS AND NEW INTERVENTIONAL STRATEGIES THAT ARE INDEPENDENT OF ADO RECEPTOR ACTIVATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19 5511  36 RIBONUCLEASES IN TUMOR GROWTH. THIS REVIEW SUMMARIZES DATA ON AMBIGUOUS BIOLOGICAL FUNCTIONS OF RIBONUCLEASES (RNASES) AT TUMOR GROWTH. IN SOME CASES THE RAISED LEVEL OF ENZYME ACTIVITY IN BIOLOGICAL FLUIDS CAN BE REGARDED AS AN ADDITIONAL MARKER OF MALIGNANT GROWTH (PANCREAS CANCER, CHRONIC MYELOID LEUKEMIA, ETC.). AT THE SAME TIME THE ACTIVITY OF RNASES IS OFTEN LOWERED IN TUMOR TISSUE. HIGH SUBSTRATE SPECIFICITY OF PARTICULAR RNASES PROVIDES METABOLIC BALANCE BETWEEN VARIOUS KINDS OF RNAS WITH VARIOUS HALF-TIME EXCHANGE TURN. RNASES ARE THE IMPORTANT FACTORS OF EPIGENETIC REGULATION OF GENE ACTIVITY IN CELLS. THE ACTIVITY OF RNASES IS ADJUSTABLE BY INHIBITORS AND OTHER FACTORS, AND DEFINES TIME OF EXISTENCE OF DIFFERENT KINDS OF RNAS. RNASES (THE MODIFIED VARIANTS OF RNASE A, RNASES OF SEMEN FLUID OF THE CATTLE, RNASE OF AMPHIBIA OOCYTES) CAN BE USED AS ANTI-TUMOR THERAPEUTIC AGENTS. ON THE OTHER HAND, SOME INHIBITORS OF RNASES OF NATURAL OR SYNTHETIC ORIGIN WERE DEMONSTRATED TO BE PERSPECTIVE DRUGS THAT INHIBIT TUMOR GROWTH.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20 6464  24 TISSUE MISREPAIR HYPOTHESIS FOR RADIATION CARCINOGENESIS. DOSE-RESPONSE CURVES FOR CHRONIC LEUKEMIA IN A-BOMB SURVIVORS AND LIVER TUMORS IN PATIENTS GIVEN THOROTRAST (COLLOIDAL THORIUM DIOXIDE) SHOW LARGE THRESHOLD EFFECTS. THE EXISTENCE OF THESE THRESHOLD EFFECTS CAN BE EXPLAINED BY THE FOLLOWING HYPOTHESIS. A HIGH DOSE OF RADIATION CAUSES A PERSISTENT WOUND IN A CELL-RENEWABLE TISSUE. DISORDER OF THE INJURED CELL SOCIETY PARTLY FREES THE COMPONENT CELLS FROM TERRITORIAL RESTRAINTS ON THEIR PROLIFERATION, ENABLING THEM TO CONTINUE DEVELOPMENT OF THEIR CELLULAR FUNCTIONS TOWARD ADVANCED AUTONOMY. THIS PROGRESSION MIGHT BE ACHIEVED BY CONTINUED EPIGENETIC AND GENETIC CHANGES AS A RESULT OF OCCASIONAL ERRORS IN THE OTHERWISE CONCERTED HEALING ACTION OF VARIOUS ENDOGENOUS FACTORS RECRUITED FOR TISSUE REPAIR. CARCINOGENESIS IS NOT SIMPLY A SINGLE-CELL PROBLEM BUT A CELL-SOCIETY PROBLEM. THEREFORE, IT IS NOT WARRANTED TO ESTIMATE RISK AT LOW DOSES BY LINEAR EXTRAPOLATION FROM CANCER DATA AT HIGH DOSES WITHOUT KNOWLEDGE OF THE MECHANISM OF RADIATION CARCINOGENESIS.	1991