1  3955 144 LONG MARCH TOWARD SAFE AND EFFECTIVE ANALGESIA BY ENHANCING GENE EXPRESSION OF KCC2: FIRST STEPS TAKEN. LOW INTRANEURONAL CHLORIDE IN SPINAL CORD DORSAL HORN PAIN RELAY NEURONS IS CRITICAL FOR PHYSIOLOGIC TRANSMISSION OF PRIMARY PAIN AFFERENTS BECAUSE LOW INTRANEURONAL CHLORIDE DICTATES WHETHER GABA-ERGIC AND GLYCIN-ERGIC NEUROTRANSMISSION IS INHIBITORY. IF THE NEURONAL CHLORIDE ELEVATES TO PATHOLOGIC LEVELS, THEN SPINAL CORD PRIMARY PAIN RELAY BECOMES LEAKY AND EXHIBITS THE BEHAVIORAL HALLMARKS OF PATHOLOGIC PAIN, NAMELY HYPERSENSITIVITY AND ALLODYNIA. LOW CHLORIDE IN SPINAL CORD DORSAL HORN NEURONS IS MAINTAINED BY PROPER GENE EXPRESSION OF KCC2 AND SUSTAINED PHYSIOLOGIC FUNCTION OF THE KCC2 CHLORIDE EXTRUDING ELECTRONEUTRAL TRANSPORTER. PERIPHERAL NERVE INJURY AND OTHER FORMS OF NEURAL INJURY EVOKE GREATLY DIMINISHED KCC2 GENE EXPRESSION AND SUBSEQUENT CORRUPTION OF INHIBITORY NEUROTRANSMISSION IN THE SPINAL CORD DORSAL HORN, THUS CAUSING DERAILMENT OF THE GATE FUNCTION FOR PAIN. HERE I REVIEW KEY DISCOVERIES THAT HAVE HELPED US UNDERSTAND THESE FUNDAMENTALS, AND FOCUS ON RECENT INSIGHTS RELATING TO THE DISCOVERY OF KCC2 GENE EXPRESSION ENHANCING COMPOUNDS VIA COMPOUND SCREENS IN NEURONS. ONE SUCH STUDY CHARACTERIZED THE KINASE INHIBITOR, KENPAULLONE, MORE IN-DEPTH, REVEALING ITS FUNCTION AS A ROBUST AND LONG-LASTING ANALGESIC IN PRECLINICAL MODELS OF NERVE INJURY AND CANCER BONE PAIN, ALSO ELUCIDATING ITS MECHANISM OF ACTION VIA GSK3BETA INHIBITION, DIMINISHING DELTA-CATENIN PHOSPHORYLATION, AND FACILITATING ITS NUCLEAR TRANSFER AND SUBSEQUENT ENHANCEMENT OF KCC2 GENE EXPRESSION BY DE-REPRESSING KAISO EPIGENETIC TRANSCRIPTIONAL REGULATOR. FUTURE DIRECTIONS RE KCC2 GENE EXPRESSION ENHANCEMENT ARE DISCUSSED, NAMELY COMBINATION WITH OTHER ANALGESICS AND ANALGESIC METHODS, SUCH AS SPINAL CORD STIMULATION AND ELECTROACUPUNCTURE, GENE THERAPY, AND LEVERAGING KCC2 GENE EXPRESSION-ENHANCING NANOMATERIALS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  3211  24 HEALTH EFFECTS OF EXPOSURE TO DIESEL EXHAUST PARTICLES. DIESEL-POWERED VEHICLES EMIT SUBSTANTIALLY MORE PARTICLES THAN DO GASOLINE-POWERED VEHICLES WITH CONTEMPORARY EMISSION CONTROL SYSTEMS. THE DEP ARE SUBMICRON IN SIZE AND READILY INHALED. APPROXIMATELY ONE-FOURTH OF THE PARTICLE MASS INHALED BY PEOPLE IS DEPOSITED IN THE PULMONARY REGION, SOME OF WHICH IS RETAINED WITH A HALF-LIFE OF SEVERAL HUNDRED DAYS. IN ANIMAL STUDIES, EXPOSURE TO HIGH LEVELS OF DEP OVERWHELMS THE NORMAL CLEARANCE MECHANISMS AND RESULTS IN LUNG BURDENS OF DEP THAT EXCEED THOSE PREDICTED FROM OBSERVATIONS AT LOWER EXPOSURE CONCENTRATIONS. A VARIABLE AMOUNT OF THE MASS OF DEP IS EXTRACTABLE WITH STRONG ORGANIC SOLVENTS. THE EXTRACTED MATERIAL CONTAINS MORE THAN A THOUSAND INDIVIDUAL COMPOUNDS AND IS MUTAGENIC IN A NUMBER OF BACTERIAL AND MAMMALIAN CELL ASSAYS. BIOASSAY-DIRECTED CHEMICAL ANALYSIS OF DEP HAD IDENTIFIED SEVERAL HUNDRED COMPOUNDS. MANY ARE PAHS, SOME OF WHICH ARE CONSIDERED TO HAVE HUMAN CARCINOGENIC POTENTIAL. A NUMBER OF NITRATED COMPOUNDS HAVE BEEN IDENTIFIED THAT ACCOUNT FOR A SIGNIFICANT PORTION OF THE MUTAGENICITY ASSAYED IN BACTERIA. THE MUTAGENICITY OF THE DEPE IS GENERALLY REDUCED BY ADDITION OF AN S-9 CELLULAR FRACTION OR OF SERUM PROTEINS. MACROPHAGES RAPIDLY REDUCE THE RECOVERABLE MUTAGENIC ACTIVITY ASSOCIATED WITH DEP. THESE FINDINGS SUPPORT A HYPOTHESIS THAT DETOXIFICATION OF DEP-ASSOCIATED ORGANICS OCCURS RAPIDLY IN VIVO. THE ASSOCIATION OF BENZO(A)PYRENE AND NITROPYRENE WITH DEP PROLONGS THEIR RETENTION IN THE LUNGS. THIS INCREASED RETENTION SUGGESTS THE NEED TO CLARIFY THE RELATIVE IMPORTANCE OF COMPETING MECHANISMS THAT DETOXIFY PARTICLE-ASSOCIATED COMPOUNDS AND THOSE THAT SERVE TO ENHANCE THE RETENTION OF TOXICOLOGICALLY IMPORTANT COMPOUNDS. SOME EXTRACTS OF DEP EVOKE TUMORIGENIC RESPONSES IN SKIN-TUMOR BIOASSAYS, SUGGESTING THEIR CARCINOGENIC POTENTIAL IN MAMMALS. A NUMBER OF LARGE-SCALE STUDIES HAVE BEEN CONDUCTED WITH LABORATORY RODENTS TO EVALUATE THE EFFECTS OF CHRONIC INHALATION EXPOSURE TO DE. AN INCREASED INCIDENCE OF LUNG TUMORS, SOME OF WHICH WERE DIAGNOSED AS MALIGNANT, WAS OBSERVED IN 5 STUDIES WITH RATS FOLLOWING EXPOSURE FOR 2 OR MORE YEARS TO HIGH LEVELS OF DE. MOST OF THE LUNG TUMORS WERE OBSERVED AFTER 2 YEARS. SIMILAR STUDIES IN SYRIAN HAMSTERS HAVE YIELDED NEGATIVE RESULTS. STUDIES WITH MICE HAVE GIVEN MIXED RESULTS. THE RESULTS OF SOME STUDIES WITH LABORATORY ANIMALS EXPOSED TO DE AND KNOWN CARCINOGENS SUGGEST THAT EXPOSURE TO DE ENHANCES THE EFFECT OF THE KNOWN CARCINOGENS. THE SPECIFIC MECHANISMS OF TUMOR INDUCTION IN THE DE-EXPOSED RATS ARE UNKNOWN. HYPOTHESES AND EXPERIMENTAL DATA HAVE BEEN ADVANCED IN SUPPORT OF BOTH GENETIC AND EPIGENETIC MECHANISMS OF ACTION OF THE DE.(ABSTRACT TRUNCATED AT 400 WORDS)	1987	
                                                                         
3  6563  29 TRANSIENT AND STABLE VECTOR TRANSFECTION: PITFALLS, OFF-TARGET EFFECTS, ARTIFACTS. TRANSIENT AND STABLE VECTOR TRANSFECTIONS HAVE PLAYED IMPORTANT ROLES IN ILLUSTRATING THE FUNCTION OF SPECIFIC GENES/PROTEINS. THE GENERAL ASSUMPTION IS THAT SUCH A PLATFORM COULD EFFECTIVELY LINK A GIVEN GENE/PROTEIN TO GAINED PHENOTYPES, REVEALING THE MECHANISM OF HOW A GENE WORKS. HOWEVER, IN REALITY, INCREASED STUDIES HAVE SURPRISINGLY NOTICED SOME UNEXPECTED RESULTS. IN THIS REVIEW, WE DEMONSTRATE THAT AN ASSUMPTION THAT EMPTY VECTOR-TRANSFECTED CELLS PRESERVE THE CYTOGENETIC AND PHENOTYPIC CHARACTERISTICS, AND REPRESENT THE ADEQUATE CONTROL IN TRANSFECTION EXPERIMENTS IS NOT UNIVERSALLY VALID. A DNA VECTOR, A TRANSFECTION REAGENT, EXPRESSION OF AN ANTIBIOTIC RESISTANCE (TRANS)GENE, EXPRESSION OF A REPORTER (TRANS)GENE, AND SELECTION BY ACUTE/CHRONIC ANTIBIOTIC TREATMENT MAY EVOKE CELLULAR RESPONSES THAT AFFECT THE BIOCHEMICAL PROCESSES UNDER INVESTIGATION. WE EXEMPLIFY A NUMBER OF STUDIES, WHICH REPORTED OBVIOUS GENOMIC, TRANSCRIPTOMIC AND PHENOTYPIC CHANGES OF TUMOR CELLS AFTER TRANSIENT/STABLE TRANSFECTION OF AN EMPTY VECTOR. TO FURTHER ADDRESS THE COMMON MECHANISMS OF THESE UNEXPECTED FINDINGS, WE WILL APPLY THE GENOME THEORY OF SOMATIC EVOLUTION TO EXPLAIN STRESS-MEDIATED SYSTEM DYNAMICS AND THE LIMITATIONS OF PREDICTING THE SYSTEM BEHAVIOR SOLELY BASED ON TARGETED GENES. WE CONCEPTUALIZE THAT THE DIVERSE EXPERIMENTAL MANIPULATIONS (E.G., TRANSGENE OVEREXPRESSION, GENE KNOCK OUT/DOWN, CHEMICAL TREATMENTS, ACUTE CHANGES IN CULTURE CONDITIONS, ETC.) MAY ACT AS A SYSTEM STRESS, PROMOTING INTENSIVE GENOME-LEVEL ALTERATIONS (CHROMOSOMAL INSTABILITY, CIN), EPIGENETIC AND PHENOTYPIC ALTERATIONS, WHICH ARE BEYOND THE FUNCTION OF MANIPULATED GENES. SUCH ANALYSIS CALLS FOR MORE ATTENTION ON THE REDUCED SPECIFICITIES OF GENE-FOCUSED METHODOLOGIES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4  2337  19 EPIGENETIC REGULATION OF INFLAMMATORY RESPONSES IN THE CONTEXT OF PHYSICAL ACTIVITY. EPIGENETIC MODIFICATIONS OCCUR IN RESPONSE TO ENVIRONMENTAL CHANGES AND PLAY A FUNDAMENTAL ROLE IN THE REGULATION OF GENE EXPRESSION. PA IS FOUND TO ELICIT AN INFLAMMATORY RESPONSE, BOTH FROM THE INNATE AND ADAPTIVE DIVISIONS OF THE IMMUNOLOGICAL SYSTEM. THE INFLAMMATORY REACTION IS CONSIDERED A VITAL TRIGGER OF EPIGENETIC CHANGES THAT IN TURN MODULATE INFLAMMATORY ACTIONS. THE TISSUE RESPONSES TO PA INVOLVE LOCAL AND GENERAL CHANGES. THE EPIGENETIC MECHANISMS INVOLVED INCLUDE: DNA METHYLATION, HISTONE PROTEINS MODIFICATION AND MICRORNA. ALL OF THEM AFFECT GENETIC EXPRESSION IN AN INFLAMMATORY MILIEU IN PHYSICAL EXERCISE DEPENDING ON THE MAGNITUDE OF PHYSIOLOGICAL STRESS EXPERIENCED BY THE EXERCISER. PA MAY EVOKE ACUTE OR CHRONIC BIOCHEMICAL AND PHYSIOLOGICAL RESPONSES AND HAVE A POSITIVE OR NEGATIVE IMMUNOMODULATORY EFFECT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5  5381  29 RECONSIDERING THE ROLE OF MITOCHONDRIA IN AGING. BACKGROUND: MITOCHONDRIAL DYSFUNCTION HAS LONG BEEN CONSIDERED A MAJOR CONTRIBUTOR TO AGING AND AGE-RELATED DISEASES. HARMAN'S MITOCHONDRIAL FREE RADICAL THEORY OF AGING POSTULATED THAT SOMATIC MITOCHONDRIAL DNA MUTATIONS THAT ACCUMULATE OVER THE LIFE SPAN CAUSE EXCESSIVE PRODUCTION OF REACTIVE OXYGEN SPECIES THAT DAMAGE MACROMOLECULES AND IMPAIR CELL AND TISSUE FUNCTION. INDEED, STUDIES HAVE SHOWN THAT MAXIMAL OXIDATIVE CAPACITY DECLINES WITH AGE WHILE REACTIVE OXYGEN SPECIES PRODUCTION INCREASES. HARMAN'S HYPOTHESIS HAS BEEN SERIOUSLY CHALLENGED BY RECENT STUDIES SHOWING THAT REACTIVE OXYGEN SPECIES EVOKE METABOLIC HEALTH AND LONGEVITY, PERHAPS THROUGH HORMETIC MECHANISMS THAT INCLUDE AUTOPHAGY. THE PURPOSE OF THIS REVIEW IS TO SCAN THE EVER-GROWING LITERATURE ON MITOCHONDRIA FROM THE PERSPECTIVE OF AGING RESEARCH AND TRY TO IDENTIFY PRIORITY QUESTIONS THAT SHOULD BE ADDRESSED IN FUTURE RESEARCH. METHODS: A SYSTEMATIC SEARCH OF PEER-REVIEWED STUDIES WAS PERFORMED USING PUBMED. SEARCH TERMS INCLUDED (I) MITOCHONDRIA OR MITOCHONDRIAL; (II) AGING, AGEING, OLDER ADULTS OR ELDERLY; AND (III) REACTIVE OXYGEN SPECIES, MITOCHONDRIA DYNAMICS, MITOCHONDRIAL PROTEOSTASIS, CYTOSOL, MITOCHONDRIAL-ASSOCIATED MEMBRANES, REDOX HOMEOSTASIS, ELECTRON TRANSPORT CHAIN, ELECTRON TRANSPORT CHAIN EFFICIENCY, EPIGENETIC REGULATION, DNA HETEROPLASMY. RESULTS: THE IMPORTANCE OF MITOCHONDRIAL BIOLOGY AS A TRAIT D'UNION BETWEEN THE BASIC BIOLOGY OF AGING AND THE PATHOGENESIS OF AGE-RELATED DISEASES IS STRONGER THAN EVER, ALTHOUGH THE EMPHASIS HAS MOVED FROM REACTIVE OXYGEN SPECIES PRODUCTION TO OTHER ASPECTS OF MITOCHONDRIAL PHYSIOLOGY, INCLUDING MITOCHONDRIAL BIOGENESIS AND TURNOVER, ENERGY SENSING, APOPTOSIS, SENESCENCE, AND CALCIUM DYNAMICS. CONCLUSIONS: MITOCHONDRIA COULD PLAY A KEY ROLE IN THE PATHOPHYSIOLOGY OF AGING OR IN THE EARLIER STAGES OF SOME EVENTS THAT LEAD TO THE AGING PHENOTYPE. THEREFORE, MITOCHONDRIA WILL INCREASINGLY BE TARGETED TO PREVENT AND TREAT CHRONIC DISEASES AND TO PROMOTE HEALTHY AGING.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6   835  28 CHEMICAL CARCINOGEN MECHANISMS OF ACTION AND IMPLICATIONS FOR TESTING METHODOLOGY. CHEMICAL CARCINOGENS ARE OF TWO DISTINCT TYPES, DNA-REACTIVE AND EPIGENETIC. TESTING METHODOLOGY CAN BE DIRECTED TOWARD DETECTING EFFECTS OF BOTH TYPES OF CARCINOGEN. CARCINOGENS OF THE DNA-REACTIVE TYPE ARE DEFINED BY THE FORMATION OF COVALENTLY BOUND DNA ADDUCTS. THESE CHEMICALS HAVE STRUCTURES THAT YIELD ELECTROPHILIC REACTANTS EITHER DIRECTLY OR AFTER BIOACTIVATION. THESE AGENTS CAUSE GENOMIC ALTERATION IN THE STRUCTURE OR FUNCTION OF DNA IN THE TARGET CELL. IN ADDITION, THESE COMPOUNDS CAN EXERT OTHER CELLULAR AND TISSUE EPIGENETIC EFFECTS, SUCH AS CELL PROLIFERATION AND GROWTH PROMOTION. CARCINOGENS OF THE EPIGENETIC (PARAGENETIC) TYPE, IN CONTRAST, DO NOT REACT WITH DNA, BUT RATHER DISPLAY CELLULAR EFFECTS SUCH AS NEOPLASM GROWTH PROMOTION, CYTOTOXICITY, INHIBITION OF TISSUE GROWTH REGULATION, PEROXISOME PROLIFERATION, ENDOCRINE MODIFICATION, IMMUNOSUPPRESSION AND/OR SUSTAINED TISSUE ISCHEMIA THAT CAN BE THE BASIS FOR INCREASES IN NEOPLASIA. THEIR CHEMICAL STRUCTURE IS SUCH THAT THEY DO NOT GIVE RISE TO A REACTIVE ELECTROPHILE. THE TESTING METHODOLOGIES TO IDENTIFY EITHER TYPE FOLLOW A DECISION POINT APPROACH DESIGNED TO IDENTIFY POTENTIAL CARCINOGENICITY AND YIELD MECHANISTIC INFORMATION ON THE PRODUCTION OF EFFECTS THAT UNDERLIE CARCINOGENICITY. IT HAS 5 STAGES FOCUSING ON THE CHEMICAL STRUCTURE, DNA-REACTIVITY, EPIGENETIC EFFECTS, LIMITED BIOASSAYS AND FINALLY THE APPLICATION OF THE ACCELERATED BIOASSAY (ABA). ABA REQUIRES 40 WEEKS AND APPLIES THE USE OF SENSITIVE MARKERS FOR INDUCTION OF NEOPLASIA IN COMPARISON TO POSITIVE CONTROL COMPOUNDS FOR IMPORTANT ORGANS IN HUMAN CARCINOGENESIS. IT ENABLES DATA ACQUISITION OF THE ENTIRE CARCINOGENIC PROCESS DIRECTED TOWARD DEVELOPING MECHANISTIC INFORMATION. THE ABA HAS THE POTENTIAL TO REPLACE THE CHRONIC BIOASSAY IN RODENTS IN SOME CIRCUMSTANCES AND CAN SERVE AS AN ALTERNATIVE TO A CHRONIC BIOASSAY IN A SECOND SPECIES.	1996	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7  4647  41 NEUROPEPTIDE AND SMALL TRANSMITTER COEXISTENCE: FUNDAMENTAL STUDIES AND RELEVANCE TO MENTAL ILLNESS. NEUROPEPTIDES ARE AUXILIARY MESSENGER MOLECULES THAT ALWAYS CO-EXIST IN NERVE CELLS WITH ONE OR MORE SMALL MOLECULE (CLASSIC) NEUROTRANSMITTERS. NEUROPEPTIDES ACT BOTH AS TRANSMITTERS AND TROPHIC FACTORS, AND PLAY A ROLE PARTICULARLY WHEN THE NERVOUS SYSTEM IS CHALLENGED, AS BY INJURY, PAIN OR STRESS. HERE NEUROPEPTIDES AND COEXISTENCE IN MAMMALS ARE REVIEWED, BUT WITH SPECIAL FOCUS ON THE 29/30 AMINO ACID GALANIN AND ITS THREE RECEPTORS GALR1, -R2 AND -R3. IN PARTICULAR, GALANIN'S ROLE AS A CO-TRANSMITTER IN BOTH RODENT AND HUMAN NORADRENERGIC LOCUS COERULEUS (LC) NEURONS IS ADDRESSED. EXTENSIVE EXPERIMENTAL ANIMAL DATA STRONGLY SUGGEST A ROLE FOR THE GALANIN SYSTEM IN DEPRESSION-LIKE BEHAVIOR. THE TRANSLATIONAL POTENTIAL OF THESE RESULTS WAS TESTED BY STUDYING THE GALANIN SYSTEM IN POSTMORTEM HUMAN BRAINS, FIRST IN NORMAL BRAINS, AND THEN IN A COMPARISON OF FIVE REGIONS OF BRAINS OBTAINED FROM DEPRESSED PEOPLE WHO COMMITTED SUICIDE, AND FROM MATCHED CONTROLS. THE DISTRIBUTION OF GALANIN AND THE FOUR GALANIN SYSTEM TRANSCRIPTS IN THE NORMAL HUMAN BRAIN WAS DETERMINED, AND SELECTIVE AND PARALLEL CHANGES IN LEVELS OF TRANSCRIPTS AND DNA METHYLATION FOR GALANIN AND ITS THREE RECEPTORS WERE ASSESSED IN DEPRESSED PATIENTS WHO COMMITTED SUICIDE: UPREGULATION OF TRANSCRIPTS, E.G., FOR GALANIN AND GALR3 IN LC, PARALLELED BY A DECREASE IN DNA METHYLATION, SUGGESTING INVOLVEMENT OF EPIGENETIC MECHANISMS. IT IS HYPOTHESIZED THAT, WHEN EXPOSED TO SEVERE STRESS, THE NORADRENERGIC LC NEURONS FIRE IN BURSTS AND RELEASE GALANIN FROM THEIR SOMA/DENDRITES. GALANIN THEN ACTS ON SOMATO-DENDRITIC, INHIBITORY GALANIN AUTORECEPTORS, OPENING POTASSIUM CHANNELS AND INHIBITING FIRING. THE PURPOSE OF THESE AUTORECEPTORS IS TO ACT AS A 'BRAKE' TO PREVENT OVEREXCITATION, A BRAKE THAT IS ALSO PART OF RESILIENCE TO STRESS THAT PROTECTS AGAINST DEPRESSION. DEPRESSION THEN ARISES WHEN THE INHIBITION IS TOO STRONG AND LONG LASTING - A MALADAPTION, ALLOSTATIC LOAD, LEADING TO DEPLETION OF NA LEVELS IN THE FOREBRAIN. IT IS SUGGESTED THAT DISINHIBITION BY A GALANIN ANTAGONIST MAY HAVE ANTIDEPRESSANT ACTIVITY BY RESTORING FOREBRAIN NA LEVELS. A ROLE OF GALANIN IN DEPRESSION IS ALSO SUPPORTED BY A RECENT CANDIDATE GENE STUDY, SHOWING THAT VARIANTS IN GENES FOR GALANIN AND ITS THREE RECEPTORS CONFER INCREASED RISK OF DEPRESSION AND ANXIETY IN PEOPLE WHO EXPERIENCED CHILDHOOD ADVERSITY OR RECENT NEGATIVE LIFE EVENTS. IN SUMMARY, GALANIN, A NEUROPEPTIDE COEXISTING IN LC NEURONS, MAY PARTICIPATE IN THE MECHANISM UNDERLYING RESILIENCE AGAINST A SERIOUS AND COMMON DISORDER, MDD. EXISTING AND FURTHER RESULTS MAY LEAD TO AN INCREASED UNDERSTANDING OF HOW THIS ILLNESS DEVELOPS, WHICH IN TURN COULD PROVIDE A BASIS FOR ITS TREATMENT.	2018	
                    
8  4932  18 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9   930  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10  5313  25 PSYCHOLOGICAL STRESS AS A MODULATOR OF FUNCTIONAL RECOVERY FOLLOWING SPINAL CORD INJURY. THERE IS STRONG EVIDENCE INDICATING THAT THE SOCIAL ENVIRONMENT TRIGGERS CHANGES TO THE PSYCHOLOGICAL STRESS RESPONSE AND GLUCOCORTICOID RECEPTOR FUNCTION. CONSIDERABLE LITERATURE LINKS THE SUBSEQUENT CHANGES IN STRESS RESILIENCY TO PHYSICAL HEALTH. HERE, CONVERGING EVIDENCE FOR THE MODULATORY ROLE OF CHRONIC PSYCHOLOGICAL STRESS IN THE RECOVERY PROCESS FOLLOWING SPINAL CORD INJURY (SCI) IS PRESENTED. DESPITE THE CONSIDERABLE ADVANCES IN SCI RESEARCH, WE ARE STILL UNABLE TO IDENTIFY THE CAUSES OF VARIABILITY IN PATIENTS' RECOVERY FOLLOWING INJURY. WE PROPOSE THAT INDIVIDUALS' PAST AND PRESENT LIFE EXPERIENCES (IN THE FORM OF STRESS EXPOSURE) MAY SIGNIFICANTLY MODULATE PATIENTS' OUTCOME POST-SCI. WE PROPOSE A THEORETICAL MODEL TO EXPLAIN THE NEGATIVE IMPACT OF CHRONIC PSYCHOLOGICAL STRESS ON PHYSICAL AND PSYCHOLOGICAL RECOVERY. THE STRESS EXPERIENCED IN LIFE PRIOR TO SCI AND ALSO AS A RESULT OF THE TRAUMATIC INJURY, COULD COMPROMISE GLUCOCORTICOID RECEPTOR SENSITIVITY AND FUNCTION, AND CONTRIBUTE TO HIGH LEVELS OF INFLAMMATION AND APOPTOSIS POST-SCI, DECREASING THE TISSUE REMAINING AT THE INJURY SITE AND UNDERMINING RECOVERY OF FUNCTION. BOTH STRESS-INDUCED GLUCOCORTICOID RESISTANCE AND STRESS-INDUCED EPIGENETIC CHANGES TO THE GLUCOCORTICOID RECEPTOR CAN MODULATE THE NUCLEAR FACTOR-KAPPA B REGULATED INFLAMMATORY PATHWAYS AND THE BCL-2 REGULATED APOPTOSIS PATHWAYS. THIS MODEL NOT ONLY CONTRIBUTES TO THE THEORETICAL UNDERSTANDING OF THE RECOVERY PROCESS FOLLOWING INJURY, BUT ALSO PROVIDES CONCRETE TESTABLE HYPOTHESES FOR FUTURE STUDIES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11  6078  20 THE EFFECT OF CHRONIC ARSENIC EXPOSURE IN ZEBRAFISH. ARSENIC IS A PREVALENT ENVIRONMENTAL TOXIN AND A GROUP ONE HUMAN CARCINOGENIC AGENT. CHRONIC ARSENIC EXPOSURE HAS BEEN ASSOCIATED WITH MANY HUMAN DISEASES. THE AIM OF THIS STUDY IS TO EVALUATE ZEBRAFISH AS AN ANIMAL MODEL TO ASSESS ARSENIC TOXICITY IN ELEVATED LONG-TERM ARSENIC EXPOSURE. WITH PROLONGED EXPOSURE (6 MONTHS) TO VARIOUS CONCENTRATIONS OF ARSENIC FROM 50 PPB TO 300 PPB, EFFECTS OF ARSENIC ACCUMULATION IN ZEBRAFISH TISSUES, AND PHENOTYPES WERE INVESTIGATED. RESULTS SHOWED THAT THERE ARE NO SIGNIFICANT CHANGES OF ARSENIC RETENTION IN ZEBRAFISH TISSUES, AND ZEBRAFISH DID NOT EXHIBIT ANY VISIBLE TUMOR FORMATION UNDER ARSENIC EXPOSURE CONDITIONS. HOWEVER, THE ZEBRAFISH DEMONSTRATE A DYSFUNCTION IN THEIR NEUROLOGICAL SYSTEM, WHICH IS REFLECTED BY A REDUCTION OF LOCOMOTIVE ACTIVITY. MOREOVER, ELEVATED LEVELS OF THE SUPEROXIDE DISMUTASE (SOD2) PROTEIN WERE DETECTED IN THE EYE AND LIVER, SUGGESTING INCREASED OXIDATIVE STRESS. IN ADDITION, THE PROGENIES OF ARSENIC-TREATED PARENTS DISPLAYED A SMALLER BIOMASS (FOUR-FOLD REDUCTION IN BODY WEIGHT) COMPARED WITH THOSE FROM THEIR PARENTAL CONTROLS. THIS RESULT INDICATES THAT ARSENIC MAY INDUCE GENETIC OR EPIGENETIC CHANGES THAT ARE THEN PASSED ON TO THE NEXT GENERATION. OVERALL, THIS STUDY DEMONSTRATES THAT ZEBRAFISH IS A CONVENIENT VERTEBRATE MODEL WITH ADVANTAGES IN THE EVALUATION OF ARSENIC-ASSOCIATED NEUROLOGICAL DISORDERS AS WELL AS ITS INFLUENCES ON THE OFFSPRING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12   108  17 A REVIEW OF THE PROTECTIVE EFFECT OF MELATONIN IN PESTICIDE-INDUCED TOXICITY. PESTICIDES ARE AMONG THE MOST IMPORTANT CHEMICALS USED IN AGRICULTURE SECTOR. HOWEVER, THEIR EXTENSIVE USE HAS POLLUTED THE ENVIRONMENT AND INCREASED HUMAN VULNERABILITY TO VARIOUS CHRONIC DISEASES. PESTICIDE EXPOSURE CAUSES GENETIC AND EPIGENETIC MODIFICATIONS, ENDOCRINE DISRUPTION, MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS. AREAS COVERED: THIS REVIEW IS BASED ON THE LITERATURE STUDIES CURRENTLY REPORTED ON PESTICIDE-INDUCED TOXICITY AND THE PROTECTIVE ROLE OF MELATONIN. SCIENTIFIC DATABASES SUCH AS PUBMED, SCOPUS AND WEB OF SCIENCE WERE SEARCHED USING KEYWORDS 'PESTICIDE' AND 'MELATONIN' UP TO JANUARY 2016. FULL LENGTH ARTICLES RELATED TO ANIMAL AND HUMAN EXPOSURE WERE RETRIEVED. A TOTAL NUMBER OF 181 RECORDS WERE OBTAINED, AND AFTER EXCLUDING THE DUPLICATES, 97 PAPERS WERE FURTHER SCREENED ON THE BASIS OF RELEVANCE TO THE TOPIC. EXPERT OPINION: MELATONIN AS A BROAD-SPECTRUM ANTIOXIDANT IS ABLE TO PENETRATE CELLULAR COMPARTMENTS SPECIFICALLY THE MITOCHONDRIA. IT IS A POTENT FREE RADICAL SCAVENGER WITH LOW TOXICITY AND DESIRABLE SOLUBILITY IN ORGANIC AND AQUEOUS PHASES. WE ARE OF THE OPINION THAT MELATONIN IS A PROMISING AGENT IN MINIMIZING ORGAN INJURIES INDUCED BY PESTICIDES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13  6267  23 THE NEUROENDOCRINOLOGY OF STRESS: A NEVER ENDING STORY. EVOLUTIONARY SUCCESS DEPENDS ON OUR ABILITY TO ADAPT TO CHANGING CIRCUMSTANCES. THE NEUROENDOCRINE RESPONSE TO STRESS IS AN EXCELLENT EXAMPLE OF A PLASTIC SYSTEM THAT RESPONDS TO THREATS TO HOMEOSTASIS AND ALTERS ITS OUTPUT TO MEET CURRENT AND EXPECTED FUTURE DEMANDS. AT THE LEVEL OF THE HYPOTHALAMUS, THE CORTICOTROPH SECRETAGOGUES CORTICOTROPHIN-RELEASING HORMONE (CRH) AND ARGININE VASOPRESSIN (AVP) RESPOND RAPIDLY TO AN ACUTE STRESSOR BUT, FOLLOWING CHRONIC STRESS, THEY ADAPT WITH A REDUCTION OF CRH BUT A MAJOR INCREASE IN AVP. THE RELEASE OF CRH AND AVP ACTIVATES PRO-OPIOMELANOCORTIN IN ANTERIOR PITUITARY CORTICOTROPH CELLS AND THE RELEASE OF ADRENOCORTICOTROPHIC HORMONE INTO PERIPHERAL BLOOD FROM WHERE IT TARGETS RECEPTORS IN THE ADRENAL CORTEX TO RELEASE GLUCOCORTICOID HORMONES. THESE HORMONES (I.E. CORTICOSTERONE IN THE RAT AND CORTISOL IN MAN) ARE RELEASED IN A PULSATILE ULTRADIAN PATTERN WHICH DEFINES THE NORMAL CIRCADIAN RHYTHM. THE FREQUENCY OF THE PULSES IS INCREASED UNDER STATES OF CHRONIC STRESS, AND IN RATS WITH GENETICALLY DETERMINED HYPER-RESPONSIVENESS OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. INTERESTINGLY, NEONATAL INFLUENCES CAN ALSO PROGRAMME ALTERATIONS IN ULTRADIAN RHYTHMICITY, IMPLICATING EPIGENETIC FACTORS IN ITS REGULATION. AT THE LEVEL OF TISSUE RECEPTORS, THE ALTERATION IN PATTERN OF GLUCOCORTICOID ULTRADIAN RHYTHM HAS DIFFERENTIAL EFFECTS ON MINERALOCORTICOID RECEPTOR AND GLUCOCORTICOID RECEPTOR (GR) BINDING TO DNA AND OFFERS A MECHANISM FOR TISSUE SPECIFIC RESPONSES TO ALTERED GLUCOCORTICOID DYNAMICS. THE EFFECTS OF NEONATAL EXPERIENCE ARE NOT ONLY SEEN AT THE LEVEL OF CRH AND GR REGULATION, BUT ALSO ARE EVIDENT IN BEHAVIOURAL RESPONSES TO STRESS AND IN THE RESPONSIVENESS OF BRAIN STEM SEROTONERGIC PATHWAYS, AS MEASURED BY TRYPTOPHAN HYDROXYLASE MRNA IN THE BRAIN STEM.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
14   611  28 BIDIRECTIONAL RESCUE OF EXTREME GENETIC PREDISPOSITIONS TO ANXIETY: IMPACT OF CRH RECEPTOR 1 AS EPIGENETIC PLASTICITY GENE IN THE AMYGDALA. THE CONTINUUM OF PHYSIOLOGICAL ANXIETY UP TO PSYCHOPATHOLOGY IS NOT MERELY DEPENDENT ON GENES, BUT IS ORCHESTRATED BY THE INTERPLAY OF GENETIC PREDISPOSITION, GENE X ENVIRONMENT AND EPIGENETIC INTERACTIONS. ACCORDINGLY, INBORN ANXIETY IS CONSIDERED A POLYGENIC, MULTIFACTORIAL TRAIT, LIKELY TO BE SHAPED BY ENVIRONMENTALLY DRIVEN PLASTICITY AT THE GENOMIC LEVEL. WE HERE TOOK ADVANTAGE OF THE EXTREME GENETIC PREDISPOSITION OF THE SELECTIVELY BRED HIGH (HAB) AND LOW ANXIETY (LAB) MOUSE MODEL EXHIBITING HIGH VS LOW ANXIETY-RELATED BEHAVIOR AND TESTED WHETHER AND HOW BENEFICIAL (ENRICHED ENVIRONMENT) VS DETRIMENTAL (CHRONIC MILD STRESS) ENVIRONMENTAL MANIPULATIONS ARE CAPABLE OF RESCUING PHENOTYPES FROM BOTH ENDS OF THE ANXIETY CONTINUUM. WE PROVIDE EVIDENCE THAT (I) EVEN INBORN AND SEEMINGLY RIGID BEHAVIORAL AND NEUROENDOCRINE PHENOTYPES CAN BIDIRECTIONALLY BE RESCUED BY APPROPRIATE ENVIRONMENTAL STIMULI, (II) CORTICOTROPIN-RELEASING HORMONE RECEPTOR 1 (CRHR1), CRITICALLY INVOLVED IN TRAIT ANXIETY, SHOWS BIDIRECTIONAL ALTERATIONS IN ITS EXPRESSION IN THE BASOLATERAL AMYGDALA (BLA) UPON ENVIRONMENTAL STIMULATION, (III) THESE ALTERATIONS ARE LINKED TO AN INCREASED METHYLATION STATUS OF ITS PROMOTER AND, FINALLY, (IV) BINDING OF THE TRANSCRIPTION FACTOR YIN YANG 1 (YY1) TO THE CRHR1 PROMOTER CONTRIBUTES TO ITS GENE EXPRESSION IN A METHYLATION-SENSITIVE MANNER. THUS, CRHR1 IN THE BLA IS CRITICALLY INVOLVED AS PLASTICITY GENE IN THE BIDIRECTIONAL EPIGENETIC RESCUE OF EXTREMES IN TRAIT ANXIETY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15   544  27 ATTAINMENT OF THERMOREGULATION AS AFFECTED BY ENVIRONMENTAL FACTORS. THE REVIEW ADDRESSES THE DEVELOPMENT OF THERMOREGULATION IN POULTRY EMBRYOS AS WELL AS THE EFFECT OF ACUTE AND CHRONIC CHANGES OF ENVIRONMENTAL FACTORS ON THIS PROCESS AND THE INCUBATION TEMPERATURE BEING THE FOREMOST. IN POULTRY, THE EARLY DEVELOPMENT OF ADAPTIVE BODY FUNCTIONS, LIKE THE THERMOREGULATORY SYSTEM, IS CHARACTERIZED BY THE FOLLOWING PECULIARITIES. FIRST, THE DEVELOPMENT OF PERIPHERAL AS WELL AS CENTRAL NERVOUS THERMOREGULATORY MECHANISMS START DURING THE PRENATAL ONTOGENY. HOWEVER, THEIR MATURITY IS ATTAINED DURING EARLY POSTNATAL DEVELOPMENT. IN THE PERINATAL PERIOD, ENVIRONMENTAL FACTORS HAVE A HIGH EFFECT ON DEVELOPMENT OF TEMPERATURE REGULATION. SECOND, ACUTE CHANGES IN THE ENVIRONMENTAL CONDITIONS INDUCE AS A RULE FIRST UNCOORDINATED AND IMMEDIATELY NONADAPTIVE REACTIONS. LATER, THE UNCOORDINATED NONADAPTIVE REACTIONS CHANGE INTO COORDINATED (ADAPTIVE) REACTIONS. PRENATAL ENVIRONMENTAL INFLUENCES MAY HAVE A TRAINING EFFECT ON THE POSTNATAL EFFICIENCY OF THE THERMO-REGULATORY SYSTEM. THIRD, FUNCTIONAL SYSTEMS OF THE ORGANISM DEVELOP FROM AN OPEN LOOP SYSTEM WITHOUT FEEDBACK CONTROL INTO A CLOSED SYSTEM CONTROLLED BY A FEEDBACK MECHANISM. DURING THIS CRITICAL PERIOD, THE ACTUAL ENVIRONMENT MODULATES THE DEVELOPMENT OF THE RESPECTIVE PHYSIOLOGICAL CONTROL SYSTEMS FOR THE ENTIRE LIFE PERIOD, ESPECIALLY BY CHANGES IN NEUROORGANIZATION AND EXPRESSION OF RELATED EFFECTOR GENES. KNOWLEDGE ON THESE MECHANISMS MIGHT BE SPECIFICALLY USED TO GENERATE LONG-TERM ADAPTATION OF THE ORGANISM TO THE POSTNATAL CLIMATIC CONDITIONS (PERINATAL EPIGENETIC TEMPERATURE ADAPTATION). IN POULTRY, PERINATAL EPIGENETIC TEMPERATURE ADAPTATION WAS DEVELOPED BY CHANGES IN THE INCUBATION TEMPERATURE. WHEN A COMPARISON IS MADE IN BIRDS, WHICH WERE INCUBATED AT 37.5 DEGREES C, A LOW INCUBATION TEMPERATURE INDUCED POSTNATAL COLD ADAPTATION, AND WARM INCUBATION TEMPERATURE INDUCED POSTNATAL HEAT ADAPTATION. PERINATAL EPIGENETIC TEMPERATURE ADAPTATION EXHIBITED CHANGES IN THE NEURONAL THERMOSENSITIVITY IN THE HYPOTHALAMUS AS WELL AS IN THE PERIPHERAL THERMOREGULATORY MECHANISMS. THESE ALTERATIONS COULD BE ALREADY FOUND AT THE END OF INCUBATION. FURTHER, TEMPERATURE-EXPERIENCED EMBRYOS HAVE A LOWER C-FOS EXPRESSION THAN IN THE CONTROL AFTER ACUTE HEAT STRESS.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16  2770  31 EXTENDING INJURY- AND DISEASE-RESISTANT CNS PHENOTYPES BY REPETITIVE EPIGENETIC CONDITIONING. SIGNIFICANT REDUCTIONS IN THE EXTENT OF ACUTE INJURY IN THE CNS CAN BE ACHIEVED BY EXPOSURE TO DIFFERENT PRECONDITIONING STIMULI, BUT THE DURATION OF THE INDUCED PROTECTIVE PHENOTYPE IS TYPICALLY SHORT-LASTING, AND THUS IS DEEMED AS LIMITING ITS CLINICAL APPLICABILITY. EXTENDING THE PERIOD OVER WHICH SUCH ADAPTIVE EPIGENETIC CHANGES PERSIST - IN EFFECT, EXPANDING CONDITIONING'S "THERAPEUTIC WINDOW" - WOULD SIGNIFICANTLY BROADEN THE POTENTIAL APPLICATIONS OF SUCH A TREATMENT APPROACH IN PATIENTS. THE FREQUENCY OF THE CONDITIONING STIMULUS MAY HOLD THE KEY. WHILE TRANSIENT (1-3 DAYS) PROTECTION AGAINST CNS ISCHEMIC INJURY IS WELL ESTABLISHED PRECLINICALLY FOLLOWING A SINGLE PRECONDITIONING STIMULUS, REPETITIVELY PRESENTING PRECONDITIONING STIMULI EXTENDS THE DURATION OF ISCHEMIC TOLERANCE BY MANY WEEKS. MOREOVER, REPETITIVE INTERMITTENT POSTCONDITIONING ENHANCES POST-ISCHEMIC RECOVERY METRICS AND IMPROVES LONG-TERM SURVIVAL. INTERMITTENT CONDITIONING IS ALSO EFFICACIOUS FOR PREVENTING OR DELAYING INJURY IN PRECLINICAL MODELS OF CHRONIC NEURODEGENERATIVE DISEASE, AND FOR PROMOTING LONG-LASTING FUNCTIONAL IMPROVEMENTS IN A NUMBER OF OTHER PATHOLOGIES AS WELL. ALTHOUGH THE DETAILED MECHANISMS UNDERLYING THESE PROTRACTED KINDS OF NEUROPLASTICITY REMAIN LARGELY UNSTUDIED, ACCUMULATING EMPIRICAL EVIDENCE SUPPORTS THE CONTENTION THAT ALL OF THESE ADAPTIVE PHENOTYPES ARE EPIGENETICALLY MEDIATED. GOING FORWARD, ADDITIONAL PRECLINICAL DEMONSTRATIONS OF THE ABILITY TO INDUCE SUSTAINED BENEFICIAL PHENOTYPES THAT REDUCE THE BURDEN OF ACUTE AND CHRONIC NEURODEGENERATION, AND EXPERIMENTAL INTERROGATIONS OF THE REGULATORY CONSTRUCTS RESPONSIBLE FOR THESE EPIGENETIC RESPONSES, WILL ACCELERATE THE IDENTIFICATION OF NOT ONLY EFFICACIOUS BUT ALSO PRACTICAL, ADAPTIVE EPIGENETICS-BASED TREATMENTS FOR INDIVIDUALS WITH NEUROLOGICAL DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  5493  15 REVIEW OF IN VITRO TEST SYSTEMS USING DNA DAMAGE AND REPAIR FOR SCREENING OF CHEMICAL CARCINOGENS. CHEMICAL CARCINOGENS ARE MECHANISTICALLY CLASSIFIED AS GENOTOXIC WHICH INTERACT DIRECTLY WITH DNA, AND EPIGENETIC WHICH CAUSE CHRONIC TISSUE INJURY, HORMONAL IMBALANCE, AND PROMOTIONAL EFFECTS. THIS REVIEW EVALUATES IN VITRO TESTS FOR THEIR CONTRIBUTION TO A BATTERY FOR IDENTIFYING GENOTOXIC CHEMICAL CARCINOGENS. IN ADDITION TO BACTERIAL MUTAGENIC ASSAYS, NONSPECIFIC DNA DAMAGE/REPAIR TESTS ARE RECOMMENDED FOR SCREENING CHEMICALS, IN PARTICULAR THE HEPATOCYTE PRIMARY CULTURE/DNA REPAIR TEST.	1979	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18   846  23 CHILDHOOD EXPOSURE TO AMBIENT POLYCYCLIC AROMATIC HYDROCARBONS IS LINKED TO EPIGENETIC MODIFICATIONS AND IMPAIRED SYSTEMIC IMMUNITY IN T CELLS. BACKGROUND: EVIDENCE SUGGESTS THAT EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) INCREASES ATOPY; IT IS UNCLEAR HOW PAH EXPOSURE IS LINKED TO INCREASED SEVERITY OF ATOPIC DISEASES. OBJECTIVE: WE HYPOTHESIZED THAT AMBIENT PAH EXPOSURE IS LINKED TO IMPAIRMENT OF IMMUNITY IN ATOPIC CHILDREN (DEFINED AS CHILDREN WITH ASTHMA AND/OR ALLERGIC RHINITIS) FROM FRESNO, CALIFORNIA, AN AREA WITH ELEVATED AMBIENT PAHS. METHODS: WE RECRUITED 256 SUBJECTS FROM FRESNO, CA. AMBIENT PAH CONCENTRATIONS (NG/M(3) ) WERE MEASURED USING A SPATIAL-TEMPORAL REGRESSION MODEL OVER MULTIPLE TIME PERIODS. ASTHMA DIAGNOSIS WAS DETERMINED BY CURRENT NHLBI CRITERIA. PHENOTYPING AND FUNCTIONAL IMMUNE MEASUREMENTS WERE PERFORMED FROM ISOLATED CELLS. FOR EPIGENETIC MEASUREMENTS, DNA WAS ISOLATED AND PYROSEQUENCED. RESULTS: WE SHOW THAT HIGHER AVERAGE PAH EXPOSURE WAS SIGNIFICANTLY ASSOCIATED WITH IMPAIRED TREG FUNCTION AND INCREASED METHYLATION IN THE FORKHEAD BOX PROTEIN 3 (FOXP3) LOCUS (P < 0.05), CONDITIONAL ON ATOPIC STATUS. THESE EPIGENETIC MODIFICATIONS WERE SIGNIFICANTLY LINKED TO DIFFERENTIAL PROTEIN EXPRESSION OF FOXP3 (P < 0.001). METHYLATION WAS ASSOCIATED WITH CELLULAR FUNCTIONAL CHANGES, SPECIFICALLY TREG DYSFUNCTION, AND AN INCREASE IN TOTAL PLASMA IGE LEVELS. PROTEIN EXPRESSION OF IL-10 DECREASED AND IFN-GAMMA INCREASED AS THE EXTENT OF PAH EXPOSURE INCREASED. THE STRENGTH OF THE ASSOCIATIONS GENERALLY INCREASED AS THE TIME WINDOW FOR AVERAGE PAH EXPOSURE INCREASED FROM 24 HR TO 1 YEAR, SUGGESTING MORE OF A CHRONIC RESPONSE. SIGNIFICANT ASSOCIATIONS WITH CHRONIC PAH EXPOSURE AND IMMUNE OUTCOMES WERE ALSO OBSERVED IN SUBJECTS WITH ALLERGIC RHINITIS. CONCLUSIONS AND CLINICAL RELEVANCE: COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT INCREASED AMBIENT PAH EXPOSURE IS ASSOCIATED WITH IMPAIRED SYSTEMIC IMMUNITY AND EPIGENETIC MODIFICATIONS IN A KEY LOCUS INVOLVED IN ATOPY: FOXP3, WITH A HIGHER IMPACT ON ATOPIC CHILDREN. THE RESULTS SUGGEST THAT INCREASED ATOPIC CLINICAL SYMPTOMS IN CHILDREN COULD BE LINKED TO INCREASED PAH EXPOSURE IN AIR POLLUTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19   338  34 ALTERATIONS IN GENE EXPRESSION DUE TO CHRONIC LEAD EXPOSURE INDUCE BEHAVIORAL CHANGES. LEAD (PB) IS A POLLUTANT COMMONLY FOUND IN THE ENVIRONMENT, DESPITE THE IMPLEMENTATION OF PUBLIC HEALTH POLICIES INTENDED TO REMOVE IT. DUE TO ITS CHEMICAL CHARACTERISTICS AS A DIVALENT ION, PB INTERACTS WITH CELLS, ENZYMES, AND TISSUES, CAUSING PATHOLOGICAL, PHYSICAL, AND BEHAVIORAL ALTERATIONS. RECENT BIOTECHNOLOGICAL ADVANCES HAVE HELPED US TO UNDERSTAND THE MECHANISMS UNDERLYING THE DAMAGE CAUSED BY PB IN HUMAN POPULATIONS AND IN EXPERIMENTAL MODELS, AND NEW EVIDENCE ON THE EPIGENETIC ALTERATIONS CAUSED BY EXPOSITION TO ENVIRONMENTAL PB IS AVAILABLE. IT IS KNOWN THAT PB EXPOSURE IMPACTS ON BEHAVIOR (CAUSING AGGRESSIVENESS, ANXIETY, AND DEPRESSION), LEADING TO LEARNING DEFICIT AND LOCOMOTOR ACTIVITY ALTERATIONS, AND ITS PRESENCE HAS BEEN LINKED WITH THE ABNORMAL RELEASE OF NEUROTRANSMITTERS AND OTHER BIOCHEMICAL CHANGES INVOLVED IN THESE DISORDERS. STILL, FURTHER REDUCTIONIST STUDIES ARE REQUIRED TO DETERMINE THE EFFECTS OF PB EXPOSURE ON DNA AND PROTEIN EXPRESSION AND UNDERSTAND THE PROCESSES UNDERLYING THE DISEASES CAUSED BY PB. THIS WILL ALSO INDICATE POSSIBLE THERAPEUTIC TARGETS TO OFFSET THE NEGATIVE EFFECTS OF THE HEAVY METAL. BY ELUCIDATING THE EPIGENETIC CHANGES INVOLVED, IT WOULD BE POSSIBLE TO MANIPULATE THEM AND PROPOSE NOVEL THERAPEUTIC APPROACHES IN THIS AREA. THIS REVIEW IS AIMED TO PROVIDE AN OVERVIEW OF STUDIES THAT LINK PB EXPOSURE TO BEHAVIORAL CHANGES, AS WELL AS BIOCHEMICAL AND EPIGENETIC ALTERATIONS AT A NEUROTRANSMITTER LEVEL, CONSIDERING THE IMPORTANCE OF THIS METAL IN BEHAVIOR ABNORMALITIES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20   265  33 ADVERSE EFFECTS OF RECREATIONAL AND MEDICAL CANNABIS. PURPOSE OF REVIEW: THIS COMPREHENSIVE REVIEW DISCUSSES THE ADVERSE EFFECTS KNOWN TODAY ABOUT MARIJUANA, FOR EITHER MEDICAL OR RECREATIONAL USE. IT REVIEWS THE ROLE OF CANNABIS IN THE TREATMENT OF CHRONIC PAIN, COGNITIVE AND NEUROLOGICAL ADVERSE EFFECTS, SPECIAL CASES AND ADDICTION. RECENT FINDINGS: CANNABINOIDS WORK THROUGH THE ENDOCANNABINOIDS SYSTEM AND INHIBIT THE RELEASE OF GABA AND GLUTAMATE IN THE BRAIN, IMPACT NEUROMODULATION, AS WELL AS DOPAMINE, ACETYLCHOLINE AND NOREPINEPHRINE RELEASE. THEY AFFECT REWARD, LEARNING AND PAIN. THE USE OF CANNABIS IS INCREASING NATIONALLY AND WORLD-WIDE FOR BOTH RECREATIONAL AND MEDICINAL PURPOSES, HOWEVER, THERE IS RELATIVELY ONLY LOW QUALITY EVIDENCE TO THE EFFICACY AND ADVERSE EFFECTS OF THIS. CANNABIS AND ITS DERIVATIVES MAY BE USED FOR TREATMENT OF CHRONIC PAIN. THEY ARE VIA CB1 RECEPTORS THAT ARE THOUGHT TO MODULATE NOCICEPTIVE SIGNALS IN THE BRAIN. CB2 RECEPTORS IN THE DRG LIKELY AFFECT PAIN INTEGRATION IN THE AFFERENT PATHWAYS, AND PERIPHERALLY CB2 ALSO AFFECTS NORADRENERGIC PATHWAYS INFLUENCING PAIN. A LARGE PROPORTION OF USERS MAY SEE MORE THAN 50% OF CHRONIC PAIN ALLEVIATION COMPARED WITH PLACEBO. CANNABIS AFFECTS COGNITION, MOST NOTABLY EXECUTIVE FUNCTION, MEMORY AND ATTENTION, AND MAY DETERIORATE THE BOUNDARY BETWEEN EMOTIONAL AND EXECUTIVE PROCESSING. CANNABIS IMPAIRS MEMORY IN THE SHORT RUN, WHICH BECOME MORE SIGNIFICANT WITH CHRONIC USE, AND MAY ALSO BE ACCOMPANIED BY POORER EFFORT, SLOWER PROCESSING AND IMPACTED ATTENTION. IT IS GENERALLY BELIEVED THAT LONG-TERM USE AND EARLIER AGE ARE RISK FACTOR FOR NEUROCOGNITIVE DEFICITS; NEUROIMAGING STUDIES HAVE SHOWN REDUCED HIPPOCAMPAL VOLUME AND DENSITY. EXECUTIVE FUNCTIONS AND MEMORY ARE WORSE IN ADOLESCENT USERS VERSUS ADULTS. CANNABIS ADDICTION IS DIFFERENT AND LIKELY LESS COMMON THAN OTHER ADDICTIVE SUBSTANCES, BUT UP TO 10% OF USERS MEET CRITERIA FOR LIFETIME CANNABIS DEPENDENCE. ADDICTION PATTERNS MAY BE LINKED TO GENETIC AND EPIGENETIC DIFFERENCES. IT IS STILL UNCLEAR WHETHER ABSTINENCE REVERSES PATTERNS OF ADDICTION, AND MORE RESEARCH IS REQUIRED INTO THIS TOPIC. SUMMARY: CANNABIS USE HAS BECOME MORE ABUNDANT FOR BOTH MEDICAL AND RECREATIONAL USE. IT CARRIES LIKELY BENEFITS IN THE FORM OF ANALGESIA, ANTI-EMESIS AND IMPROVED APPETITE IN CHRONIC PATIENTS. THE EVIDENCE REVIEWING ADVERSE EFFECTS OF THIS USE ARE STILL LIMITED, HOWEVER, EXITING DATA POINTS TO A CLEAR LINK WITH NEUROCOGNITIVE DETERIORATION, BACKED BY LOSS OF BRAIN VOLUME AND DENSITY. ADDICTION IS LIKELY COMPLEX AND VARIABLE, AND NO GOOD DATA EXISTS TO SUPPORT TREATMENT AT THIS POINT. IT IS BECOMING CLEAR THAT USE IN EARLIER AGES CARRIES A HIGHER RISK FOR LONG-TERM DEFICITS. AS WITH ANY OTHER DRUG, THESE RISKS SHOULD BE CONSIDERED ALONGSIDE BENEFITS PRIOR TO A DECISION ON CANNABIS USE.	2021