1 2387 120 EPIGENETIC REMODELING BY VITAMIN C POTENTIATES PLASMA CELL DIFFERENTIATION. ASCORBATE (VITAMIN C) IS AN ESSENTIAL MICRONUTRIENT IN HUMANS. THE SEVERE CHRONIC DEFICIENCY OF ASCORBATE, TERMED SCURVY, HAS LONG BEEN ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO INFECTIONS. HOW ASCORBATE AFFECTS THE IMMUNE SYSTEM AT THE CELLULAR AND MOLECULAR LEVELS REMAINED UNCLEAR. FROM A MICRONUTRIENT ANALYSIS, WE IDENTIFIED ASCORBATE AS A POTENT ENHANCER FOR ANTIBODY RESPONSE BY FACILITATING THE IL-21/STAT3-DEPENDENT PLASMA CELL DIFFERENTIATION IN MOUSE AND HUMAN B CELLS. THE EFFECT OF ASCORBATE IS UNIQUE AS OTHER ANTIOXIDANTS FAILED TO PROMOTE PLASMA CELL DIFFERENTIATION. ASCORBATE IS ESPECIALLY CRITICAL DURING EARLY B CELL ACTIVATION BY POISING THE CELLS TO PLASMA CELL LINEAGE WITHOUT AFFECTING THE PROXIMAL IL-21/STAT3 SIGNALING AND THE OVERALL TRANSCRIPTOME. AS A COFACTOR FOR EPIGENETIC ENZYMES, ASCORBATE FACILITATES TET2/3-MEDIATED DNA MODIFICATION AND DEMETHYLATION OF MULTIPLE ELEMENTS AT THE PRDM1 LOCUS. DNA DEMETHYLATION AUGMENTS STAT3 ASSOCIATION AT THE PRDM1 PROMOTER AND A DOWNSTREAM ENHANCER, THUS ENSURING EFFICIENT GENE EXPRESSION AND PLASMA CELL DIFFERENTIATION. THE RESULTS SUGGEST THAT AN ADEQUATE LEVEL OF ASCORBATE IS REQUIRED FOR ANTIBODY RESPONSE AND HIGHLIGHT HOW MICRONUTRIENTS MAY REGULATE THE ACTIVITY OF EPIGENETIC ENZYMES TO REGULATE GENE EXPRESSION. OUR FINDINGS IMPLY THAT EPIGENETIC ENZYMES CAN FUNCTION AS SENSORS TO GAUGE THE AVAILABILITY OF METABOLITES AND INFLUENCE CELL FATE DECISIONS. 2022 2 5295 29 PROTECTIVE POTENTIAL OF THYMOQUINONE AGAINST CADMIUM, ARSENIC, AND LEAD TOXICITY: A SHORT REVIEW WITH EMPHASIS ON OXIDATIVE PATHWAYS. HEAVY METALS ARE AMONG THE MOST IMPORTANT ENVIRONMENTAL POLLUTIONS USED IN VARIOUS INDUSTRIES. THEIR EXTENSIVE USE HAS INCREASED HUMAN SUSCEPTIBILITY TO DIFFERENT CHRONIC DISEASES. TOXIC METAL EXPOSURE, ESPECIALLY CADMIUM, ARSENIC, AND LEAD, CAUSES OXIDATIVE DAMAGES, MITOCHONDRIAL DYSFUNCTION, AND GENETIC AND EPIGENETIC MODIFICATIONS. MEANWHILE, THYMOQUINONE (TQ) IS AN EFFECTIVE COMPONENT OF NIGELLA SATIVA OIL THAT PLAYS AN IMPORTANT ROLE IN PREVENTING THE DESTRUCTIVE EFFECTS OF HEAVY METALS. THE PRESENT REVIEW DISCUSSES HOW TQ CAN PROTECT VARIOUS TISSUES AGAINST OXIDATIVE DAMAGE OF HEAVY METALS. THIS REVIEW IS BASED ON THE RESEARCH REPORTED ABOUT THE PROTECTIVE EFFECTS OF TQ IN THE TOXICITY OF HEAVY METALS, APPROXIMATELY THE LAST 10 YEARS (2010-2021). SCIENTIFIC DATABASES, INCLUDING SCOPUS, WEB OF SCIENCE, AND PUBMED, WERE SEARCHED USING THE FOLLOWING KEYWORDS EITHER ALONE OR IN COMBINATION: CADMIUM, ARSENIC, LEAD, TQ, AND OXIDATIVE STRESS. TQ, AS A POTENT ANTIOXIDANT, CAN DISTRIBUTE TO CELLULAR COMPARTMENTS AND PREVENT OXIDATIVE DAMAGE OF TOXIC METALS. HOWEVER, DEPENDING ON THE TYPE OF TOXIC METAL AND THE CARRIER SYSTEM USED TO RELEASE TQ IN BIOLOGICAL SYSTEMS, ITS THERAPEUTIC DOSAGE RANGE MAY BE VARIED. 2023 3 2961 37 GENETIC AND EPIGENETIC MECHANISMS IN METAL CARCINOGENESIS AND COCARCINOGENESIS: NICKEL, ARSENIC, AND CHROMIUM. CHRONIC EXPOSURE TO NICKEL(II), CHROMIUM(VI), OR INORGANIC ARSENIC (IAS) HAS LONG BEEN KNOWN TO INCREASE CANCER INCIDENCE AMONG AFFECTED INDIVIDUALS. RECENT EPIDEMIOLOGICAL STUDIES HAVE FOUND THAT CARCINOGENIC RISKS ASSOCIATED WITH CHROMATE AND IAS EXPOSURES WERE SUBSTANTIALLY HIGHER THAN PREVIOUSLY THOUGHT, WHICH LED TO MAJOR REVISIONS OF THE FEDERAL STANDARDS REGULATING AMBIENT AND DRINKING WATER LEVELS. GENOTOXIC EFFECTS OF CR(VI) AND IAS ARE STRONGLY INFLUENCED BY THEIR INTRACELLULAR METABOLISM, WHICH CREATES SEVERAL REACTIVE INTERMEDIATES AND BYPRODUCTS. TOXIC METALS ARE CAPABLE OF POTENT AND SURPRISINGLY SELECTIVE ACTIVATION OF STRESS-SIGNALING PATHWAYS, WHICH ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF HUMAN CANCERS. DEPENDING ON THE METAL, ASCORBATE (VITAMIN C) HAS BEEN FOUND TO ACT EITHER AS A STRONG ENHANCER OR SUPPRESSOR OF TOXIC RESPONSES IN HUMAN CELLS. IN ADDITION TO GENETIC DAMAGE VIA BOTH OXIDATIVE AND NONOXIDATIVE (DNA ADDUCTS) MECHANISMS, METALS CAN ALSO CAUSE SIGNIFICANT CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS, LEADING TO EPIGENETIC SILENCING OR REACTIVATION OF GENE EXPRESSION. IN VITRO GENOTOXICITY EXPERIMENTS AND RECENT ANIMAL CARCINOGENICITY STUDIES PROVIDED STRONG SUPPORT FOR THE IDEA THAT METALS CAN ACT AS COCARCINOGENS IN COMBINATION WITH NONMETAL CARCINOGENS. COCARCINOGENIC AND COMUTAGENIC EFFECTS OF METALS ARE LIKELY TO STEM FROM THEIR ABILITY TO INTERFERE WITH DNA REPAIR PROCESSES. OVERALL, METAL CARCINOGENESIS APPEARS TO REQUIRE THE FORMATION OF SPECIFIC METAL COMPLEXES, CHROMOSOMAL DAMAGE, AND ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS PROMOTING SURVIVAL AND EXPANSION OF GENETICALLY/EPIGENETICALLY ALTERED CELLS. 2008 4 4984 26 PATHWAYS OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI VIRULENCE AND INTERACTIONS WITH ANTIOXIDANT SYSTEMS, VITAMIN C AND PHYTOCHEMICALS. HELICOBACTER PYLORI IS A CLASS ONE CARCINOGEN WHICH CAUSES CHRONIC ATROPHIC GASTRITIS, GASTRIC INTESTINAL METAPLASIA, DYSPLASIA AND ADENOCARCINOMA. THE MECHANISMS BY WHICH H. PYLORI INTERACTS WITH OTHER RISK AND PROTECTIVE FACTORS, PARTICULARLY VITAMIN C IN GASTRIC CARCINOGENESIS ARE COMPLEX. GASTRIC CARCINOGENESIS INCLUDES METABOLIC, ENVIRONMENTAL, EPIGENETIC, GENOMIC, INFECTIVE, INFLAMMATORY AND ONCOGENIC PATHWAYS. THE MOLECULAR CLASSIFICATION OF GASTRIC CANCER SUBTYPES HAS REVOLUTIONIZED THE UNDERSTANDING OF GASTRIC CARCINOGENESIS. THIS INCLUDES THE TUMOUR MICROENVIRONMENT, GERMLINE MUTATIONS, AND THE ROLE OF HELICOBACTER PYLORI BACTERIA, EPSTEIN BARR VIRUS AND EPIGENETICS IN SOMATIC MUTATIONS. THERE IS EVIDENCE THAT ASCORBIC ACID, PHYTOCHEMICALS AND ENDOGENOUS ANTIOXIDANT SYSTEMS CAN MODIFY THE RISK OF GASTRIC CANCER. GASTRIC JUICE ASCORBATE LEVELS DEPEND ON DIETARY INTAKE OF ASCORBIC ACID BUT CAN ALSO BE DECREASED BY H. PYLORI INFECTION, H. PYLORI CAGA SECRETION, TOBACCO SMOKING, ACHLORHYDRIA AND CHRONIC ATROPHIC GASTRITIS. ASCORBIC ACID MAY BE PROTECTIVE AGAINST GASTRIC CANCER BY ITS ANTIOXIDANT EFFECT IN GASTRIC CYTOPROTECTION, REGENERATING ACTIVE VITAMIN E AND GLUTATHIONE, INHIBITING ENDOGENOUS N-NITROSATION, REDUCING TOXIC EFFECTS OF INGESTED NITROSODIMETHYLAMINES AND HETEROCYCLIC AMINES, AND PREVENTING H. PYLORI INFECTION. THE EFFECTIVENESS OF SUCH CYTOPROTECTION IS RELATED TO H. PYLORI STRAIN VIRULENCE, PARTICULARLY CAGA EXPRESSION. THE ROLE OF VITAMIN C IN EPIGENETIC REPROGRAMMING IN GASTRIC CANCER IS STILL EVOLVING. OTHER FACTORS IN CONJUNCTION WITH VITAMIN C ALSO PLAY A ROLE IN GASTRIC CARCINOGENESIS. ERADICATION OF H. PYLORI MAY LEAD TO RECOVERY OF VITAMIN C SECRETION BY GASTRIC EPITHELIUM AND ENABLE REGRESSION OF PREMALIGNANT GASTRIC LESIONS, THEREBY INTERRUPTING THE CORREA CASCADE OF GASTRIC CARCINOGENESIS. 2020 5 5048 35 PHARMACOLOGICAL APPROACHES IN EITHER INTERMITTENT OR PERMANENT HYPOXIA: A TALE OF TWO EXPOSURES. HYPOXIA INDUCES SEVERAL RESPONSES AT CARDIOVASCULAR, PULMONARY AND REPRODUCTIVE LEVELS, WHICH MAY LEAD TO CHRONIC DISEASES. THIS IS RELEVANT IN HUMAN POPULATIONS EXPOSED TO HIGH ALTITUDE (HA), IN EITHER CHRONIC CONTINUOUS (PERMANENT INHABITANTS) OR INTERMITTENT FASHION (HA WORKERS, TOURISTS AND MOUNTAINEERS). IN CHILE, IT IS ESTIMATED THAT 1.000.000 PEOPLE LIVE AT HIGHLANDS AND MORE THAN 55.000 WORK IN HA SHIFTS. INITIAL RESPONSES TO HYPOXIA ARE COMPENSATORY AND INDUCE ACTIVATION OF CARDIOPROTECTIVE MECHANISMS, SUCH AS THOSE SEEN UNDER INTERMITTENT HYPOBARIC (IH) HYPOXIA, EVENTS THAT COULD MEDIATE PRECONDITIONING. HOWEVER, WHENEVER HYPOXIA IS PROLONGED, THE CHRONIC ACTIVATION OF CELLULAR RESPONSES INDUCES LONG-LASTING MODIFICATIONS THAT MAY RESULT IN ACCLIMATIZATION OR PRODUCE MALADAPTIVE CHANGES WITH INCREASE IN CARDIOVASCULAR RISK. HA EXPOSURE DURING PREGNANCY INDUCES HYPOXIA AND OXIDATIVE STRESS, WHICH IN TURN MAY PROMOTE CELLULAR RESPONSES AND EPIGENETIC MODIFICATIONS RESULTING IN SEVERE IMPAIRMENT IN GROWTH AND DEVELOPMENT. SADLY, THIS CONDITION IS ACCOMPANIED WITH AN INCREASED FETAL AND NEONATAL MORBI-MORTALITY. FURTHER, DEVELOPMENTAL HYPOXIA MAY PROGRAM CARDIO-PULMONARY CIRCULATIONS LATER IN POSTNATAL LIFE, ENDING IN VASCULAR STRUCTURAL AND FUNCTIONAL ALTERATIONS WITH AUGMENTED RISK ON PULMONARY AND CARDIOVASCULAR FAILURE. ADDITIONALLY, PERMANENT HA INHABITANTS HAVE AUGMENTED RISK AND PREVALENCE OF CHRONIC HYPOXIC PULMONARY HYPERTENSION, RIGHT VENTRICULAR HYPERTROPHY AND CARDIOPULMONARY REMODELING. SIMILAR RESPONSES ARE SEEN IN ADULTS THAT ARE INTERMITTENTLY EXPOSED TO CHRONIC HYPOXIA (CH) SUCH AS SHIFT WORKERS IN HA AREAS. THE MECHANISMS INVOLVED DETERMINING THE IMMEDIATE, SHORT AND LONG-LASTING EFFECTS ARE STILL UNCLEAR. FOR SEVERAL YEARS, THE STUDY OF THE RESPONSES TO HYPOXIC INSULTS AND PHARMACOLOGICAL TARGETS HAS BEEN THE MOTIVATION OF OUR GROUP. THIS REVIEW DESCRIBES SOME OF THE MECHANISMS UNDERLYING HYPOXIC RESPONSES AND POTENTIAL THERAPEUTIC APPROACHES WITH ANTIOXIDANTS SUCH AS MELATONIN, ASCORBATE, OMEGA 3 (OMEGA3) OR COMPOUNDS THAT INCREASE THE NITRIC OXIDE (NO) BIOAVAILABILITY. 2015 6 6455 33 THYMOQUINONE ENHANCES APOPTOSIS OF K562 CHRONIC MYELOID LEUKEMIA CELLS THROUGH HYPOMETHYLATION OF SHP-1 AND INHIBITION OF JAK/STAT SIGNALING PATHWAY. THE EPIGENETIC SILENCING OF TUMOR SUPPRESSOR GENES (TSGS) IS CRITICAL IN THE DEVELOPMENT OF CHRONIC MYELOID LEUKEMIA (CML). SHP-1 FUNCTIONS AS A TSG AND NEGATIVELY REGULATES JAK/STAT SIGNALING. ENHANCEMENT OF SHP-1 EXPRESSION BY DEMETHYLATION PROVIDES MOLECULAR TARGETS FOR THE TREATMENT OF VARIOUS CANCERS. THYMOQUINONE (TQ), A CONSTITUENT OF NIGELLA SATIVA SEEDS, HAS SHOWN ANTI-CANCER ACTIVITIES IN VARIOUS CANCERS. HOWEVER, TQS EFFECT ON METHYLATION IS NOT FULLY CLEAR. THEREFORE, THE AIM OF THIS STUDY IS TO ASSESS TQS ABILITY TO ENHANCE THE EXPRESSION OF SHP-1 THROUGH MODIFYING DNA METHYLATION IN K562 CML CELLS. THE ACTIVITIES OF TQ ON CELL CYCLE PROGRESSION AND APOPTOSIS WERE EVALUATED USING A FLUOROMETRIC-RED CELL CYCLE ASSAY AND ANNEXIN V-FITC/PI, RESPECTIVELY. THE METHYLATION STATUS OF SHP-1 WAS STUDIED BY PYROSEQUENCING ANALYSIS. THE EXPRESSION OF SHP-1, TET2, WT1, DNMT1, DNMT3A, AND DNMT3B WAS DETERMINED USING RT-QPCR. THE PROTEIN PHOSPHORYLATION OF STAT3, STAT5, AND JAK2 WAS ASSESSED USING JESS WESTERN ANALYSIS. TQ SIGNIFICANTLY DOWNREGULATED THE DNMT1 GENE, DNMT3A GENE, AND DNMT3B GENE AND UPREGULATED THE WT1 GENE AND TET2 GENE. THIS LED TO HYPOMETHYLATION AND RESTORATION OF SHP-1 EXPRESSION, RESULTING IN INHIBITION OF JAK/STAT SIGNALING, INDUCTION OF APOPTOSIS, AND CELL CYCLE ARREST. THE OBSERVED FINDINGS IMPLY THAT TQ PROMOTES APOPTOSIS AND CELL CYCLE ARREST IN CML CELLS BY INHIBITING JAK/STAT SIGNALING VIA RESTORATION OF THE EXPRESSION OF JAK/STAT-NEGATIVE REGULATOR GENES. 2023 7 1993 32 EPIGENETIC AND EPITRANSCRIPTOMIC MECHANISMS OF CHROMIUM CARCINOGENESIS. HEXAVALENT CHROMIUM [CR(VI)], A GROUP I CARCINOGEN CLASSIFIED BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC), REPRESENTS ONE OF THE MOST COMMON OCCUPATIONAL AND ENVIRONMENTAL POLLUTANTS. THE FINDINGS FROM HUMAN EPIDEMIOLOGICAL AND LABORATORY ANIMAL STUDIES SHOW THAT LONG-TERM EXPOSURE TO CR(VI) CAUSES LUNG CANCER AND OTHER CANCER. ALTHOUGH CR(VI) IS A WELL-RECOGNIZED CARCINOGEN, THE MECHANISM OF CR(VI) CARCINOGENESIS HAS NOT BEEN WELL UNDERSTOOD. DUE TO THE FACT THAT CR(VI) UNDERGOES A SERIES OF METABOLIC REDUCTIONS ONCE ENTERING CELLS TO GENERATE REACTIVE CR METABOLITES AND REACTIVE OXYGEN SPECIES (ROS) CAUSING GENOTOXICITY, CR(VI) IS GENERALLY CONSIDERED AS A GENOTOXIC CARCINOGEN. HOWEVER, MORE AND MORE STUDIES HAVE DEMONSTRATED THAT ACUTE OR CHRONIC CR(VI) EXPOSURE ALSO CAUSES EPIGENETIC DYSREGULATIONS INCLUDING CHANGING DNA METHYLATION, HISTONE POSTTRANSLATIONAL MODIFICATIONS AND REGULATORY NON-CODING RNA (MICRORNA AND LONG NON-CODING RNA) EXPRESSIONS. MOREOVER, EMERGING EVIDENCE SHOWS THAT CR(VI) EXPOSURE IS ALSO CAPABLE OF ALTERING CELLULAR EPITRANSCRIPTOME. GIVEN THE INCREASINGLY RECOGNIZED IMPORTANCE OF EPIGENETIC AND EPITRANSCRIPTOMIC DYSREGULATIONS IN CANCER INITIATION AND PROGRESSION, IT IS BELIEVED THAT CR(VI) EXPOSURE-CAUSED EPIGENETIC AND EPITRANSCRIPTOMIC CHANGES COULD PLAY IMPORTANT ROLES IN CR(VI) CARCINOGENESIS. THE GOAL OF THIS CHAPTER IS TO REVIEW THE EPIGENETIC AND EPITRANSCRIPTOMIC EFFECTS OF CR(VI) EXPOSURE AND DISCUSS THEIR ROLES IN CR(VI) CARCINOGENESIS. BETTER UNDERSTANDING THE MECHANISM OF CR(VI) CARCINOGENESIS MAY IDENTIFY NEW MOLECULAR TARGETS FOR MORE EFFICIENT PREVENTION AND TREATMENT OF CANCER RESULTING FROM CR(VI) EXPOSURE. 2023 8 6387 26 THE ROLE OF REACTIVE OXYGEN SPECIES IN ARSENIC TOXICITY. ARSENIC POISONING IS A GLOBAL HEALTH PROBLEM. CHRONIC EXPOSURE TO ARSENIC HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF A WIDE RANGE OF DISEASES AND HEALTH PROBLEMS IN HUMANS. ARSENIC EXPOSURE INDUCES THE GENERATION OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS), WHICH MEDIATE MULTIPLE CHANGES TO CELL BEHAVIOR BY ALTERING SIGNALING PATHWAYS AND EPIGENETIC MODIFICATIONS, OR CAUSE DIRECT OXIDATIVE DAMAGE TO MOLECULES. ANTIOXIDANTS WITH THE POTENTIAL TO REDUCE ROS LEVELS HAVE BEEN SHOWN TO AMELIORATE ARSENIC-INDUCED LESIONS. HOWEVER, EMERGING EVIDENCE SUGGESTS THAT CONSTRUCTIVE ACTIVATION OF ANTIOXIDATIVE PATHWAYS AND DECREASED ROS LEVELS CONTRIBUTE TO CHRONIC ARSENIC TOXICITY IN SOME CASES. THIS REVIEW DETAILS THE PATHWAYS INVOLVED IN ARSENIC-INDUCED REDOX IMBALANCE, AS WELL AS CURRENT STUDIES ON PROPHYLAXIS AND TREATMENT STRATEGIES USING ANTIOXIDANTS. 2020 9 4409 36 MOLECULAR ANATOMY AND PATHOGENIC ACTIONS OF HELICOBACTER PYLORI CAGA THAT UNDERPIN GASTRIC CARCINOGENESIS. CHRONIC INFECTION WITH HELICOBACTER PYLORI CAGA-POSITIVE STRAINS IS THE STRONGEST RISK FACTOR FOR GASTRIC CANCER. THE CAGA GENE PRODUCT, CAGA, IS DELIVERED INTO GASTRIC EPITHELIAL CELLS VIA THE BACTERIAL TYPE IV SECRETION SYSTEM. DELIVERED CAGA THEN UNDERGOES TYROSINE PHOSPHORYLATION AT THE GLU-PRO-ILE-TYR-ALA (EPIYA) MOTIFS IN ITS C-TERMINAL REGION AND ACTS AS AN ONCOGENIC SCAFFOLD PROTEIN THAT PHYSICALLY INTERACTS WITH MULTIPLE HOST SIGNALING PROTEINS IN BOTH TYROSINE PHOSPHORYLATION-DEPENDENT AND -INDEPENDENT MANNERS. ANALYSIS OF CAGA USING IN VITRO CULTURED GASTRIC EPITHELIAL CELLS HAS INDICATED THAT THE NONPHYSIOLOGICAL SCAFFOLDING ACTIONS OF CAGA CELL-AUTONOMOUSLY PROMOTE THE MALIGNANT TRANSFORMATION OF THE CELLS BY ENDOWING THE CELLS WITH MULTIPLE PHENOTYPIC CANCER HALLMARKS: SUSTAINED PROLIFERATION, EVASION OF GROWTH SUPPRESSORS, INVASIVENESS, RESISTANCE TO CELL DEATH, AND GENOMIC INSTABILITY. TRANSGENIC EXPRESSION OF CAGA IN MICE LEADS TO IN VIVO ONCOGENIC ACTION OF CAGA WITHOUT ANY OVERT INFLAMMATION. THE IN VIVO ONCOGENIC ACTIVITY OF CAGA IS FURTHER POTENTIATED IN THE PRESENCE OF CHRONIC INFLAMMATION. SINCE HELICOBACTER PYLORI INFECTION TRIGGERS A PROINFLAMMATORY RESPONSE IN HOST CELLS, A FEEDFORWARD STIMULATION LOOP THAT AUGMENTS THE ONCOGENIC ACTIONS OF CAGA AND INFLAMMATION IS CREATED IN CAGA-INJECTED GASTRIC MUCOSA. GIVEN THAT HELICOBACTER PYLORI IS NO LONGER COLONIZED IN ESTABLISHED GASTRIC CANCER LESIONS, THE MULTISTEP NATURE OF GASTRIC CANCER DEVELOPMENT SHOULD INCLUDE A "HIT-AND-RUN" PROCESS OF CAGA ACTION. THUS, ACQUISITION OF GENETIC AND EPIGENETIC ALTERATIONS THAT COMPENSATE FOR CAGA-DIRECTED CANCER HALLMARKS MAY BE REQUIRED FOR COMPLETION OF THE "HIT-AND-RUN" PROCESS OF GASTRIC CARCINOGENESIS. 2020 10 948 27 CHRONIC METABOLIC DERANGEMENT-INDUCED COGNITIVE DEFICITS AND NEUROTOXICITY ARE ASSOCIATED WITH REST INACTIVATION. CHRONIC METABOLIC ALTERATIONS MAY REPRESENT A RISK FACTOR FOR THE DEVELOPMENT OF COGNITIVE IMPAIRMENT, DEMENTIA, OR NEURODEGENERATIVE DISEASES. HYPERGLYCEMIA AND OBESITY ARE KNOWN TO IMPRINT EPIGENETIC MARKERS THAT COMPROMISE THE PROPER EXPRESSION OF CELL SURVIVAL GENES. HERE, WE SHOWED THAT CHRONIC HYPERGLYCEMIA (60 DAYS) INDUCED BY A SINGLE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN COMPROMISED COGNITION BY REDUCING HIPPOCAMPAL ERK SIGNALING AND BY INDUCING NEUROTOXICITY IN RATS. THE MECHANISMS APPEAR TO BE LINKED TO REDUCED ACTIVE DNA DEMETHYLATION AND DIMINISHED EXPRESSION OF THE NEUROPROTECTIVE TRANSCRIPTION FACTOR REST. THE IMPACT OF THE RELATIONSHIP BETWEEN ADIPOSITY AND DNA HYPERMETHYLATION ON REST EXPRESSION WAS ALSO DEMONSTRATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN OBESE CHILDREN WITH REDUCED LEVELS OF BLOOD ASCORBATE. THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS AND THE COGNITIVE IMPAIRMENT REPORTED IN OBESE CHILDREN, ADOLESCENTS, AND ADULTS SUGGEST THAT THE CORRECTION OF THE ANTHROPOMETRY AND THE PERIPHERAL METABOLIC ALTERATIONS WOULD PROTECT BRAIN HOMEOSTASIS AND REDUCE THE RISK OF DEVELOPING NEURODEGENERATIVE DISEASES. 2019 11 4119 43 MECHANISMS OF CADMIUM CARCINOGENICITY IN THE GASTROINTESTINAL TRACT. CANCER, A SERIOUS PUBLIC HEALTH PROBLEM IN WORLDWIDE, RESULTS FROM AN EXCESSIVE AND UNCONTROLLED PROLIFERATION OF THE BODY CELLS WITHOUT OBVIOUS PHYSIOLOGICAL DEMANDS OF ORGANS. THE GASTROINTESTINAL TRACT, INCLUDING THE ESOPHAGUS, STOMACH AND INTESTINE, IS A UNIQUE ORGAN SYSTEM. IT HAS THE HIGHEST CANCER INCIDENCE AND CANCER- RELATED MORTALITY IN THE BODY AND IS INFLUENCEED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. AMONG THE VARIOUS CHEMICAL ELEMENTS RECOGNIZED IN THE NATURE, SOME OF THEM INCLUDING ZINC, IRON, COBALT, AND COPPER HAVE ESSENTIAL ROLES IN THE VARIOUS BIOCHEMICAL AND PHYSIOLOGICAL PROCESSES, BUT ONLY AT LOW LEVELS AND OTHERS SUCH AS CADMIUM, LEAD, MERCURY, ARSENIC, AND NICKEL ARE CONSIDERED AS THREATS FOR HUMAN HEALTH ESPECIALLY WITH CHRONIC EXPOSURE AT HIGH LEVELS. CADMIUM, AN ENVIRONMENT CONTAMINANT, CANNOT BE DESTROYED IN NATURE. THROUGH IMPAIRMENT OF VITAMIN D METABOLISM IN THE KIDNEY IT CAUSES NEPHROTOXICITY AND SUBSEQUENTLY BONE METABOLISM IMPAIRMENT AND FRAGILITY. THE MAJOR MECHANISMS INVOLVED IN CADMIUM CARCINOGENESIS COULD BE RELATED TO THE SUPPRESSION OF GENE EXPRESSION, INHIBITION OF DNA DAMAGE REPAIR, INHIBITION OF APOPTOSIS, AND INDUCTION OF OXIDATIVE STRESS. IN ADDITION, CADMIUM MAY ACT THROUGH ABERRANT DNA METHYLATION. CADMIUM AFFECTS MULTIPLE CELLULAR PROCESSES, INCLUDING SIGNAL TRANSDUCTION PATHWAYS, CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. DOWN-REGULATION OF METHYLTRANSFERASES ENZYMES AND REDUCTION OF DNA METHYLATION HAVE BEEN STATED AS EPIGENETIC EFFECTS OF CADMIUM. FURTHERMORE, INCREASING INTRACELLULAR FREE CALCIUM ION LEVELS INDUCES NEURONAL APOPTOSIS IN ADDITION TO OTHER DELETERIOUS INFLUENCE ON THE STABILITY OF THE GENOME. 2015 12 4208 21 METAL CARCINOGEN EXPOSURE INDUCES CANCER STEM CELL-LIKE PROPERTY THROUGH EPIGENETIC REPROGRAMING: A NOVEL MECHANISM OF METAL CARCINOGENESIS. ARSENIC, CADMIUM, NICKEL AND HEXAVALENT CHROMIUM ARE AMONG THE MOST COMMON ENVIRONMENTAL POLLUTANTS AND POTENT CARCINOGENS. CHRONIC EXPOSURE TO THESE METALS CAUSES VARIOUS TYPES OF CANCER IN HUMANS, REPRESENTING A SIGNIFICANT ENVIRONMENTAL HEALTH ISSUE. ALTHOUGH UNDER ACTIVE INVESTIGATION, THE MECHANISMS OF METAL CARCINOGENESIS HAVE NOT BEEN CLEARLY DEFINED. ONE COMMON FEATURE OF THESE METAL CARCINOGENS IS THAT THEY ARE ALL ABLE TO CAUSE VARIOUS EPIGENETIC DYSREGULATIONS, WHICH ARE BELIEVED TO PLAY IMPORTANT ROLES IN THEIR CARCINOGENICITY. HOWEVER, HOW METAL CARCINOGEN-CAUSED EPIGENETIC DYSREGULATION CONTRIBUTES TO METAL CARCINOGENESIS REMAINS LARGELY UNKNOWN. THE EVOLUTION OF CANCER STEM CELL (CSC) THEORY HAS OPENED EXCITING NEW AVENUES FOR STUDYING THE MECHANISM OF METAL CARCINOGENESIS. INCREASING EVIDENCE INDICATES THAT CHRONIC METAL CARCINOGEN EXPOSURE PRODUCES CSC-LIKE CELLS THROUGH DYSREGULATED EPIGENETIC MECHANISMS. THIS REVIEW WILL FIRST PROVIDE SOME BRIEF INTRODUCTIONS ABOUT CSC, EPIGENETICS AND EPIGENETIC REGULATION OF CSCS; THEN SUMMARIZE PROGRESSES IN RECENT STUDIES ON METAL CARCINOGEN-INDUCED CSC-LIKE PROPERTY THROUGH EPIGENETIC REPROGRAMING AS A NOVEL MECHANISM OF METAL CARCINOGENESIS. SOME PERSPECTIVES FOR FUTURE STUDIES IN THIS FIELD ARE ALSO PRESENTED. 2019 13 975 25 CHRONIC OCCUPATIONAL EXPOSURE TO ARSENIC INDUCES CARCINOGENIC GENE SIGNALING NETWORKS AND NEOPLASTIC TRANSFORMATION IN HUMAN LUNG EPITHELIAL CELLS. CHRONIC ARSENIC EXPOSURE REMAINS A HUMAN HEALTH RISK; HOWEVER A CLEAR MODE OF ACTION TO UNDERSTAND GENE SIGNALING-DRIVEN ARSENIC CARCINOGENESIS IS CURRENTLY LACKING. THIS STUDY CHRONICALLY EXPOSED HUMAN LUNG EPITHELIAL BEAS-2B CELLS TO LOW-DOSE ARSENIC TRIOXIDE TO ELUCIDATE CANCER PROMOTING GENE SIGNALING NETWORKS ASSOCIATED WITH ARSENIC-TRANSFORMED (B-AS) CELLS. FOLLOWING A 6MONTH EXPOSURE, EXPOSED CELLS WERE ASSESSED FOR ENHANCED CELL PROLIFERATION, COLONY FORMATION, INVASION ABILITY AND IN VIVO TUMOR FORMATION COMPARED TO CONTROL CELL LINES. COLLECTED MRNA WAS SUBJECTED TO WHOLE GENOME EXPRESSION MICROARRAY PROFILING FOLLOWED BY IN SILICO INGENUITY PATHWAY ANALYSIS (IPA) TO IDENTIFY LUNG CARCINOGENESIS MODES OF ACTION. B-AS CELLS DISPLAYED SIGNIFICANT INCREASES IN PROLIFERATION, COLONY FORMATION AND INVASION ABILITY COMPARED TO BEAS-2B CELLS. B-AS INJECTIONS INTO NUDE MICE RESULTED IN DEVELOPMENT OF PRIMARY AND SECONDARY METASTATIC TUMORS. ARSENIC EXPOSURE RESULTED IN WIDESPREAD UP-REGULATION OF GENES ASSOCIATED WITH MITOCHONDRIAL METABOLISM AND INCREASED REACTIVE OXYGEN SPECIES PROTECTION SUGGESTING MITOCHONDRIAL DYSFUNCTION. CARCINOGENIC INITIATION VIA REACTIVE OXYGEN SPECIES AND EPIGENETIC MECHANISMS WAS FURTHER SUPPORTED BY ALTERED DNA REPAIR, HISTONE, AND ROS-SENSITIVE SIGNALING. NF-KAPPAB, MAPK AND NCOR1 SIGNALING DISRUPTED PPARALPHA/DELTA-MEDIATED LIPID HOMEOSTASIS. A 'PRO-CANCER' GENE SIGNALING NETWORK IDENTIFIED INCREASED SURVIVAL, PROLIFERATION, INFLAMMATION, METABOLISM, ANTI-APOPTOSIS AND MOBILITY SIGNALING. IPA-RANKED SIGNALING NETWORKS IDENTIFIED ALTERED P21, EF1ALPHA, AKT, MAPK, AND NF-KAPPAB SIGNALING NETWORKS PROMOTING GENETIC DISORDER, ALTERED CELL CYCLE, CANCER AND CHANGES IN NUCLEIC ACID AND ENERGY METABOLISM. IN CONCLUSION, TRANSFORMED B-AS CELLS WITH THEIR WHOLE GENOME EXPRESSION PROFILE PROVIDE AN IN VITRO ARSENIC MODEL FOR FUTURE LUNG CANCER SIGNALING RESEARCH AND DATA FOR CHRONIC ARSENIC EXPOSURE RISK ASSESSMENT. 2012 14 2950 22 GENETIC AND EPIGENETIC DAMAGE INDUCED BY REACTIVE NITROGEN SPECIES: IMPLICATIONS IN CARCINOGENESIS. CHRONIC INFECTION AND INFLAMMATION ARE RECOGNIZED RISK FACTORS FOR HUMAN CANCER AT VARIOUS SITES. INFECTION AND INFLAMMATION CAN ACTIVATE AND INDUCE A VARIETY OF OXIDANT-GENERATING ENZYMES, INCLUDING NADPH OXIDASE AND INDUCIBLE NITRIC OXIDE SYNTHASE. REACTIVE OXYGEN AND NITROGEN SPECIES PRODUCED BY SUCH ENZYMES REACT WITH EACH OTHER TO GENERATE NEW AND MORE POTENT REACTIVE SPECIES. THESE OXIDANTS NOT ONLY CAN DAMAGE DNA AND INDUCE MUTATIONS, BUT ALSO CAN ACTIVATE ONCOGENE PRODUCTS AND/OR INACTIVATE TUMOR-SUPPRESSOR PROTEINS, THUS CONTRIBUTING TO MOST PROCESSES OF CARCINOGENESIS. APPROPRIATE TREATMENT OF INFLAMMATION SHOULD BE FURTHER EXPLORED FOR CHEMOPREVENTION OF HUMAN CANCERS, ESPECIALLY THOSE ASSOCIATED WITH CHRONIC INFLAMMATION. 2003 15 6166 37 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 16 474 16 ARSENIC BIOTRANSFORMATION AS A CANCER PROMOTING FACTOR BY INDUCING DNA DAMAGE AND DISRUPTION OF REPAIR MECHANISMS. CHRONIC EXPOSURE TO ARSENIC IN DRINKING WATER POSES A MAJOR GLOBAL HEALTH CONCERN. POPULATIONS EXPOSED TO HIGH CONCENTRATIONS OF ARSENIC-CONTAMINATED DRINKING WATER SUFFER SERIOUS HEALTH CONSEQUENCES, INCLUDING ALARMING CANCER INCIDENCE AND DEATH RATES. ARSENIC IS BIOTRANSFORMED THROUGH SEQUENTIAL ADDITION OF METHYL GROUPS, ACQUIRED FROM S-ADENOSYLMETHIONINE (SAM). METABOLISM OF ARSENIC GENERATES A VARIETY OF GENOTOXIC AND CYTOTOXIC SPECIES, DAMAGING DNA DIRECTLY AND INDIRECTLY, THROUGH THE GENERATION OF REACTIVE OXIDATIVE SPECIES AND INDUCTION OF DNA ADDUCTS, STRAND BREAKS AND CROSS LINKS, AND INHIBITION OF THE DNA REPAIR PROCESS ITSELF. SINCE SAM IS THE METHYL GROUP DONOR USED BY DNA METHYLTRANSFERASES TO MAINTAIN NORMAL EPIGENETIC PATTERNS IN ALL HUMAN CELLS, ARSENIC IS ALSO POSTULATED TO AFFECT MAINTENANCE OF NORMAL DNA METHYLATION PATTERNS, CHROMATIN STRUCTURE, AND GENOMIC STABILITY. THE BIOLOGICAL PROCESSES UNDERLYING THE CANCER PROMOTING FACTORS OF ARSENIC METABOLISM, RELATED TO DNA DAMAGE AND REPAIR, WILL BE DISCUSSED HERE. 2011 17 4822 23 OCHRATOXIN A: 50 YEARS OF RESEARCH. SINCE OCHRATOXIN A (OTA) WAS DISCOVERED, IT HAS BEEN UBIQUITOUS AS A NATURAL CONTAMINANT OF MOLDY FOOD AND FEED. THE MULTIPLE TOXIC EFFECTS OF OTA ARE A REAL THREAT FOR HUMAN BEINGS AND ANIMAL HEALTH. FOR EXAMPLE, OTA CAN CAUSE PORCINE NEPHROPATHY BUT CAN ALSO DAMAGE POULTRIES. HUMANS EXPOSED TO OTA CAN DEVELOP (NOTABLY BY INHALATION IN THE DEVELOPMENT OF ACUTE RENAL FAILURE WITHIN 24 H) A RANGE OF CHRONIC DISORDERS SUCH AS UPPER UROTHELIAL CARCINOMA. OTA PLAYS THE MAIN ROLE IN THE PATHOGENESIS OF SOME RENAL DISEASES INCLUDING BALKAN ENDEMIC NEPHROPATHY, KIDNEY TUMORS OCCURRING IN CERTAIN ENDEMIC REGIONS OF THE BALKAN PENINSULA, AND CHRONIC INTERSTITIAL NEPHROPATHY OCCURRING IN NORTHERN AFRICAN COUNTRIES AND LIKELY IN OTHER PARTS OF THE WORLD. OTA LEADS TO DNA ADDUCT FORMATION, WHICH IS KNOWN FOR ITS GENOTOXICITY AND CARCINOGENICITY. THE PRESENT ARTICLE DISCUSSES HOW RENAL CARCINOGENICITY AND NEPHROTOXICITY CAUSE BOTH OXIDATIVE STRESS AND DIRECT GENOTOXICITY. CAREFUL ANALYSES OF THE DATA SHOW THAT OTA CARCINOGENIC EFFECTS ARE DUE TO COMBINED DIRECT AND INDIRECT MECHANISMS (E.G., GENOTOXICITY, OXIDATIVE STRESS, EPIGENETIC FACTORS). ALTOGETHER THIS PROVIDES STRONG EVIDENCE THAT OTA CARCINOGENICITY CAN ALSO OCCUR IN HUMANS. 2016 18 1157 21 CONTAMINANT METALS AS CARDIOVASCULAR RISK FACTORS: A SCIENTIFIC STATEMENT FROM THE AMERICAN HEART ASSOCIATION. EXPOSURE TO ENVIRONMENTAL POLLUTANTS IS LINKED TO INCREASED RISK OF CARDIOVASCULAR DISEASE. BEYOND THE EXTENSIVE EVIDENCE FOR PARTICULATE AIR POLLUTION, ACCUMULATING EVIDENCE SUPPORTS THAT EXPOSURE TO NONESSENTIAL METALS SUCH AS LEAD, CADMIUM, AND ARSENIC IS A SIGNIFICANT CONTRIBUTOR TO CARDIOVASCULAR DISEASE WORLDWIDE. HUMANS ARE EXPOSED TO METALS THROUGH AIR, WATER, SOIL, AND FOOD AND EXTENSIVE INDUSTRIAL AND PUBLIC USE. CONTAMINANT METALS INTERFERE WITH CRITICAL INTRACELLULAR REACTIONS AND FUNCTIONS LEADING TO OXIDATIVE STRESS AND CHRONIC INFLAMMATION THAT RESULT IN ENDOTHELIAL DYSFUNCTION, HYPERTENSION, EPIGENETIC DYSREGULATION, DYSLIPIDEMIA, AND CHANGES IN MYOCARDIAL EXCITATION AND CONTRACTILE FUNCTION. LEAD, CADMIUM, AND ARSENIC HAVE BEEN LINKED TO SUBCLINICAL ATHEROSCLEROSIS, CORONARY ARTERY STENOSIS, AND CALCIFICATION AS WELL AS TO INCREASED RISK OF ISCHEMIC HEART DISEASE AND STROKE, LEFT VENTRICULAR HYPERTROPHY AND HEART FAILURE, AND PERIPHERAL ARTERY DISEASE. EPIDEMIOLOGICAL STUDIES SHOW THAT EXPOSURE TO LEAD, CADMIUM, OR ARSENIC IS ASSOCIATED WITH CARDIOVASCULAR DEATH MOSTLY ATTRIBUTABLE TO ISCHEMIC HEART DISEASE. PUBLIC HEALTH MEASURES REDUCING METAL EXPOSURE ARE ASSOCIATED WITH REDUCTIONS IN CARDIOVASCULAR DISEASE DEATH. POPULATIONS OF COLOR AND LOW SOCIOECONOMIC MEANS ARE MORE COMMONLY EXPOSED TO METALS AND THEREFORE AT GREATER RISK OF METAL-INDUCED CARDIOVASCULAR DISEASE. TOGETHER WITH STRENGTHENING PUBLIC HEALTH MEASURES TO PREVENT METAL EXPOSURES, DEVELOPMENT OF MORE SENSITIVE AND SELECTIVE MEASUREMENT MODALITIES, CLINICAL MONITORING OF METAL EXPOSURES, AND THE DEVELOPMENT OF METAL CHELATION THERAPIES COULD FURTHER DIMINISH THE BURDEN OF CARDIOVASCULAR DISEASE ATTRIBUTABLE TO METAL EXPOSURE. 2023 19 5941 26 TARGETING MICRORNAS WITH THYMOQUINONE: A NEW APPROACH FOR CANCER THERAPY. CANCER IS A GLOBAL DISEASE INVOLVING TRANSFORMATION OF NORMAL CELLS INTO TUMOR TYPES VIA NUMEROUS MECHANISMS, WITH MORTALITY AMONG ALL GENERATIONS, IN SPITE OF THE BREAKTHROUGHS IN CHEMOTHERAPY, RADIOTHERAPY AND/OR SURGERY FOR CANCER TREATMENT. SINCE ONE IN SIX DEATHS IS DUE TO CANCER, IT IS ONE OF THE OVERRIDING PRIORITIES OF WORLD HEALTH. RECENTLY, BIOACTIVE NATURAL COMPOUNDS HAVE BEEN WIDELY RECOGNIZED DUE TO THEIR THERAPEUTIC EFFECTS FOR TREATMENT OF VARIOUS CHRONIC DISORDERS, NOTABLY CANCER. THYMOQUINONE (TQ), THE MOST VALUABLE CONSTITUENT OF BLACK CUMIN SEEDS, HAS SHOWN ANTI-CANCER CHARACTERISTICS IN A WIDE RANGE OF ANIMAL MODELS. THE REVOLUTIONARY FINDINGS HAVE REVEALED TQ'S ABILITY TO REGULATE MICRORNA (MIRNA) EXPRESSION, OFFERING A PROMISING APPROACH FOR CANCER THERAPY. MIRNAS ARE SMALL NONCODING RNAS THAT MODULATE GENE EXPRESSION BY MEANS OF VARIATION IN FEATURES OF MRNA. MIRNAS MANAGE SEVERAL BIOLOGICAL PROCESSES INCLUDING GENE EXPRESSION AND CELLULAR SIGNALING PATHWAYS. ACCORDINGLY, MIRNAS CAN BE CONSIDERED AS HALLMARKS FOR CANCER DIAGNOSIS, PROGNOSIS AND THERAPY. THE PURPOSE OF THIS STUDY WAS TO REVIEW THE VARIOUS MOLECULAR MECHANISMS BY WHICH TQ EXERTS ITS POTENTIAL AS AN ANTI-CANCER AGENT THROUGH MODULATING MIRNAS. 2021 20 3775 26 INTERACTIONS BETWEEN ARSENIC-INDUCED TOXICITY AND NUTRITION IN EARLY LIFE. EXPOSURE TO ARSENIC THROUGH DRINKING WATER IS A MAJOR PUBLIC HEALTH PROBLEM AFFECTING MOST COUNTRIES, ALTHOUGH THE SITUATION IS PARTICULARLY SEVERE IN LOW-INCOME NATIONS. THE HEALTH CONSEQUENCES OF CHRONIC ARSENIC EXPOSURE INCLUDE INCREASED RISK FOR VARIOUS FORMS OF CANCER AND NUMEROUS NONCANCER EFFECTS, INCLUDING DIABETES, SKIN DISEASES, CHRONIC COUGH, AND TOXIC EFFECTS ON LIVER, KIDNEY, CARDIOVASCULAR SYSTEM, AND PERIPHERAL AND CENTRAL NERVOUS SYSTEMS. IN RECENT YEARS INCREASING REPORTS OF EFFECTS ON FETAL AND CHILD DEVELOPMENT HAVE APPEARED. THERE SEEMS TO BE A WIDE VARIATION IN SUSCEPTIBILITY TO ARSENIC TOXICITY, WHICH IS LIKELY TO BE RELATED TO FACTORS SUCH AS VARIATION IN ARSENIC METABOLISM, NUTRITION, HOST-RELATED DEFENSE MECHANISMS, AND GENETIC PREDISPOSITION. THE MAIN MECHANISMS OF ARSENIC-NUTRITION INTERACTIONS INCLUDE ARSENIC-INDUCED OXIDATIVE STRESS, WHICH REQUIRES NUTRIENT-DEPENDENT DEFENSE SYSTEMS, AND ARSENIC METABOLISM (METHYLATION) VIA 1-CARBON METABOLISM, WHICH REQUIRES METHYL GROUPS, FOLIC ACID, VITAMIN B-12, AND BETAINE FOR THE REMETHYLATION OF HOMOCYSTEINE TO METHIONINE. AN EFFICIENT FIRST METHYLATION STEP IN COMBINATION WITH A SLOW SECOND METHYLATION STEP SEEMS TO BE MOST CRITICAL FROM A TOXICOLOGICAL POINT OF VIEW. A THIRD MODE OF ARSENIC-NUTRITION INTERACTION INVOLVES EPIGENETIC EFFECTS AND FETAL PROGRAMMING VIA DNA METHYLATION. 2007