1 6166 166 THE GLUTATHIONE SYSTEM: A NEW DRUG TARGET IN NEUROIMMUNE DISORDERS. GLUTATHIONE (GSH) HAS A CRUCIAL ROLE IN CELLULAR SIGNALING AND ANTIOXIDANT DEFENSES EITHER BY REACTING DIRECTLY WITH REACTIVE OXYGEN OR NITROGEN SPECIES OR BY ACTING AS AN ESSENTIAL COFACTOR FOR GSH S-TRANSFERASES AND GLUTATHIONE PEROXIDASES. GSH ACTING IN CONCERT WITH ITS DEPENDENT ENZYMES, KNOWN AS THE GLUTATHIONE SYSTEM, IS RESPONSIBLE FOR THE DETOXIFICATION OF REACTIVE OXYGEN AND NITROGEN SPECIES (ROS/RNS) AND ELECTROPHILES PRODUCED BY XENOBIOTICS. ADEQUATE LEVELS OF GSH ARE ESSENTIAL FOR THE OPTIMAL FUNCTIONING OF THE IMMUNE SYSTEM IN GENERAL AND T CELL ACTIVATION AND DIFFERENTIATION IN PARTICULAR. GSH IS A UBIQUITOUS REGULATOR OF THE CELL CYCLE PER SE. GSH ALSO HAS CRUCIAL FUNCTIONS IN THE BRAIN AS AN ANTIOXIDANT, NEUROMODULATOR, NEUROTRANSMITTER, AND ENABLER OF NEURON SURVIVAL. DEPLETION OF GSH LEADS TO EXACERBATION OF DAMAGE BY OXIDATIVE AND NITROSATIVE STRESS; HYPERNITROSYLATION; INCREASED LEVELS OF PROINFLAMMATORY MEDIATORS AND INFLAMMATORY POTENTIAL; DYSFUNCTIONS OF INTRACELLULAR SIGNALING NETWORKS, E.G., P53, NUCLEAR FACTOR-KAPPAB, AND JANUS KINASES; DECREASED CELL PROLIFERATION AND DNA SYNTHESIS; INACTIVATION OF COMPLEX I OF THE ELECTRON TRANSPORT CHAIN; ACTIVATION OF CYTOCHROME C AND THE APOPTOTIC MACHINERY; BLOCKADE OF THE METHIONINE CYCLE; AND COMPROMISED EPIGENETIC REGULATION OF GENE EXPRESSION. AS SUCH, GSH DEPLETION HAS MARKED CONSEQUENCES FOR THE HOMEOSTATIC CONTROL OF THE IMMUNE SYSTEM, OXIDATIVE AND NITROSATIVE STRESS (O&NS) PATHWAYS, REGULATION OF ENERGY PRODUCTION, AND MITOCHONDRIAL SURVIVAL AS WELL. GSH DEPLETION AND CONCOMITANT INCREASE IN O&NS AND MITOCHONDRIAL DYSFUNCTIONS PLAY A ROLE IN THE PATHOPHYSIOLOGY OF DIVERSE NEUROIMMUNE DISORDERS, INCLUDING DEPRESSION, MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME AND PARKINSON'S DISEASE, SUGGESTING THAT DEPLETED GSH IS AN INTEGRAL PART OF THESE DISEASES. THERAPEUTICAL INTERVENTIONS THAT AIM TO INCREASE GSH CONCENTRATIONS IN VIVO INCLUDE N-ACETYL CYSTEINE; NRF-2 ACTIVATION VIA HYPERBARIC OXYGEN THERAPY; DIMETHYL FUMARATE; PHYTOCHEMICALS, INCLUDING CURCUMIN, RESVERATROL, AND CINNAMON; AND FOLATE SUPPLEMENTATION. 2014 2 6456 34 THYMOSIN BETA4 PREVENTS OXIDATIVE STRESS, INFLAMMATION, AND FIBROSIS IN ETHANOL- AND LPS-INDUCED LIVER INJURY IN MICE. THYMOSIN BETA 4 (TBETA4), AN ACTIN-SEQUESTERING PROTEIN, IS INVOLVED IN TISSUE DEVELOPMENT AND REGENERATION. IT PREVENTS INFLAMMATION AND FIBROSIS IN SEVERAL TISSUES. WE INVESTIGATED THE ROLE OF TBETA4 IN CHRONIC ETHANOL- AND ACUTE LIPOPOLYSACCHARIDE- (LPS-) INDUCED MOUSE LIVER INJURY. C57BL/6 MICE WERE FED 5% ETHANOL IN LIQUID DIET FOR 4 WEEKS PLUS BINGE ETHANOL (5 G/KG, GAVAGE) WITH OR WITHOUT LPS (2 MG/KG, INTRAPERITONEAL) FOR 6 HOURS. TBETA4 (1 MG/KG, INTRAPERITONEAL) WAS ADMINISTERED FOR 1 WEEK. WE DEMONSTRATED THAT TBETA4 PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN LIVER INJURY MARKERS AS WELL AS CHANGES IN LIVER PATHOLOGY. IT ALSO PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN OXIDATIVE STRESS BY DECREASING ROS AND LIPID PEROXIDATION AND INCREASING THE ANTIOXIDANTS, REDUCED GLUTATHIONE AND MANGANESE-DEPENDENT SUPEROXIDE DISMUTASE. IT ALSO PREVENTED THE ACTIVATION OF NUCLEAR FACTOR KAPPA B BY BLOCKING THE PHOSPHORYLATION OF THE INHIBITORY PROTEIN, IKAPPAB, THEREBY PREVENTED PROINFLAMMATORY CYTOKINE PRODUCTION. MOREOVER, TBETA4 PREVENTED FIBROGENESIS BY SUPPRESSING THE EPIGENETIC REPRESSOR, METHYL-CPG-BINDING PROTEIN 2, THAT COORDINATELY REVERSED THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND DOWNREGULATED FIBROGENIC GENES, PLATELET-DERIVED GROWTH FACTOR-BETA RECEPTOR, ALPHA-SMOOTH MUSCLE ACTIN, COLLAGEN 1, AND FIBRONECTIN, RESULTING IN REDUCED FIBROSIS. OUR DATA SUGGEST THAT TBETA4 HAS ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTIFIBROTIC POTENTIAL DURING ALCOHOLIC LIVER INJURY. 2018 3 5010 30 PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA DAMAGE AND CYTOGENETIC EFFECTS. IN THE PRESENT STUDY, THE POSSIBLE ROLE OF THE POLYUNSATURATED FATTY ACIDS LINOLEIC AND ARACHIDONIC ACID IN THE CHEMICAL INDUCTION OF CARCINOGENESIS HAS BEEN INVESTIGATED. ANALYSIS OF 7,8-DIHYDRO-8-OXO-2'-DEOXYGUANOSINE (8-OXODG) LEVELS IN 2'-DEOXYGUANOSINE (DG) AND ISOLATED DNA HAS DEMONSTRATED THAT LINOLEIC AND ARACHIDONIC ACID ARE CAPABLE OF INDUCING THIS SPECIFIC GENOTOXIC DAMAGE. THIS EFFECT APPEARS TO BE RELATED TO THE DEGREE OF FATTY ACID UNSATURATION, SINCE IT WAS NOT INDUCED BY MONOUNSATURATED OLEIC ACID. ENZYMATIC PEROXIDATION OF LINOLEIC AND ARACHIDONIC ACID RESULTED IN A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE. STUDIES ON THE INTERFERENCE OF RADICAL SCAVENGERS WITH THE INDUCTION OF 8-OXODG IN COMBINATION WITH ELECTRON SPIN RESONANCE SPECTROSCOPY DEMONSTRATED THAT THE SUPEROXIDE ANION WAS GENERATED DURING PEROXIDATION OF THESE FATTY ACIDS AND THAT SINGLET OXYGEN IS MOST LIKELY INVOLVED IN THE FORMATION OF OXIDATIVE DNA DAMAGE. THE LEVEL OF OXIDATIVE DAMAGE IN DG AND SINGLE-STRANDED DNA WAS HIGHER AS COMPARED TO THAT IN NATIVE DNA AFTER EQUIMOLAR TREATMENT. EXPOSURE OF HUMAN LYMPHOCYTES TO LINOLEIC OR ARACHIDONIC ACID DID NOT RESULT IN A SIGNIFICANT INCREASE IN LEVELS OF 8-OXODG. THIS MAY INDICATE THAT THE RATE OF INTRACELLULAR PEROXIDATION IS RELATIVELY LOW AND/OR THAT NUCLEAR DNA IN INTACT CELLS IS EFFECTIVELY PROTECTED AGAINST GENETIC DAMAGE INDUCED BY REACTIVE OXYGEN SPECIES. IT IS THEREFORE CONCLUDED THAT RELATIVELY SHORT PERIODS OF LINOLEIC OR ARACHIDONIC ACID ADMINISTRATION ARE NOT LIKELY TO IMPOSE A DIRECT GENOTOXIC RISK. IT CAN, HOWEVER, NOT BE EXCLUDED THAT CHRONIC EXPOSURE TO POLYUNSATURATED FATTY ACIDS INDUCES OXIDATIVE DNA DAMAGE OR IS RELATED TO CANCER RISK BY EPIGENETIC MECHANISMS, AS IS ALSO INDICATED BY THE OBSERVED CYTOTOXIC EFFECTS OF LINOLEIC AND ARACHIDONIC ACID. 1994 4 558 35 B-VITAMIN DEPENDENT METHIONINE METABOLISM AND ALCOHOLIC LIVER DISEASE. CONVINCING EVIDENCE LINKS ABERRANT B-VITAMIN DEPENDENT HEPATIC METHIONINE METABOLISM TO THE PATHOGENESIS OF ALCOHOLIC LIVER DISEASE (ALD). THIS REVIEW FOCUSES ON THE ESSENTIAL ROLES OF FOLATE AND VITAMINS B6 AND B12 IN HEPATIC METHIONINE METABOLISM, THE CAUSES OF THEIR DEFICIENCIES AMONG CHRONIC ALCOHOLIC PERSONS, AND HOW THEIR DEFICIENCIES TOGETHER WITH CHRONIC ALCOHOL EXPOSURE IMPACT ON ABERRANT METHIONINE METABOLISM IN THE PATHOGENESIS OF ALD. FOLATE IS THE DIETARY TRANSMETHYLATION DONOR FOR THE PRODUCTION OF S-ADENOSYLMETHIONINE (SAM), WHICH IS THE SUBSTRATE FOR ALL METHYLTRANSFERASES THAT REGULATE GENE EXPRESSIONS IN PATHWAYS OF LIVER INJURY, AS WELL AS A REGULATOR OF THE TRANSSULFURATION PATHWAY THAT IS ESSENTIAL FOR PRODUCTION OF GLUTATHIONE (GSH), THE PRINCIPAL ANTIOXIDANT FOR DEFENSE AGAINST OXIDATIVE LIVER INJURY. VITAMIN B12 REGULATES TRANSMETHYLATION REACTIONS FOR SAM PRODUCTION AND VITAMIN B6 REGULATES TRANSSULFURATION REACTIONS FOR GSH PRODUCTION. FOLATE DEFICIENCY ACCELERATES THE EXPERIMENTAL DEVELOPMENT OF ALD IN ETHANOL-FED ANIMALS WHILE REDUCING LIVER SAM LEVELS WITH RESULTANT ABNORMAL GENE EXPRESSION AND DECREASED PRODUCTION OF ANTIOXIDANT GSH. THROUGH ITS EFFECTS ON FOLATE METABOLISM, REDUCED SAM ALSO IMPAIRS NUCLEOTIDE BALANCE WITH RESULTANT INCREASED DNA STRAND BREAKS, OXIDATION, HEPATOCELLULAR APOPTOSIS, AND RISK OF CARCINOGENESIS. THE REVIEW ENCOMPASSES REFERENCED STUDIES ON MECHANISMS FOR PERTURBATIONS OF METHIONINE METABOLISM IN ALD, EVIDENCE FOR ALTERED GENE EXPRESSIONS AND THEIR EPIGENETIC REGULATION IN THE PATHOGENESIS OF ALD, AND CLINICAL STUDIES ON POTENTIAL PREVENTION AND TREATMENT OF ALD BY CORRECTION OF METHIONINE METABOLISM WITH SAM. 2013 5 5448 35 REPRESSION OF HDAC5 BY ACETATE RESTORES HYPOTHALAMIC-PITUITARY-OVARIAN FUNCTION IN TYPE 2 DIABETES MELLITUS. TYPE 2 DIABETES MELLITUS (T2DM) ACCOUNTS FOR 90-95 % OF WORLDWIDE DIABETES CASES AND IS PRIMARILY CHARACTERIZED BY INSULIN RESISTANCE. ITS PROGRESSION AS A CHRONIC METABOLIC DISEASE HAS BEEN LARGELY ASSOCIATED WITH FEMALE REPRODUCTIVE ABNORMALITIES, INCLUDING OVARIAN DYSFUNCTION WITH CONSEQUENT INFERTILITY. EPIGENETIC MODIFICATIONS HAVE BEEN SUGGESTED AS A POSSIBLE LINK TO METABOLIC COMORBIDITIES. WE THEREFORE HYPOTHESIZED THAT SHORT CHAIN FATTY ACIDS, ACETATE (ACA), A POTENTIAL HISTONE DEACETYLASE INHIBITOR (HDAC) AMELIORATES HYPOTHALAMIC-PITUITARY-OVARIAN (HPO) DYSFUNCTION IN T2DM. FEMALE WISTAR RATS WEIGHING 160-190 G WERE ALLOTTED INTO THREE GROUPS (N = 6/GROUP): CONTROL (VEHICLE; PO), T2D AND T2D + ACA (200 MG/KG; PO). T2DM WAS INDUCED BY FRUCTOSE ADMINISTRATION (10 %; W/V) FOR 6 WEEKS AND SINGLE DOSE OF STREPTOZOTOCIN (35 MG/KG; IP). THE PRESENT DATA SHOWED THAT IN ADDITION TO INSULIN RESISTANCE, INCREASED FASTING BLOOD GLUCOSE AND INSULIN, T2DM INDUCED ELEVATED PLASMA, HYPOTHALAMIC AND OVARIAN TRIGLYCERIDE, LIPID PEROXIDATION, TNF-ALPHA AND GLUTATHIONE DEPLETION. ASIDE, T2DM ALSO LED TO INCREASED PLASMA LACTATE PRODUCTION AND GAMMA-GLUTAMYL TRANSFERASE AS WELL AS DECREASED GONADOTROPINS/17BETA-ESTRADIOL. HISTOLOGICALLY, HYPOTHALAMUS, PITUITARY AND OVARIES REVEALED DISRUPTED NEURONAL CELLS/MODERATE HEMORRHAGE, ALTERED MORPHOLOGY/VASCULAR CONGESTIONS, AND DEGENERATED ANTRAL FOLLICLE/GRAAFIAN FOLLICLE WITH MILD FIBROSIS AND INFILTRATED INFLAMMATORY CELLS RESPECTIVELY IN T2D ANIMALS. INTERESTINGLY, THESE ALTERATIONS WERE ACCOMPANIED BY ELEVATED PLASMA/HYPOTHALAMIC HDAC5 AND ATTENUATED WHEN TREATED WITH ACETATE. THE PRESENT RESULTS DEMONSTRATE THAT T2DM INDUCES HPO DYSFUNCTION, WHICH IS ACCOMPANIED BY ELEVATED CIRCULATING/HYPOTHALAMIC HDAC5. THE RESULTS IN ADDITION SUGGEST THAT ACETATE RESTORES HPO FUNCTION IN T2DM BY SUPPRESSION OF HDAC5 AND ENHANCEMENT OF INSULIN SENSITIVITY. 2021 6 6038 33 THE CHEMICAL DEFENSIVE SYSTEM IN THE PATHOBIOLOGY OF IDIOPATHIC ENVIRONMENT-ASSOCIATED DISEASES. CHEMICAL DEFENSIVE SYSTEM CONSISTING OF BIO-SENSORING, TRANSMITTING, AND RESPONSIVE ELEMENTS HAS BEEN EVOLVED TO PROTECT MULTI-CELLULAR ORGANISMS AGAINST ENVIRONMENTAL CHEMICAL INSULTS (XENOBIOTICS) AND TO MAINTAIN HOMEOSTASIS OF ENDOGENOUS LOW MOLECULAR WEIGHT METABOLITES (ENDOBIOTICS). BOTH GENETIC AND EPIGENETIC DEFECTS OF THE SYSTEM IN ASSOCIATION WITH CARCINOGENESIS AND INDIVIDUAL SENSITIVITY TO ANTI-TUMOR THERAPIES HAVE BEEN INTENSELY STUDIED. RECENTLY, SEVERAL NON-TUMOR HUMAN PATHOLOGIES WITH EVIDENT ENVIRONMENTAL COMPONENTS SUCH AS RATHER RARE FUNCTIONAL SYNDROMES (MULTIPLE CHEMICAL SENSITIVITY, CHRONIC FATIGUE, PERSIAN GULF, AND FIBROMYALGIA NOW COLLECTIVELY LABELED AS IDIOPATHIC ENVIRONMENTAL INTOLERANCES) AND COMMON DISEASES (VITILIGO AND SYSTEMIC LUPUS ERYTHEMATOSUS) HAVE BECOME SUBJECTS OF THE RESEARCH ON THE IMPAIRED METABOLISM AND DETOXIFICATION OF XENOBIOTICS AND ENDOGENOUS TOXINS. HERE, WE COLLECTED AND CRITICALLY REVIEWED EPIDEMIOLOGICAL, GENETIC, AND BIOCHEMICAL DATA ON THE INVOLVEMENT AND POSSIBLE ROLE OF CYTOCHROME P450 SUPER FAMILY ENZYMES, GLUTATHIONE-S-TRANSFERASE ISOZYMES, CATECHOL-O-METHYL-TRANSFERASE, UDP-GLUCURONOSYL TRANSFERASES, AND PROTEINS DETOXIFYING INORGANIC AND ORGANIC PEROXIDES (CATALASE, GLUTATHIONE PEROXIDASE, AND PEROXIREDOXIN) IN THE ABOVE PATHOLOGIES. GENETIC PREDISPOSITION ASSESSED MAINLY BY SINGLE NUCLEOTIDE POLYMORPHISM AND GENE EXPRESSION ANALYSES REVEALED CORRELATIONS BETWEEN DEFECTS IN GENES ENCODING XENOBIOTIC-METABOLIZING AND/OR DETOXIFYING ENZYMES AND RISK/SEVERITY OF THESE SYNDROMES/DISEASES. PROTEOME ANALYSIS IDENTIFIED ABNORMAL EXPRESSION OF THE ENZYMES. THEIR FUNCTIONS WERE AFFECTED EPIGENETICALLY LEADING TO METABOLIC IMPAIRMENT AND, AS A CONSEQUENCE, TO THE NEGATIVE HEALTH OUTCOMES SHARED BY SOME OF THESE PATHOLOGIES. DATA OBTAINED SO FAR SUGGEST THAT DISTINCT COMPONENTS OF THE CHEMICAL DEFENSIVE SYSTEM COULD BE SUITABLE MOLECULAR TARGETS FOR FUTURE PATHOGENIC THERAPIES. 2009 7 449 25 APOCYNIN PREVENTS ANXIETY-LIKE BEHAVIOR AND HISTONE DEACETYLASES OVEREXPRESSION INDUCED BY SUB-CHRONIC STRESS IN MICE. ANXIETY DISORDERS ARE COMMON MENTAL HEALTH DISEASES AFFECTING UP TO 7% OF PEOPLE AROUND THE WORLD. STRESS IS CONSIDERED ONE OF THE MAJOR ENVIRONMENTAL RISK FACTORS TO PROMOTE ANXIETY DISORDERS THROUGH MECHANISMS INVOLVING EPIGENETIC CHANGES. MOREOVER, ALTERATION IN REDOX BALANCE AND INCREASED REACTIVE OXYGEN SPECIES (ROS) PRODUCTION HAVE BEEN DETECTED IN ANXIETY PATIENTS AND IN STRESSED-ANIMAL MODELS OF ANXIETY. HERE WE TESTED IF THE ADMINISTRATION OF APOCYNIN, A NATURAL ORIGIN ANTIOXIDANT, MAY PREVENT THE ANXIETY-LIKE PHENOTYPE AND REDUCTION OF HISTONE ACETYLATION INDUCED BY A SUBCHRONIC FORCED SWIMMING STRESS (FSS) PARADIGM. WE FOUND THAT APOCYNIN PREVENTED THE ENHANCED LATENCY TIME IN THE NOVELTY-SUPPRESSED FEEDING TEST, AND THE PRODUCTION OF MALONDIALDEHYDE INDUCED BY FSS. MOREOVER, APOCYNIN WAS ABLE TO BLOCK THE UPREGULATION OF P47PHOX, A KEY SUBUNIT OF THE NADPH OXIDASE COMPLEX. FINALLY, APOCYNIN PREVENTED THE RISE OF HIPPOCAMPAL HDAC1, HDAC4 AND HDAC5, AND THE REDUCTION OF HISTONE-3 ACETYLATION LEVELS PROMOTED BY FSS EXPOSURE. IN CONCLUSION, OUR RESULTS PROVIDE EVIDENCE THAT APOCYNIN REDUCES THE DELETERIOUS EFFECT OF STRESS AND SUGGESTS THAT OXIDATIVE STRESS MAY REGULATE EPIGENETIC MECHANISMS. 2021 8 5057 21 PHENOBARBITAL MECHANISTIC DATA AND RISK ASSESSMENT: ENZYME INDUCTION, ENHANCED CELL PROLIFERATION, AND TUMOR PROMOTION. CHRONIC EXPOSURE TO HIGH DOSES OF PHENOBARBITAL (PB) CAUSES HEPATOCELLULAR ADENOMAS IN BOTH MICE AND RATS AND HEPATOCELLULAR CARCINOMAS IN SOME STRAINS OF MICE. LONG-TERM PB THERAPY HAS NOT BEEN FOUND TO CAUSE HUMAN TUMORS. PB IS NOT DNA REACTIVE, AND MOST GENOTOXICITY TESTS HAVE YIELDED NEGATIVE RESULTS. PB HAS BEEN EXTENSIVELY STUDIED AS AN EPIGENETIC, RODENT LIVER TUMOR PROMOTER. AT EXPOSURES CAUSING RODENT LIVER TUMORS, PB HAS MEASURABLE EFFECTS ON HEPATOCYTES: PB INHIBITS CELL-TO-CELL COMMUNICATION; PB INDUCES ENZYMES, INCLUDING P450 CYTOCHROMES; PB STIMULATES PROLIFERATION AND INHIBITS APOPTOSIS OF HEPATOCYTES IN NEOPLASTIC FOCI. THRESHOLD EXPOSURES FOR SOME OF THESE ENDPOINTS COINCIDE WITH THE THRESHOLD EXPOSURE FOR TUMORIGENESIS. 1996 9 6406 31 THE SEARCH FOR RELIABLE BIOMARKERS OF DISEASE IN MULTIPLE CHEMICAL SENSITIVITY AND OTHER ENVIRONMENTAL INTOLERANCES. WHILST FACING A WORLDWIDE FAST INCREASE OF FOOD AND ENVIRONMENTAL ALLERGIES, THE MEDICAL COMMUNITY IS ALSO CONFRONTED WITH ANOTHER INHOMOGENEOUS GROUP OF ENVIRONMENT-ASSOCIATED DISABLING CONDITIONS, INCLUDING MULTIPLE CHEMICAL SENSITIVITY (MCS), FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, ELECTRIC HYPERSENSITIVITY, AMALGAM DISEASE AND OTHERS. THESE SHARE THE FEATURES OF POLY-SYMPTOMATIC MULTI-ORGAN CUTANEOUS AND SYSTEMIC MANIFESTATIONS, WITH POSTULATED INHERITED/ACQUIRED IMPAIRED METABOLISM OF CHEMICAL/PHYSICAL/NUTRITIONAL XENOBIOTICS, TRIGGERING ADVERSE REACTIONS AT EXPOSURE LEVELS FAR BELOW TOXICOLOGICALLY-RELEVANT VALUES, OFTEN IN THE ABSENCE OF CLEAR-CUT ALLERGOLOGIC AND/OR IMMUNOLOGIC INVOLVEMENT. DUE TO THE LACK OF PROVEN PATHOGENIC MECHANISMS GENERATING MEASURABLE DISEASE BIOMARKERS, THESE ENVIRONMENTAL HYPERSENSITIVITIES ARE GENERALLY IGNORED BY SANITARY AND SOCIAL SYSTEMS, AS PSYCHOGENIC OR "MEDICALLY UNEXPLAINED SYMPTOMS". THE UNCONTROLLED APPLICATION OF DIAGNOSTIC AND TREATMENT PROTOCOLS NOT CORRESPONDING TO ACCEPTABLE LEVELS OF VALIDATION, SAFETY, AND CLINICAL EFFICACY, TO A STEADILY INCREASING NUMBER OF PATIENTS DEMANDING ASSISTANCE, OCCURS IN MANY COUNTRIES IN THE ABSENCE OF EVIDENCE-BASED GUIDELINES. HERE WE REVISE AVAILABLE INFORMATION SUPPORTING THE ORGANIC NATURE OF THESE CLINICAL CONDITIONS. FOLLOWING INTENSE RESEARCH ON GENE POLYMORPHISMS OF PHASE I/II DETOXIFICATION ENZYME GENES, SO FAR STATISTICALLY INCONCLUSIVE, EPIGENETIC AND METABOLIC FACTORS ARE UNDER INVESTIGATION, IN PARTICULAR FREE RADICAL/ANTIOXIDANT HOMEOSTASIS DISTURBANCES. THE FINDING OF RELEVANT ALTERATIONS OF CATALASE, GLUTATHIONE-TRANSFERASE AND PEROXIDASE DETOXIFYING ACTIVITIES SIGNIFICANTLY CORRELATING WITH CLINICAL MANIFESTATIONS OF MCS, HAS RECENTLY REGISTERED SOME PROGRESS TOWARDS THE IDENTIFICATION OF RELIABLE BIOMARKERS OF DISEASE ONSET, PROGRESSION, AND TREATMENT OUTCOMES. 2011 10 6865 36 [OXIDATIVE STRESS IN PROSTATE HYPERTROPHY AND CARCINOGENESIS]. AGING, SIGNIFICANT IMPAIRMENT OF THE OXIDATION/REDUCTION BALANCE, INFECTION, AND INFLAMMATION ARE RECOGNIZED RISK FACTORS OF BENIGN HYPERPLASIA AND PROSTATE CANCER. CHRONIC SYMPTOMATIC AND ASYMPTOMATIC PROSTATE INFLAMMATORY PROCESSES GENERATE SIGNIFICANTLY ELEVATED LEVELS OF REACTIVE OXYGEN AND NITROGEN SPECIES, AND HALOGENATED COMPOUNDS. PROSTATE CANCER PATIENTS SHOWED SIGNIFICANTLY HIGHER LIPID PEROXIDATION AND LOWER ANTIOXIDANT LEVELS IN PERIPHERAL BLOOD THAN HEALTHY CONTROLS, WHEREAS PATIENTS WITH PROSTATE HYPERPLASIA DID NOT SHOW SUCH SYMPTOMS. OXIDATIVE/NITROSATIVE/HALOGENATIVE STRESS CAUSES DNA MODIFICATIONS LEADING TO GENOME INSTABILITY THAT MAY INITIATE CARCINOGENESIS; HOWEVER, IT WAS SHOWN THAT OXIDATIVE DAMAGE ALONE IS NOT SUFFICIENT TO INITIATE THIS PROCESS. PEROXIDATION PRODUCTS INDUCED BY REACTIVE OXYGEN AND NITROGEN SPECIES SEEM TO TAKE PART IN EPIGENETIC MECHANISMS REGULATING GENOME ACTIVITY. ONE OF THE MOST COMMON CHANGES OCCURRING IN MORE THAN 90% OF ALL ANALYZED PROSTATE CANCERS IS THE SILENCING OF GSTP1 GENE ACTIVITY. THE GENE ENCODES GLUTATHIONE TRANSFERASE, AN ENZYME PARTICIPATING IN DETOXIFICATION PROCESSES. PROSTATE HYPERPLASIA IS OFTEN ACCOMPANIED BY CHRONIC INFLAMMATION AND SUCH A RELATIONSHIP WAS NOT OBSERVED IN PROSTATE CANCER. THE PARTICIPATION OF INFECTION AND INFLAMMATION IN THE DEVELOPMENT OF HYPERPLASIA IS UNQUESTIONABLE AND THESE FACTORS PROBABLY ALSO TAKE PART IN INITIATING THE EARLY STAGES OF PROSTATE CARCINOGENESIS. THUS IT SEEMS THAT THERAPEUTIC STRATEGIES THAT PREVENT GENOME OXIDATIVE DAMAGE IN SITUATIONS INVOLVING OXIDATIVE/NITROSATIVE/HALOGENATIVE STRESS, I.E. USE OF ANTIOXIDANTS, PLANT STEROIDS, ANTIBIOTICS, AND NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, COULD HELP PREVENT CARCINOGENESIS. 2009 11 1848 38 EFFECTS OF VENLAFAXINE ON THE EXPRESSION LEVEL AND METHYLATION STATUS OF GENES INVOLVED IN OXIDATIVE STRESS IN RATS EXPOSED TO A CHRONIC MILD STRESS. RECENT HUMAN AND ANIMAL STUDIES INDICATE THAT OXIDATIVE AND NITROSATIVE STRESS MAY PLAY A ROLE IN THE AETIOLOGY AND PATHOGENESIS OF DEPRESSION. THIS STUDY INVESTIGATES THE EFFECT OF CHRONIC ADMINISTRATION OF THE SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITOR, VENLAFAXINE, ON THE EXPRESSION AND METHYLATION STATUS OF SOD1, SOD2, GPX1, GPX4, CAT, NOS1 AND NOS2 IN THE BRAIN AND BLOOD OF RATS EXPOSED TO A CHRONIC MILD STRESS (CMS) MODEL OF DEPRESSION. SEPARATE GROUPS OF ANIMALS WERE EXPOSED TO CMS FOR 2 OR 7 WEEKS; THE SECOND GROUP RECEIVED SALINE OR VENLAFAXINE (10 MG/KG/D, IP) FOR 5 WEEKS. AFTER COMPLETION OF BOTH STRESS CONDITIONS AND DRUG ADMINISTRATION, THE MRNA AND PROTEIN EXPRESSION OF SELECTED GENES AND THE METHYLATION STATUS OF THEIR PROMOTERS WERE MEASURED IN PERIPHERAL MONONUCLEAR BLOOD CELLS (PBMCS) AND IN BRAIN STRUCTURES (HIPPOCAMPUS, AMYGDALA, HYPOTHALAMUS, MIDBRAIN, CORTEX, BASAL GANGLIA) WITH THE USE OF TAQMAN GENE EXPRESSION ASSAY, WESTERN BLOT AND METHYLATION-SENSITIVE HIGH-RESOLUTION MELTING TECHNIQUES. CMS CAUSED A DECREASE IN SUCROSE CONSUMPTION, AND THIS EFFECT WAS NORMALIZED BY FLUOXETINE. IN PBMCS, SOD1, SOD2 AND NOS2 MRNA EXPRESSION CHANGED ONLY AFTER VENLAFAXINE ADMINISTRATION. IN BRAIN, CAT, GPX1, GPX4 AND NOS1 GENE EXPRESSION CHANGED FOLLOWING CMS OR VENLAFAXINE EXPOSURE, MOST PROMINENTLY IN THE HIPPOCAMPUS, MIDBRAIN AND BASAL GANGLIA. CMS INCREASED THE METHYLATION OF THE GPX1 PROMOTER IN PBMCS, THE SECOND GPX4 PROMOTER IN MIDBRAIN AND BASAL GANGLIA, AND SOD1 AND SOD2 IN HIPPOCAMPUS. THE CMS ANIMALS TREATED WITH VENLAFAXINE DISPLAYED A SIGNIFICANTLY HIGHER CAT LEVEL IN MIDBRAIN AND CEREBRAL CORTEX. CMS CAUSED AN ELEVATION OF GPX4 IN THE HIPPOCAMPUS, WHICH WAS LOWERED IN CEREBRAL CORTEX BY VENLAFAXINE. THE RESULTS INDICATE THAT CMS AND VENLAFAXINE ADMINISTRATION AFFECT THE METHYLATION OF PROMOTERS OF GENES INVOLVED IN OXIDATIVE AND NITROSATIVE STRESS. THEY ALSO INDICATE THAT PERIPHERAL AND CENTRAL TISSUE DIFFER IN THEIR RESPONSE TO STRESS OR ANTIDEPRESSANT TREATMENTS. IT IS POSSIBLE THAT THAT APART FROM DNA METHYLATION, A CRUCIAL ROLE OF EXPRESSION LEVEL OF GENES MAY BE PLAYED BY OTHER FORMS OF EPIGENETIC REGULATION, SUCH AS HISTONE MODIFICATION OR MICRORNA INTERFERENCE. THESE FINDINGS PROVIDE STRONG EVIDENCE FOR THESIS THAT ANALYSIS OF THE LEVEL OF MRNA AND PROTEIN EXPRESSION AS WELL AS THE STATUS OF PROMOTER METHYLATION CAN HELP IN UNDERSTANDING THE PATHOMECHANISMS OF MENTAL DISEASES, INCLUDING DEPRESSION, AND THE MECHANISMS OF ACTION OF DRUGS EFFECTIVE IN THEIR THERAPY. 2020 12 169 28 ABNORMALITIES OF AMPK ACTIVATION AND GLUCOSE UPTAKE IN CULTURED SKELETAL MUSCLE CELLS FROM INDIVIDUALS WITH CHRONIC FATIGUE SYNDROME. BACKGROUND: POST EXERTIONAL MUSCLE FATIGUE IS A KEY FEATURE IN CHRONIC FATIGUE SYNDROME (CFS). ABNORMALITIES OF SKELETAL MUSCLE FUNCTION HAVE BEEN IDENTIFIED IN SOME BUT NOT ALL PATIENTS WITH CFS. TO TRY TO LIMIT POTENTIAL CONFOUNDERS THAT MIGHT CONTRIBUTE TO THIS CLINICAL HETEROGENEITY, WE DEVELOPED A NOVEL IN VITRO SYSTEM THAT ALLOWS COMPARISON OF AMP KINASE (AMPK) ACTIVATION AND METABOLIC RESPONSES TO EXERCISE IN CULTURED SKELETAL MUSCLE CELLS FROM CFS PATIENTS AND CONTROL SUBJECTS. METHODS: SKELETAL MUSCLE CELL CULTURES WERE ESTABLISHED FROM 10 SUBJECTS WITH CFS AND 7 AGE-MATCHED CONTROLS, SUBJECTED TO ELECTRICAL PULSE STIMULATION (EPS) FOR UP TO 24H AND EXAMINED FOR CHANGES ASSOCIATED WITH EXERCISE. RESULTS: IN THE BASAL STATE, CFS CULTURES SHOWED INCREASED MYOGENIN EXPRESSION BUT DECREASED IL6 SECRETION DURING DIFFERENTIATION COMPARED WITH CONTROL CULTURES. CONTROL CULTURES SUBJECTED TO 16 H EPS SHOWED A SIGNIFICANT INCREASE IN BOTH AMPK PHOSPHORYLATION AND GLUCOSE UPTAKE COMPARED WITH UNSTIMULATED CELLS. IN CONTRAST, CFS CULTURES SHOWED NO INCREASE IN AMPK PHOSPHORYLATION OR GLUCOSE UPTAKE AFTER 16 H EPS. HOWEVER, GLUCOSE UPTAKE REMAINED RESPONSIVE TO INSULIN IN THE CFS CELLS POINTING TO AN EXERCISE-RELATED DEFECT. IL6 SECRETION IN RESPONSE TO EPS WAS SIGNIFICANTLY REDUCED IN CFS COMPARED WITH CONTROL CULTURES AT ALL TIME POINTS MEASURED. CONCLUSION: EPS IS AN EFFECTIVE MODEL FOR ELICITING MUSCLE CONTRACTION AND THE METABOLIC CHANGES ASSOCIATED WITH EXERCISE IN CULTURED SKELETAL MUSCLE CELLS. WE FOUND FOUR MAIN DIFFERENCES IN CULTURED SKELETAL MUSCLE CELLS FROM SUBJECTS WITH CFS; INCREASED MYOGENIN EXPRESSION IN THE BASAL STATE, IMPAIRED ACTIVATION OF AMPK, IMPAIRED STIMULATION OF GLUCOSE UPTAKE AND DIMINISHED RELEASE OF IL6. THE RETENTION OF THESE DIFFERENCES IN CULTURED MUSCLE CELLS FROM CFS SUBJECTS POINTS TO A GENETIC/EPIGENETIC MECHANISM, AND PROVIDES A SYSTEM TO IDENTIFY NOVEL THERAPEUTIC TARGETS. 2015 13 2792 23 FAT10 IS AN EPIGENETIC MARKER FOR LIVER PRENEOPLASIA IN A DRUG-PRIMED MOUSE MODEL OF TUMORIGENESIS. THERE IS CLINICAL EVIDENCE THAT CHRONIC LIVER DISEASES IN WHICH MDBS (MALLORY DENK BODIES) FORM PROGRESS TO HEPATOCELLULAR CARCINOMA. THE PRESENT STUDY PROVIDES EVIDENCE THAT LINKS MDB FORMATION INDUCED BY CHRONIC DRUG INJURY, WITH PRENEOPLASIA AND LATER TO THE FORMATION OF TUMORS, WHICH DEVELOP LONG AFTER DRUG WITHDRAWAL. EVIDENCE INDICATED THAT THIS LINK WAS DUE TO AN EPIGENETIC CELLULAR MEMORY INDUCED BY CHRONIC DRUG INGESTION. MICROARRAY ANALYSIS SHOWED THAT THE EXPRESSIONS OF MANY MARKERS OF PRENEOPLASIA (UBD, ALPHA FETOPROTEIN, KLF6 AND GLUTATHIONE-S-TRANSFERASE MU2) WERE INCREASED TOGETHER WHEN THE DRUG DDC WAS REFED. THESE CHANGES WERE SUPPRESSED BY S-ADENOSYLMETHIONINE FEEDING, INDICATING THAT THE DRUG WAS AFFECTING DNA AND HISTONES METHYLATION IN AN EPIGENETIC MANNER. THE LINK BETWEEN MDB FORMATION AND NEOPLASIA FORMATION WAS LIKELY DUE TO THE OVER EXPRESSION OF UBD (ALSO CALLED FAT10), WHICH IS UP REGULATED IN 90% OF HUMAN HEPATOCELLULAR CARCINOMAS. IMMUNOHISTOCHEMICAL STAINING OF DRUG-PRIMED MOUSE LIVERS SHOWED THAT FAT10 POSITIVE LIVER CELLS PERSISTED UP TO 4 MONTHS AFTER DRUG WITHDRAWAL AND THEY WERE STILL FOUND IN THE LIVERS OF MICE, 14 MONTHS AFTER DRUG WITHDRAWAL. THE REFEEDING OF DDC INCREASED THE PERCENT OF FAT10 HEPATOCYTES. 2008 14 6078 29 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 15 1140 23 CONCENTRATION OF FOLIC ACID (FA) IN SERUM OF JAPANESE PREGNANT WOMEN. OBJECTIVES EXPOSURE TO INORGANIC ARSENIC (IAS) IS A WORLD-WIDE HEALTH CONCERN. WE REPORTED THAT JAPANESE CHILDREN AND PREGNANT WOMEN ARE EXPOSED TO MODERATE LEVELS OF IAS THROUGH FOOD. REDUCING IAS CONTAMINATION FROM FOODS OF HIGH IAS IS AN IMPORTANT ISSUE UNIQUE IN JAPAN. INTEGRATED IAS IS METHYLATED TO LESS TOXIC ORGANIC FORMS, AND S-ADENOSYL-L-METHYONINE (SAM), A COMMON METHYL-DONOR OF DNA AND HISTONES, IS UTILIZED IN THIS PROCESS. CHRONIC CONSUMPTION OF SAM BY IAS METABOLISM DUE TO EXPOSURE TO IAS MIGHT ALTER THE EPIGENETIC MODIFICATION OF GENOME. THE SAM BIOSYNTHESIS PATHWAY IS DEPENDENT ON FOLATE CYCLE, AND IT IS POSSIBLE THAT INGESTION OF SUFFICIENT FOLIC ACID (FA) IS PROTECTIVE TO IAS INDUCED TOXICITY. METHODS IN THE COURSE OF OUR CROSS-SECTIONAL BODY BURDEN ANALYSES OF PB AND IAS IN JAPANESE CHILDREN AND PREGNANT WOMEN, TERMED "PBAS STUDY", FA CONCENTRATION IN SERUM OF 104 PREGNANT WOMEN WAS MEASURED. RESULTS MEAN (+/-SEM) OF SERUM FA CONCENTRATION WAS 15.8 +/- 1.3 (NG/ML). THERE ARE SIGNIFICANT NUMBER OF PEOPLE SHOWING VERY HIGH FA (>30 NG/ ML), AND LARGE FRACTION OF THEM WERE TAKING SUPPLEMENTS DAILY. CONCLUSIONS THESE RESULTS SUGGESTED THAT LEVEL OF FA INGESTION OF JAPANESE PREGNANT WOMEN IS HIGH FOR SUPPORTING NORMAL FETAL DEVELOPMENT. 2020 16 126 40 A TOXICOGENOMICS APPROACH TO IDENTIFY NEW PLAUSIBLE EPIGENETIC MECHANISMS OF OCHRATOXIN A CARCINOGENICITY IN RAT. OCHRATOXIN A (OTA) IS A MYCOTOXIN OCCURRING NATURALLY IN A WIDE RANGE OF FOOD COMMODITIES. IN ANIMALS, IT HAS BEEN SHOWN TO CAUSE A VARIETY OF ADVERSE EFFECTS, NEPHROCARCINOGENICITY BEING THE MOST PROMINENT. BECAUSE OF ITS HIGH TOXIC POTENCY AND THE CONTINUOUS EXPOSURE OF THE HUMAN POPULATION, OTA HAS RAISED PUBLIC HEALTH CONCERNS. THERE IS SIGNIFICANT DEBATE ON HOW TO USE THE RAT CARCINOGENICITY DATA TO ASSESS THE POTENTIAL RISK TO HUMANS. IN THIS CONTEXT, THE QUESTION OF THE MECHANISM OF ACTION OF OTA APPEARS OF KEY IMPORTANCE AND WAS STUDIED THROUGH THE APPLICATION OF A TOXICOGENOMICS APPROACH. MALE FISCHER RATS WERE FED OTA FOR UP TO 2 YEARS. RENAL TUMORS WERE DISCOVERED DURING THE LAST 6 MONTHS OF THE STUDY. THE TOTAL TUMOR INCIDENCE REACHED 25% AT THE END OF THE STUDY. GENE EXPRESSION PROFILE WAS ANALYZED IN GROUPS OF ANIMALS TAKEN IN INTERVALS FROM 7 DAYS TO 12 MONTHS. TISSUE-SPECIFIC RESPONSES WERE OBSERVED IN KIDNEY VERSUS LIVER. FOR SELECTED GENES, MICROARRAY DATA WERE CONFIRMED AT BOTH MRNA AND PROTEIN LEVELS. IN KIDNEY, SEVERAL GENES KNOWN AS MARKERS OF KIDNEY INJURY AND CELL REGENERATION WERE SIGNIFICANTLY MODULATED BY OTA. THE EXPRESSION OF GENES KNOWN TO BE INVOLVED IN DNA SYNTHESIS AND REPAIR, OR GENES INDUCED AS A RESULT OF DNA DAMAGE, WAS ONLY MARGINALLY MODULATED. VERY LITTLE OR NO EFFECT WAS FOUND AMONGST GENES ASSOCIATED WITH APOPTOSIS. ALTERATIONS OF GENE EXPRESSION INDICATING EFFECTS ON CALCIUM HOMEOSTASIS AND A DISRUPTION OF PATHWAYS REGULATED BY THE TRANSCRIPTION FACTORS HEPATOCYTE NUCLEAR FACTOR 4 ALPHA (HNF4ALPHA) AND NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) WERE OBSERVED IN THE KIDNEY BUT NOT IN THE LIVER. PREVIOUS DATA HAVE SUGGESTED THAT A REDUCTION IN HNF4ALPHA MAY BE ASSOCIATED WITH NEPHROCARCINOGENICITY. MANY NRF2-REGULATED GENES ARE INVOLVED IN CHEMICAL DETOXICATION AND ANTIOXIDANT DEFENSE. THE DEPLETION OF THESE GENES IS LIKELY TO IMPAIR THE DEFENSE POTENTIAL OF THE CELLS, RESULTING IN CHRONIC ELEVATION OF OXIDATIVE STRESS IN THE KIDNEY. THE INHIBITION OF DEFENSE MECHANISM APPEARS AS A HIGHLY PLAUSIBLE NEW MECHANISM, WHICH COULD CONTRIBUTE TO OTA CARCINOGENICITY. 2006 17 837 45 CHEMICALLY INDUCED RENAL TUBULE TUMORS IN THE LABORATORY RAT AND MOUSE: REVIEW OF THE NCI/NTP DATABASE AND CATEGORIZATION OF RENAL CARCINOGENS BASED ON MECHANISTIC INFORMATION. THE INCIDENCE OF RENAL TUBULE CARCINOGENESIS IN MALE AND FEMALE RATS OR MICE WITH 69 CHEMICALS FROM THE 513 BIOASSAYS CONDUCTED TO DATE BY THE NCI/NTP HAS BEEN COLLATED, THE CHEMICALS CATEGORIZED, AND THE RELATIONSHIP BETWEEN CARCINOGENESIS AND RENAL TUBULE HYPERPLASIA AND EXACERBATION OF THE SPONTANEOUS, AGE-RELATED RODENT DISEASE CHRONIC PROGRESSIVE NEPHROPATHY (CPN) EXAMINED. WHERE INFORMATION ON MECHANISM OR MODE OF ACTION EXISTS, THE CHEMICALS HAVE BEEN CATEGORIZED BASED ON THEIR ABILITY TO DIRECTLY OR INDIRECTLY INTERACT WITH RENAL DNA, OR ON THEIR ACTIVITY VIA EPIGENETIC PATHWAYS INVOLVING EITHER DIRECT OR INDIRECT CYTOTOXICITY WITH REGENERATIVE HYPERPLASIA, OR EXACERBATION OF CPN. NINE CHEMICALS WERE IDENTIFIED AS DIRECTLY INTERACTING WITH DNA, WITH SIX OF THESE PRODUCING RENAL TUBULE TUMORS AT HIGH INCIDENCE IN RATS OF BOTH SEXES, AND IN SOME CASES ALSO IN MICE. OCHRATOXIN A WAS THE MOST POTENT COMPOUND IN THIS GROUP, PRODUCING A HIGH TUMOR INCIDENCE AT VERY LOW DOSES, OFTEN WITH METASTASIS. THREE CHEMICALS WERE DISCUSSED IN THE CONTEXT OF INDIRECT DNA DAMAGE MEDIATED BY AN OXIDATIVE FREE RADICAL MECHANISM, ONE OF THESE BEING FROM THE NTP DATABASE. A THIRD CATEGORY INCLUDED FOUR CHEMICALS THAT HAD THE POTENTIAL TO CAUSE DNA DAMAGE FOLLOWING CONJUGATION WITH GLUTATHIONE AND SUBSEQUENT ENZYMATIC ACTIVATION TO A REACTIVE SPECIES, USUALLY A THIOL-CONTAINING ENTITY. TWO CHEMICALS WERE ALLOCATED INTO THE CATEGORY INVOLVING A DIRECT CYTOTOXIC ACTION ON THE RENAL TUBULE FOLLOWED BY SUSTAINED COMPENSATORY CELL PROLIFERATION, WHILE NINE WERE INCLUDED IN A GROUP WHERE THE CELL LOSS AND SUSTAINED INCREASE IN RENAL TUBULE CELL TURNOVER WERE DEPENDENT ON LYSOSOMAL ACCUMULATION OF THE MALE RAT-SPECIFIC PROTEIN, ALPHA2MU-GLOBULIN. IN A SIXTH CATEGORY, MORPHOLOGIC EVIDENCE ON TWO CHEMICALS INDICATED THAT THE RENAL TUMORS WERE A CONSEQUENCE OF EXACERBATED CPN. FOR THE REMAINING CHEMICALS, THERE WERE NO PERTINENT DATA ENABLING ASSIGNMENT TO A MECHANISTIC CATEGORY. ACCORDINGLY, THESE CHEMICALS, ACTING THROUGH AN AS YET UNKNOWN MECHANISM, WERE GROUPED AS EITHER BEING ASSOCIATED WITH AN ENHANCEMENT OF CPN (CATEGORY 7, 16 CHEMICALS), OR NOT ASSOCIATED WITH ENHANCED CPN (CATEGORY 8, 4 CHEMICALS). A NINTH CATEGORY DEALT WITH 11 CHEMICALS THAT WERE REGARDED AS PRODUCING INCREASES IN RENAL TUBULE TUMORS THAT DID NOT REACH STATISTICAL SIGNIFICANCE. A 10TH CATEGORY DISCUSSED 6 CHEMICALS THAT INDUCED RENAL TUMORS IN MICE BUT NOT IN RATS, PLUS 8 CHEMICALS THAT PRODUCED A LOW INCIDENCE OF RENAL TUBULE TUMORS IN MICE THAT DID NOT REACH STATISTICAL SIGNIFICANCE. AS MORE MECHANISTIC DATA ARE GENERATED, SOME CHEMICALS WILL INEVITABLY BE PLACED IN DIFFERENT GROUPS, PARTICULARLY THOSE FROM CATEGORIES 7 AND 8. A LARGE NUMBER OF CHEMICALS IN THE SERIES EXACERBATED CPN, BUT THOSE IN CATEGORY 7 ESPECIALLY MAY BE CANDIDATES FOR INCLUSION IN CATEGORY 6 WHEN FURTHER INFORMATION IS GLEANED FROM THE RELEVANT NTP STUDIES. ALSO, NEW DATA ON SPECIFIC CHEMICALS WILL PROBABLY EXPAND CATEGORY 5 AS CYTOTOXICITY AND CELL REGENERATION ARE IDENTIFIED AS OBLIGATORY STEPS IN RENAL CARCINOGENESIS IN MORE CASES. ADDITIONAL CONFIRMATORY OUTCOMES ARISING FROM THIS REVIEW ARE THAT METASTASES FROM RENAL TUBULE TUMORS, WHILE ENCOUNTERED WITH CHEMICALS CAUSING DNA DAMAGE, ARE RARE WITH THOSE ACTING THROUGH AN EPIGENETIC PATHWAY, WITH THE EXCEPTION BEING FUMONISIN B1; THAT MALE RATS AND MICE ARE GENERALLY MORE SUSCEPTIBLE THAN FEMALE RATS AND MICE TO CHEMICAL INDUCTION OF RENAL TUBULE TUMORS; AND THAT A BACKGROUND OF ATYPICAL TUBULE HYPERPLASIA IS A USEFUL INDICATOR REFLECTING A CHEMICALLY ASSOCIATED RENAL TUBULE TUMOR RESPONSE. WITH RESPECT TO RENAL TUBULE TUMORS AND HUMAN RISK ASSESSMENT, CHEMICALS IN CATEGORIES 1 AND 2, AND POSSIBLY 3, WOULD CURRENTLY BE JUDGED BY LINEAR DEFAULT METHODS; CHEMICALS IN CATEGORY 4 (AND PROBABLY SOME IN CATEGORY 3) AS EXHIBITING A THRESHOLD OF ACTIVITY WARRANTING THE BENCHMARK APPROACH; AND THOSE IN CATEGORIES 5 AND 6 AS REPRESENTING MECHANISMS THAT HAVE NO RELEVANCE FOR EXTRAPOLATION TO HUMANS. 2004 18 219 25 ACUTE IMMOBILIZATION STRESS FOLLOWING CONTEXTUAL FEAR CONDITIONING REDUCES FEAR MEMORY: TIMING IS ESSENTIAL. BACKGROUND: HISTONE ACETYLATION IS REGULATED IN RESPONSE TO STRESS AND PLAYS AN IMPORTANT ROLE IN LEARNING AND MEMORY. CHRONIC STRESS IS KNOWN TO DETERIORATE COGNITION, WHEREAS ACUTE STRESS FACILITATES MEMORY FORMATION. HOWEVER, WHETHER ACUTE STRESS FACILITATES MEMORY FORMATION WHEN IT IS APPLIED AFTER FEAR STIMULATION IS NOT YET KNOWN. THEREFORE, THIS STUDY AIMED TO INVESTIGATE THE EFFECT OF ACUTE STRESS APPLIED AFTER FEAR TRAINING ON MEMORY FORMATION, MRNA EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), EPIGENETIC REGULATION OF BDNF EXPRESSION, AND CORTICOSTERONE LEVEL IN MICE IN VIVO. METHODS: MICE WERE SUBJECTED TO ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 OR 90 MIN AFTER CONTEXTUAL FEAR CONDITIONING TRAINING, AND ACETYLATION OF HISTONE 3 AT LYSINE 14 (H3K14) AND LEVEL OF CORTICOSTERONE WERE MEASURED USING WESTERN BLOT ANALYSIS AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. A FREEZING BEHAVIOR TEST WAS PERFORMED 24 H AFTER TRAINING, AND MRNA EXPRESSION OF BDNF WAS MEASURED USING REAL-TIME POLYMERASE CHAIN REACTIONS. DIFFERENT GROUPS OF MICE WERE USED FOR EACH TEST. RESULTS: FREEZING BEHAVIOR SIGNIFICANTLY DECREASED WITH THE DOWN-REGULATION OF BDNF MRNA EXPRESSION CAUSED BY ACUTE IMMOBILIZATION STRESS AT 60 MIN AFTER FEAR CONDITIONING TRAINING OWING TO THE REDUCTION OF H3K14 ACETYLATION. HOWEVER, BDNF MRNA EXPRESSION AND H3K14 ACETYLATION WERE NOT REDUCED IN ANIMALS SUBJECTED TO IMMOBILIZATION STRESS AT 90 MIN AFTER THE TRAINING. FURTHER, THE CORTICOSTERONE LEVEL WAS SIGNIFICANTLY HIGH IN MICE SUBJECTED TO IMMOBILIZATION STRESS AT 60 MIN AFTER THE TRAINING. CONCLUSION: ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 MIN AFTER FEAR CONDITIONING TRAINING IMPAIRED MEMORY FORMATION AND REDUCED BDNF MRNA EXPRESSION AND H3K14 ACETYLATION IN THE HIPPOCAMPUS OF MICE OWING TO THE HIGH LEVEL OF CORTICOSTERONE. 2016 19 894 21 CHRONIC ETHANOL FEEDING ALTERS HEPATOCYTE MEMORY WHICH IS NOT ALTERED BY ACUTE FEEDING. BACKGROUND: GENE EXPRESSION CHANGES IN THE LIVER AFTER ACUTE BINGE DRINKING MAY DIFFER FROM THE CHANGES SEEN IN CHRONIC ETHANOL FEEDING IN THE RAT. THE CHANGES IN GENE EXPRESSION AFTER CHRONIC ETHANOL FEEDING MAY SENSITIZE THE LIVER TO ALCOHOL-INDUCED LIVER DAMAGE, WHICH IS NOT SEEN AFTER ACUTE BINGE DRINKING. METHODS: TO TEST THIS HYPOTHESIS, GENE MICROARRAY ANALYSIS WAS PERFORMED ON THE LIVERS OF RATS (N = 3) FED AN ACUTE BINGE DOSE OF ETHANOL (6 G/KG BODY WT) AND KILLED AT 3 AND 12 HOURS AFTER ETHANOL BY GAVAGE. THE GENE MICROARRAYS WERE COMPARED WITH THOSE MADE ON THE LIVER OF RATS FROM A PREVIOUS STUDY, IN WHICH THE RATS WERE FED ETHANOL BY INTRAGASTRIC TUBE FOR 1 MONTH (36% OF CALORIES DERIVED FROM ETHANOL). RESULTS: MICROARRAY ANALYSIS DATA VARIED BETWEEN THE ACUTE AND CHRONIC MODELS IN SEVERAL IMPORTANT RESPECTS. GROWTH FACTORS INCREASED MAINLY IN THE CHRONIC ALCOHOL FED RAT. CHANGES IN ENZYMES INVOLVED IN OXIDATIVE STRESS WERE NOTED ONLY WITH CHRONIC ETHANOL FEEDING. GENE EXPRESSION OF FAT METABOLISM WAS INCREASED ONLY WITH CHRONIC ETHANOL FEEDING. MOST IMPORTANTLY, EPIGENETIC RELATED ENZYMES AND ACETYLATION AND METHYLATION OF HISTONES CHANGED ONLY AFTER CHRONIC ETHANOL FEEDING. CONCLUSIONS: THE RESULTS SUPPORT THE CONCEPT THAT CHRONIC ETHANOL INGESTION INDUCES ALTERED GENE EXPRESSION AS A RESULT OF CHANGES IN EPIGENETIC MECHANISMS, WHERE ACETYLATION AND METHYLATION OF HISTONES WERE ALTERED. 2009 20 4890 38 OXIDATIVE STRESS AND HEPATIC NOX PROTEINS IN CHRONIC HEPATITIS C AND HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON LIVER CANCER AND A LEADING CAUSE OF CANCER-RELATED MORTALITY IN THE WORLD. HEPATITIS C VIRUS (HCV) IS A MAJOR ETIOLOGIC AGENT OF HCC. A MAJORITY OF HCV INFECTIONS LEAD TO CHRONIC INFECTION THAT CAN PROGRESS TO CIRRHOSIS AND, EVENTUALLY, HCC AND LIVER FAILURE. A COMMON PATHOGENIC FEATURE PRESENT IN HCV INFECTION, AND OTHER CONDITIONS LEADING TO HCC, IS OXIDATIVE STRESS. HCV DIRECTLY INCREASES SUPEROXIDE AND H2O2 FORMATION IN HEPATOCYTES BY ELEVATING NOX PROTEIN EXPRESSION AND SENSITIZING MITOCHONDRIA TO REACTIVE OXYGEN SPECIES GENERATION WHILE DECREASING GLUTATHIONE. NITRIC OXIDE SYNTHESIS AND HEPATIC IRON ARE ALSO ELEVATED. FURTHERMORE, ACTIVATION OF PHAGOCYTIC NADPH OXIDASE (NOX) 2 OF HOST IMMUNE CELLS IS LIKELY TO EXACERBATE OXIDATIVE STRESS IN HCV-INFECTED PATIENTS. KEY MECHANISMS OF HCC INCLUDE GENOME INSTABILITY, EPIGENETIC REGULATION, INFLAMMATION WITH CHRONIC TISSUE INJURY AND SUSTAINED CELL PROLIFERATION, AND MODULATION OF CELL GROWTH AND DEATH. OXIDATIVE STRESS, OR NOX PROTEINS, PLAYS VARIOUS ROLES IN THESE MECHANISMS. NOX PROTEINS ALSO FUNCTION IN HEPATIC FIBROSIS, WHICH COMMONLY PRECEDES HCC, AND NOX4 ELEVATION BY HCV IS MEDIATED BY TRANSFORMING GROWTH FACTOR BETA. THIS REVIEW SUMMARIZES MECHANISMS OF ONCOGENESIS BY HCV, HIGHLIGHTING THE ROLES OF OXIDATIVE STRESS AND HEPATIC NOX ENZYMES IN HCC. 2014