1 399 168 ANABOLIC STEROIDS-DRIVEN REGULATION OF PORCINE OVARIAN PUTATIVE STEM CELLS FAVORS THE ONSET OF THEIR NEOPLASTIC TRANSFORMATION. NANDROLONE (NDN) AND BOLDENONE (BDN), THE SYNTHETIC TESTOSTERONE ANALOGUES WITH STRONG ANABOLIC EFFECTS, DESPITE BEING RECOGNIZED AS POTENTIALLY CARCINOGENIC COMPOUNDS, ARE COMMONLY ABUSED BY ATHLETES AND BODYBUILDERS, WHICH INCLUDES WOMEN, WORLDWIDE. THIS STUDY TESTED THE HYPOTHESIS THAT DIFFERENT DOSES OF NDN AND BDN CAN INITIATE NEOPLASTIC TRANSFORMATION OF PORCINE OVARIAN PUTATIVE STEM CELLS (POPSCS). IMMUNOMAGNETICALLY ISOLATED POPSCS WERE EXPANDED EX VIVO IN THE PRESENCE OF NDN OR BDN, FOR 7 AND 14 DAYS. RESULTS SHOW THAT PHARMACOLOGICAL DOSES OF BOTH NDN AND BDN, ALREADY AFTER 7 DAYS OF POPSCS CULTURE, CAUSED A SIGNIFICANT INCREASE OF SELECTED, STEMNESS-RELATED MARKERS OF CANCER CELLS: CD44 AND CD133. NOTABLY, NDN ALSO NEGATIVELY AFFECTED POPSCS GROWTH NOT ONLY BY SUPPRESSING THEIR PROLIFERATION AND MITOCHONDRIAL RESPIRATION BUT ALSO BY INDUCING APOPTOSIS. THIS OBSERVATION SHOWS, FOR THE FIRST TIME, THAT CHRONIC EXPOSURE TO NDN OR BDN REPRESENTS A PRECONDITION THAT MIGHT ENHANCE RISK OF POPSCS NEOPLASTIC TRANSFORMATION. THESE STUDIES CARRIED OUT TO ACCOMPLISH DETAILED MOLECULAR CHARACTERIZATION OF THE EX VIVO EXPANDED POPSCS AND THEIR POTENTIALLY CANCEROUS DERIVATIVES (PCDS) MIGHT BE HELPFUL TO DETERMINE THEIR SUITABILITY AS NUCLEAR DONOR CELLS (NDCS) FOR FURTHER INVESTIGATIONS FOCUSED ON CLONING BY SOMATIC CELL NUCLEAR TRANSFER (SCNT). SUCH INVESTIGATIONS MIGHT ALSO BE INDISPENSABLE TO ESTIMATE THE CAPABILITIES OF NUCLEAR GENOMES INHERITED FROM POPSCS AND THEIR PCDS TO BE EPIGENETICALLY REPROGRAMMED (DEDIFFERENTIATED) IN CLONED PIG EMBRYOS GENERATED BY SCNT. THIS MIGHT OPEN UP NEW POSSIBILITIES FOR BIOMEDICAL RESEARCH AIMED AT MORE COMPREHENSIVELY RECOGNIZING GENETIC AND EPIGENETIC MECHANISMS UNDERLYING NOT ONLY TUMORIGENESIS BUT ALSO REVERSAL/RETARDATION OF PRO-TUMORIGENIC INTRACELLULAR EVENTS. 2021 2 6484 27 TOXICOLOGIC PROFILE OF ACRYLONITRILE. ACRYLONITRILE IS A MONOMER USED EXTENSIVELY AS A RAW MATERIAL IN THE MANUFACTURING OF ACRYLIC FIBERS, PLASTICS, SYNTHETIC RUBBERS, AND ACRYLAMIDE. IT HAS BEEN CLASSIFIED AS A PROBABLE HUMAN CARCINOGEN ACCORDING TO THE RESULTS OF NUMEROUS CHRONIC RAT BIOASSAYS. THE PRESENT REPORT SUMMARIZES THE TOXICITY DATA ON ACRYLONITRILE AND REVIEWS AVAILABLE DATA CONCERNING THE MECHANISM (GENETIC VERSUS EPIGENETIC) BY WHICH ACRYLONITRILE IS CARCINOGENIC IN RATS. FROM THE EVALUATION OF THE RELEVANT TOXICITY DATA, IT CAN BE CONCLUDED THAT ACRYLONITRILE IS INDEED CARCINOGENIC TO RATS AFTER EITHER ORAL OR INHALATIONAL EXPOSURE. HOWEVER, INFORMATION ON OTHER MAMMALIAN SPECIES IS LACKING, AND, MOREOVER, THE EXACT MECHANISM OF THE CARCINOGENIC PROCESS IS UNCLEAR. THEREFORE, IT IS RECOMMENDED TO CONDUCT AN ADDITIONAL LONG-TERM INHALATION CARCINOGENICITY STUDY WITH ACRYLONITRILE IN MICE, AS WELL AS STUDIES INTO THE MECHANISM BY WHICH ACRYLONITRILE INDUCES (BRAIN) TUMORS IN RATS (GENETIC VERSUS EPIGENETIC). 1998 3 3074 28 GENOME-WIDE DNA METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INORGANIC NANOPARTICLES IN HUMAN KIDNEY CELLS AFTER CHRONIC EXPOSURE. THE UNIQUE PHYSICOCHEMICAL PROPERTIES MAKE INORGANIC NANOPARTICLES (INPS) AN EXCITING TOOL IN DIAGNOSIS AND DISEASE MANAGEMENT. HOWEVER, AS INPS ARE RELATIVELY DIFFICULT TO FULLY DEGRADE AND EXCRETE, THEIR UNINTENDED ACCUMULATION IN THE TISSUE MIGHT RESULT IN ADVERSE HEALTH EFFECTS. HEREIN, WE PROVIDE A METHYLOME-TRANSCRIPTOME FRAMEWORK FOR CHRONIC EFFECTS OF INPS, COMMONLY USED IN BIOMEDICAL APPLICATIONS, IN HUMAN KIDNEY TH-1 CELLS. RENAL CLEARANCE IS ONE OF THE MOST IMPORTANT ROUTES OF NANOPARTICLE EXCRETION; THEREFORE, A DETAILED EVALUATION OF NANOPARTICLE-MEDIATED NEPHROTOXICITY IS AN IMPORTANT TASK. INTEGRATED ANALYSIS OF METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INPS (PEG-AUNPS, FE(3)O(4)NPS, SIO(2)NPS, AND TIO(2)NPS) REVEALED SIGNIFICANTLY DEREGULATED GENES WITH FUNCTIONAL CLASSIFICATION IN IMMUNE RESPONSE, DNA DAMAGE, AND CANCER-RELATED PATHWAYS. ALTHOUGH MOST DEREGULATED GENES WERE UNIQUE TO INDIVIDUAL INPS, A RELATIVELY HIGH PROPORTION OF THEM ENCODED THE TRANSCRIPTION FACTORS. INTERESTINGLY, FOS HYPERMETHYLATION INVERSELY CORRELATING WITH GENE EXPRESSION WAS ASSOCIATED WITH ALL INPS EXPOSURES. OUR STUDY EMPHASIZES THE NEED FOR A MORE COMPREHENSIVE INVESTIGATION OF INPS' BIOLOGICAL SAFETY, ESPECIALLY AFTER CHRONIC EXPOSURE. 2022 4 2818 16 FIBROSIS UNDER ARREST. APPROXIMATELY 5% OF PEOPLE THAT ARE HOSPITALIZED FOR ANY REASON DEVELOP ACUTE KIDNEY FAILURE, WHICH, IN SOME CASES, PROGRESSES TO A CHRONIC CONDITION RESULTING IN FIBROSIS OF THE KIDNEY AND PERMANENT CHANGES IN THE ORGAN'S FUNCTION. TWO NEW STUDIES SUGGEST THAT CELL CYCLE ARREST OF EPITHELIAL CELLS AND EPIGENETIC MODIFICATIONS HAVE KEY ROLES IN THE SWITCH TO CHRONIC DISEASE (PAGES 535-543 AND 544-550). 2010 5 5511 27 RIBONUCLEASES IN TUMOR GROWTH. THIS REVIEW SUMMARIZES DATA ON AMBIGUOUS BIOLOGICAL FUNCTIONS OF RIBONUCLEASES (RNASES) AT TUMOR GROWTH. IN SOME CASES THE RAISED LEVEL OF ENZYME ACTIVITY IN BIOLOGICAL FLUIDS CAN BE REGARDED AS AN ADDITIONAL MARKER OF MALIGNANT GROWTH (PANCREAS CANCER, CHRONIC MYELOID LEUKEMIA, ETC.). AT THE SAME TIME THE ACTIVITY OF RNASES IS OFTEN LOWERED IN TUMOR TISSUE. HIGH SUBSTRATE SPECIFICITY OF PARTICULAR RNASES PROVIDES METABOLIC BALANCE BETWEEN VARIOUS KINDS OF RNAS WITH VARIOUS HALF-TIME EXCHANGE TURN. RNASES ARE THE IMPORTANT FACTORS OF EPIGENETIC REGULATION OF GENE ACTIVITY IN CELLS. THE ACTIVITY OF RNASES IS ADJUSTABLE BY INHIBITORS AND OTHER FACTORS, AND DEFINES TIME OF EXISTENCE OF DIFFERENT KINDS OF RNAS. RNASES (THE MODIFIED VARIANTS OF RNASE A, RNASES OF SEMEN FLUID OF THE CATTLE, RNASE OF AMPHIBIA OOCYTES) CAN BE USED AS ANTI-TUMOR THERAPEUTIC AGENTS. ON THE OTHER HAND, SOME INHIBITORS OF RNASES OF NATURAL OR SYNTHETIC ORIGIN WERE DEMONSTRATED TO BE PERSPECTIVE DRUGS THAT INHIBIT TUMOR GROWTH. 2009 6 1109 30 COMMERCIAL PROCESSED SOY-BASED FOOD PRODUCT CONTAINS GLYCATED AND GLYCOXIDATED LUNASIN PROTEOFORMS. NUTRACEUTICALS HAVE BEEN PROPOSED TO EXERT POSITIVE EFFECTS ON HUMAN HEALTH AND CONFER PROTECTION AGAINST MANY CHRONIC DISEASES. A MAJOR BIOACTIVE COMPONENT OF SOY-BASED FOODS IS LUNASIN PEPTIDE, WHICH HAS POTENTIAL TO EXERT A MAJOR IMPACT ON THE HEALTH OF HUMAN CONSUMERS WORLDWIDE, BUT THE BIOCHEMICAL FEATURES OF DIETARY LUNASIN STILL REMAIN POORLY CHARACTERIZED. IN THIS STUDY, LUNASIN WAS PURIFIED FROM A SOY-BASED FOOD PRODUCT VIA STRONG ANION EXCHANGE SOLID PHASE EXTRACTION AND THEN SUBJECTED TO TOP-DOWN MASS SPECTROMETRY ANALYSIS THAT REVEALED IN DETAIL THE MOLECULAR DIVERSITY OF LUNASIN IN PROCESSED SOYBEAN FOODS. WE DETECTED MULTIPLE GLYCATED PROTEOFORMS TOGETHER WITH POTENTIALLY TOXIC ADVANCED GLYCATION END PRODUCTS (AGES) DERIVED FROM LUNASIN. IN BOTH CASES, MODIFICATION SITES WERE LYS24 AND LYS29 LOCATED AT THE HELICAL REGION THAT SHOWS STRUCTURAL HOMOLOGY WITH A CONSERVED REGION OF CHROMATIN-BINDING PROTEINS. THE IDENTIFIED POST-TRANSLATIONAL MODIFICATIONS MAY HAVE AN IMPORTANT REPERCUSSION ON LUNASIN EPIGENETIC REGULATORY CAPACITY. TAKING TOGETHER, OUR RESULTS DEMONSTRATE THE IMPORTANCE OF PROPER CHEMICAL CHARACTERIZATION OF COMMERCIAL PROCESSED FOOD PRODUCTS TO ASSESS THEIR IMPACT ON CONSUMER'S HEALTH AND RISK OF CHRONIC DISEASES. 2016 7 2761 32 EXPRESSION OF TESTIS-SPECIFIC GENES, TEX101 AND ODF4, IN CHRONIC MYELOID LEUKEMIA AND EVALUATION OF TEX101 IMMUNOGENICITY. BACKGROUND AND OBJECTIVES: CANCER-TESTIS (CT) ANTIGENS ARE A GROUP OF ANTIGENS WITH A RESTRICTED EXPRESSION IN NORMAL TISSUES, EXCEPT TESTIS, AND THEY HAVE ABERRANT EXPRESSION IN DIFFERENT TUMORS. THIS PATTERN OF EXPRESSION HAS MADE THEM PROMISING TARGETS FOR IMMUNOTHERAPY AND CANCER DETECTION. OUR AIM WAS TO FIND NEW MEMBERS OF THIS GROUP THAT MIGHT BE USEFUL AS MARKERS IN THE DETECTION OF CANCER AND IMMUNOTHERAPY. DESIGN AND SETTING: A DESCRIPTIVE STUDY CONDUCTED IN REFERRAL CENTERS OF TEHRAN UNIVERSITY OF MEDICAL SCIENCE FROM JANUARY 2008 TO JANUARY 2009. PATIENTS AND METHODS: WE ANALYZED THE EXPRESSION OF TWO TESTIS-SPECIFIC GENES NAMED ODF4 (OUTER DENSE FIBER OF SPERM TAILS 4) AND TEX101 (TESTIS EXPRESSED 101) IN 20 CHRONIC MYELOID LEUKEMIA (CML) AND 20 NORMAL SAMPLES BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION AND SEQUENCING. IMMUNOGENICITY OF TEX101 WAS EVALUATED BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY. RESULTS: THESE TWO GENES WERE EXPRESSED IN 30% OF CML PATIENTS BUT NOT IN ANY OF THE HEALTHY DONORS. HUMORAL RESPONSE AGAINST TEX101 WAS NOT DETECTED IN ANY SAMPLES. CONCLUSIONS: TEX101 AND ODF4 ARE CT GENES USEFUL FOR DETECTION OF CML. UNLIKE MANY CT GENES, OVEREXPRESSION OF TEX101 WAS NOT SHOWN TO INDUCE IMMUNOLOGIC RESPONSES IN THESE SAMPLES. ACCORDING TO THE PREVIOUS STUDIES, OVEREXPRESSION OF TEX101 LEADS TO SUPPRESSION OF CANCER INVASION AND METASTASIS; THUS, THE INDUCTION OF THE EXPRESSION OF TEX101 IN CANCER BY EPIGENETIC MECHANISMS MAY BE A TREATMENT STRATEGY. 2012 8 1335 24 DERMAL FIBROBLASTS CULTURED FROM DONORS WITH TYPE 2 DIABETES MELLITUS RETAIN AN EPIGENETIC MEMORY ASSOCIATED WITH POOR WOUND HEALING RESPONSES. THE PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) IS ESCALATING GLOBALLY. PATIENTS SUFFER FROM MULTIPLE COMPLICATIONS INCLUDING THE DEVELOPMENT OF CHRONIC WOUNDS THAT CAN LEAD TO AMPUTATION. THESE WOUNDS ARE CHARACTERISED BY AN INFLAMMATORY ENVIRONMENT INCLUDING ELEVATED TUMOUR NECROSIS FACTOR ALPHA (TNF-ALPHA). DERMAL FIBROBLASTS (DF) ARE CRITICAL FOR EFFECTIVE WOUND HEALING, SO WE SOUGHT TO ESTABLISH WHETHER THERE WERE ANY DIFFERENCES IN DF CULTURED FROM T2DM DONORS OR THOSE WITHOUT DIABETES (ND-DF). ND- AND T2DM-DF WHEN CULTURED SIMILARLY IN VITRO SECRETED COMPARABLE CONCENTRATIONS OF TNF-ALPHA. FUNCTIONALLY, PRE-TREATMENT WITH TNF-ALPHA REDUCED THE PROLIFERATION OF ND-DF AND TRANSIENTLY ALTERED ND-DF MORPHOLOGY; HOWEVER, T2DM-DF WERE RESISTANT TO THESE TNF-ALPHA INDUCED CHANGES. IN CONTRAST, TNF-ALPHA INHIBITED ND- AND T2DM-DF MIGRATION AND MATRIX METALLOPROTEASE EXPRESSION TO THE SAME DEGREE, ALTHOUGH T2DM-DF EXPRESSED SIGNIFICANTLY HIGHER LEVELS OF TISSUE INHIBITOR OF METALLOPROTEASES (TIMP)-2. FINALLY, TNF-ALPHA SIGNIFICANTLY INCREASED THE SECRETION OF PRO-INFLAMMATORY CYTOKINES (INCLUDING CCL2, CXCL1 AND SERPINE1) IN ND-DF, WHILST THIS EFFECT IN T2DM-DF WAS BLUNTED, PRESUMABLY DUE TO THE TENDENCY TO HIGHER BASELINE PRO-INFLAMMATORY CYTOKINE EXPRESSION OBSERVED IN THIS CELL TYPE. COLLECTIVELY, THESE DATA DEMONSTRATE THAT T2DM-DF EXHIBIT A SELECTIVE LOSS OF RESPONSIVENESS TO TNF-ALPHA, PARTICULARLY REGARDING PROLIFERATIVE AND SECRETORY FUNCTIONS. THIS HIGHLIGHTS IMPORTANT PHENOTYPIC CHANGES IN T2DM-DF THAT MAY EXPLAIN THE SUSCEPTIBILITY TO CHRONIC WOUNDS IN THESE PATIENTS. 2021 9 2758 28 EXPRESSION OF HORMONAL CARCINOGENESIS GENES AND RELATED REGULATORY MICRORNAS IN UTERUS AND OVARIES OF DDT-TREATED FEMALE RATS. THE INSECTICIDE DICHLORODIPHENYLTRICHLOROETHANE (DDT) IS A NONMUTAGENIC XENOBIOTIC COMPOUND ABLE TO EXERT ESTROGEN-LIKE EFFECTS RESULTING IN ACTIVATION OF ESTROGEN RECEPTOR-ALPHA (ERALPHA) FOLLOWED BY CHANGED EXPRESSION OF ITS DOWNSTREAM TARGET GENES. IN ADDITION, STUDIES PERFORMED OVER RECENT YEARS SUGGEST THAT DDT MAY ALSO INFLUENCE EXPRESSION OF MICRORNAS. HOWEVER, AN IMPACT OF DDT ON EXPRESSION OF ER, MICRORNAS, AND RELATED TARGET GENES HAS NOT BEEN FULLY ELUCIDATED. HERE, USING REAL-TIME PCR, WE ASSESSED CHANGES IN EXPRESSION OF KEY GENES INVOLVED IN HORMONAL CARCINOGENESIS AS WELL AS POTENTIALLY RELATED REGULATORY ONCOGENIC/TUMOR SUPPRESSOR MICRORNAS AND THEIR TARGET GENES IN THE UTERUS AND OVARIES OF FEMALE WISTAR RATS DURING SINGLE AND CHRONIC MULTIPLE-DOSE DDT EXPOSURE. WE FOUND THAT APPLYING DDT RESULTS IN ALTERED EXPRESSION OF MICRORNAS-221, -222, -205, -126A, AND -429, THEIR TARGET GENES (PTEN, DICER1), AS WELL AS GENES INVOLVED IN HORMONAL CARCINOGENESIS (ESR1, PGR, CCND1, CYP19A1). NOTABLY, CYP19A1 EXPRESSION SEEMS TO BE ALSO REGULATED BY MICRORNAS-221, -222, AND -205. THE DATA SUGGEST THAT EPIGENETIC EFFECTS INDUCED BY DDT AS A POTENTIAL CARCINOGEN MAY BE BASED ON AT LEAST TWO MECHANISMS: (I) ACTIVATION OF ERALPHA FOLLOWED BY ALTERED EXPRESSION OF THE TARGET GENES ENCODING RECEPTOR PGR AND CCND1 AS WELL AS IMPAIRED EXPRESSION OF CYP19A1, AFFECTING, THEREBY, CELL HORMONE BALANCE; AND (II) CHANGED EXPRESSION OF MICRORNAS RESULTING IN IMPAIRED EXPRESSION OF RELATED TARGET GENES INCLUDING REDUCED LEVEL OF CYP19A1 MRNA. 2017 10 1449 29 DIRECT LINEAGE REPROGRAMMING FOR INDUCED KERATINOCYTE STEM CELLS: A POTENTIAL APPROACH FOR SKIN REPAIR. SEVERE TRAUMA OR CHRONIC WOUNDS CAN DEPLETE THE KERATINOCYTE STEM CELLS (KSCS) PRESENT IN THE EPIDERMAL BASAL LAYER OR INHIBIT THEIR MIGRATION LEADING TO COMPROMISED WOUND HEALING. SUPPLEMENTING KSCS IS THE KEY TO SOLUTION WHILE LINEAGE REPROGRAMMING PROVIDES A NEW APPROACH TO ACQUIRING KSCS. THROUGH DIRECT LINEAGE REPROGRAMMING, INDUCED KSCS (IKSCS) CAN BE PRODUCED FROM SOMATIC CELLS, WHICH EXHIBIT GREAT APPLICATION POTENTIAL. TWO STRATEGIES ARE CURRENTLY BEING USED TO DIRECTLY GENERATE IKSCS, LINEAGE TRANSCRIPTION FACTOR (TF)-MEDIATED AND PLURIPOTENCY FACTORS-MEDIATED. THIS REVIEW FOCUSES ON LINEAGE TF-MEDIATED DIRECT REPROGRAMMING AND DESCRIBES THE CONVERSION PROCESS ALONG WITH THE UNDERLYING EPIGENETIC MECHANISMS. IT ALSO DISCUSSES OTHER POTENTIAL INDUCTION STRATEGIES TO GENERATE IKSCS AND CHALLENGES ASSOCIATED WITH IN SITU REPROGRAMMING FOR SKIN REPAIR. 2023 11 3883 39 KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. BACKGROUND: A RECENT REVIEW BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) UPDATED THE ASSESSMENTS OF THE > 100 AGENTS CLASSIFIED AS GROUP 1, CARCINOGENIC TO HUMANS (IARC MONOGRAPHS VOLUME 100, PARTS A-F). THIS EXERCISE WAS COMPLICATED BY THE ABSENCE OF A BROADLY ACCEPTED, SYSTEMATIC METHOD FOR EVALUATING MECHANISTIC DATA TO SUPPORT CONCLUSIONS REGARDING HUMAN HAZARD FROM EXPOSURE TO CARCINOGENS. OBJECTIVES AND METHODS: IARC THEREFORE CONVENED TWO WORKSHOPS IN WHICH AN INTERNATIONAL WORKING GROUP OF EXPERTS IDENTIFIED 10 KEY CHARACTERISTICS, ONE OR MORE OF WHICH ARE COMMONLY EXHIBITED BY ESTABLISHED HUMAN CARCINOGENS. DISCUSSION: THESE CHARACTERISTICS PROVIDE THE BASIS FOR AN OBJECTIVE APPROACH TO IDENTIFYING AND ORGANIZING RESULTS FROM PERTINENT MECHANISTIC STUDIES. THE 10 CHARACTERISTICS ARE THE ABILITIES OF AN AGENT TO 1) ACT AS AN ELECTROPHILE EITHER DIRECTLY OR AFTER METABOLIC ACTIVATION; 2) BE GENOTOXIC; 3) ALTER DNA REPAIR OR CAUSE GENOMIC INSTABILITY; 4) INDUCE EPIGENETIC ALTERATIONS; 5) INDUCE OXIDATIVE STRESS; 6) INDUCE CHRONIC INFLAMMATION; 7) BE IMMUNOSUPPRESSIVE; 8) MODULATE RECEPTOR-MEDIATED EFFECTS; 9) CAUSE IMMORTALIZATION; AND 10) ALTER CELL PROLIFERATION, CELL DEATH, OR NUTRIENT SUPPLY. CONCLUSION: WE DESCRIBE THE USE OF THE 10 KEY CHARACTERISTICS TO CONDUCT A SYSTEMATIC LITERATURE SEARCH FOCUSED ON RELEVANT END POINTS AND CONSTRUCT A GRAPHICAL REPRESENTATION OF THE IDENTIFIED MECHANISTIC INFORMATION. NEXT, WE USE BENZENE AND POLYCHLORINATED BIPHENYLS AS EXAMPLES TO ILLUSTRATE HOW THIS APPROACH MAY WORK IN PRACTICE. THE APPROACH DESCRIBED IS SIMILAR IN MANY RESPECTS TO THOSE CURRENTLY BEING IMPLEMENTED BY THE U.S. EPA'S INTEGRATED RISK INFORMATION SYSTEM PROGRAM AND THE U.S. NATIONAL TOXICOLOGY PROGRAM. CITATION: SMITH MT, GUYTON KZ, GIBBONS CF, FRITZ JM, PORTIER CJ, RUSYN I, DEMARINI DM, CALDWELL JC, KAVLOCK RJ, LAMBERT P, HECHT SS, BUCHER JR, STEWART BW, BAAN R, COGLIANO VJ, STRAIF K. 2016. KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. ENVIRON HEALTH PERSPECT 124:713-721; HTTP://DX.DOI.ORG/10.1289/EHP.1509912. 2016 12 491 34 ASSESSING THE IMPACT OF POLYETHYLENE NANO/MICROPLASTIC EXPOSURE ON HUMAN VAGINAL KERATINOCYTES. THE GLOBAL RISE OF SINGLE-USE THROW-AWAY PLASTIC PRODUCTS HAS ELICITED A MASSIVE INCREASE IN THE NANO/MICROPLASTICS (N/MPLS) EXPOSURE BURDEN IN HUMANS. RECENTLY, IT HAS BEEN DEMONSTRATED THAT DISPOSABLE PERIOD PRODUCTS MAY RELEASE N/MPLS WITH USAGE, WHICH REPRESENTS A POTENTIAL THREAT TO WOMEN'S HEALTH WHICH HAS NOT BEEN SCIENTIFICALLY ADDRESSED YET. BY USING POLYETHYL ENE (PE) PARTICLES (200 NM TO 9 MUM), WE SHOWED THAT ACUTE EXPOSURE TO A HIGH CONCENTRATION OF N/MPLS INDUCED CELL TOXICITY IN VAGINAL KERATINOCYTES AFTER EFFECTIVE CELLULAR UPTAKE, AS VIABILITY AND APOPTOSIS DATA SUGGEST, ALONG WITH TRANSMISSION ELECTRON MICROSCOPY (TEM) OBSERVATIONS. THE INTERNALISED N/MPLS ALTERED THE EXPRESSION OF JUNCTIONAL AND ADHERENCE PROTEINS AND THE ORGANISATION OF THE ACTIN CORTEX, INFLUENCING THE LEVEL OF GENES INVOLVED IN OXIDATIVE STRESS SIGNALLING PATHWAYS AND THAT OF MIRNAS RELATED TO EPITHELIAL BARRIER FUNCTION. WHEN THE EXPOSURE TO PE N/MPLS WAS DISCONTINUED OR BECAME CHRONIC, CELLS WERE ABLE TO RECOVER FROM THE NEGATIVE EFFECTS ON VIABILITY AND DIFFERENTIATION/PROLIFERATION GENE EXPRESSION IN A FEW DAYS. HOWEVER, IN ALL CASES, PE N/MPL EXPOSURE PROMPTED A SUSTAINED ALTERATION OF DNA METHYLTRANSFERASE AND DNA DEMETHYLASE EXPRESSION, WHICH MIGHT IMPACT EPIGENETIC REGULATION PROCESSES, LEADING TO ACCELERATED CELL AGEING AND INFLAMMATION, OR THE OCCURRENCE OF MALIGNANT TRANSFORMATION. 2023 13 3198 29 HDAC-LINKED "PROLIFERATIVE" MIRNA EXPRESSION PATTERN IN PANCREATIC NEUROENDOCRINE TUMORS. EPIGENETIC FACTORS ARE ESSENTIALLY INVOLVED IN CARCINOGENESIS, TUMOR PROMOTION, AND CHEMORESISTANCE. TWO EPIGENETIC KEY PLAYERS ARE MIRNAS AND HISTONE DEACETYLASES (HDACS). AS PREVIOUSLY SHOWN BY OWN THEORETICAL DATABANK ANALYSIS, THE CROSSTALK BETWEEN MIRNAS AND HDACS IS RELEVANT IN DIFFERENT HUMAN CHRONIC DISEASES AND CANCEROGENIC PATHWAYS. WE AIMED TO INVESTIGATE A POTENTIAL CONNECTION BETWEEN THE EXPRESSION OF A WELL-DEFINED SUBSET OF "PROLIFERATION-ASSOCIATED" MIRNAS AND THE EXPRESSION OF HDACS AS WELL AS CLINICAL PARAMETERS IN PANCREATIC NEUROENDOCRINE TUMORS (PNETS). MATERIALS AND METHODS: EXPRESSION LEVELS OF MIRNA132-3P, MIRNA145-5P, MIRNA183-5P, MIRNA34A-5P, AND MIRNA449A IN 57 PNETS RESECTED BETWEEN 1997 AND 2015 WERE MEASURED AND LINKED TO THE IMMUNOHISTOCHEMICAL EXPRESSION PATTERN OF MEMBERS OF THE FOUR HDAC CLASSES ON HUMAN TISSUE MICROARRAYS. ALL PNET CASES WERE CLINICALLY AND PATHOLOGICALLY CHARACTERIZED ACCORDING TO PUBLISHED GUIDELINES. CORRELATION ANALYSIS REVEALED A SIGNIFICANT ASSOCIATION BETWEEN EXPRESSION OF SPECIFIC MIRNAS AND TWO MEMBERS OF THE HDAC FAMILY (HDAC3 AND HDAC4). ADDITIONALLY, A LINKAGE BETWEEN MIRNA EXPRESSION AND CLINICO-PATHOLOGICAL PARAMETERS LIKE GRADING, TNM-STAGING, AND HORMONE ACTIVITY WAS FOUND. MOREOVER, OVERALL AND DISEASE-FREE SURVIVAL IS STATISTICALLY CORRELATED WITH THE EXPRESSION OF THE INVESTIGATED MIRNAS. OVERALL, WE DEMONSTRATED THAT SPECIFIC MIRNAS COULD BE LINKED TO HDAC EXPRESSION IN PNETS. ESPECIALLY MIRNA449A (ASSOCIATED WITH HDAC3/4) SEEMS TO PLAY AN IMPORTANT ROLE IN PNET PROLIFERATION AND COULD BE A POTENTIAL PROGNOSTIC FACTOR FOR POOR SURVIVAL. THESE FIRST DATA COULD HELP, TO IMPROVE OUR KNOWLEDGE OF THE COMPLEX INTERACTIONS OF THE EPIGENETIC DRIVERS IN PNETS FOR FURTHER THERAPEUTIC APPROACHES. 2018 14 2666 34 ESTABLISHMENT OF AN INTERMITTENT COLD STRESS MODEL USING TUPAIA BELANGERI AND EVALUATION OF COMPOUND C737 TARGETING NEURON-RESTRICTIVE SILENCER FACTOR. PREVIOUS STUDIES HAVE SHOWN THAT INTERMITTENT COLD STRESS (ICS) INDUCES DEPRESSION-LIKE BEHAVIORS IN MAMMALS. TUPAIA BELANGERI (THE TREE SHREW) IS THE ONLY EXPERIMENTAL ANIMAL OTHER THAN THE CHIMPANZEE THAT HAS BEEN SHOWN TO BE SUSCEPTIBLE TO INFECTION BY HEPATITIS B AND C VIRUSES. MOREOVER, FULL GENOME SEQUENCE ANALYSIS HAS REVEALED STRONG HOMOLOGY BETWEEN HOST PROTEINS IN TUPAIA AND IN HUMANS AND OTHER PRIMATES. TUPAIA NEUROMODULATOR RECEPTOR PROTEINS ARE ALSO KNOWN TO HAVE A HIGH DEGREE OF HOMOLOGY WITH THEIR CORRESPONDING PRIMATE PROTEINS. BASED ON THESE SIMILARITIES, WE HYPOTHESIZED THAT INDUCTION OF ICS IN TUPAIA WOULD PROVIDE A USEFUL ANIMAL MODEL OF STRESS RESPONSES. WE EXPOSED YOUNG ADULT TUPAIA TO ICS AND OBSERVED DECREASES IN BODY TEMPERATURE AND BODY WEIGHT IN BOTH FEMALE AND MALE TUPAIA, SUGGESTING THAT TUPAIA ARE AN APPROPRIATE ANIMAL MODEL FOR ICS STUDIES. WE FURTHER EXAMINED THE EFFICACY OF A NEW SMALL-MOLECULE COMPOUND, C737, AGAINST THE EFFECTS OF ICS. C737 MIMICS THE HELICAL STRUCTURE OF NEURON-RESTRICTIVE SILENCER FACTOR (NRSF/REST), WHICH REGULATES A WIDE RANGE OF TARGET GENES INVOLVED IN NEURONAL FUNCTION AND PAIN MODULATION. TREATMENT WITH C737 SIGNIFICANTLY REDUCED STRESS-INDUCED WEIGHT LOSS IN FEMALE TUPAIA; THESE EFFECTS WERE STRONGER THAN THOSE ELICITED BY THE ANTIDEPRESSANT AGOMELATINE. THESE RESULTS SUGGEST THAT TUPAIA REPRESENTS A USEFUL NON-RODENT ICS MODEL. OUR DATA ALSO PROVIDE NEW INSIGHTS INTO THE FUNCTION OF NRSF/REST IN STRESS-INDUCED DEPRESSION AND OTHER DISORDERS WITH EPIGENETIC INFLUENCES OR THOSE WITH HIGH PREVALENCE IN WOMEN. 2016 15 238 25 ADENOSINE KINASE: A KEY REGULATOR OF PURINERGIC PHYSIOLOGY. ADENOSINE (ADO) IS AN ESSENTIAL BIOMOLECULE FOR LIFE THAT PROVIDES CRITICAL REGULATION OF ENERGY UTILIZATION AND HOMEOSTASIS. ADENOSINE KINASE (ADK) IS AN EVOLUTIONARY ANCIENT RIBOKINASE DERIVED FROM BACTERIAL SUGAR KINASES THAT IS WIDELY EXPRESSED IN ALL FORMS OF LIFE, TISSUES AND ORGAN SYSTEMS THAT TIGHTLY REGULATES INTRACELLULAR AND EXTRACELLULAR ADO CONCENTRATIONS. THE FACILE ABILITY OF ADK TO ALTER ADO AVAILABILITY PROVIDES A "SITE AND EVENT" SPECIFICITY TO THE ENDOGENOUS PROTECTIVE EFFECTS OF ADO IN SITUATIONS OF CELLULAR STRESS. IN ADDITION TO MODULATING THE ABILITY OF ADO TO ACTIVATE ITS COGNATE RECEPTORS (P1 RECEPTORS), NUCLEAR ADK ISOFORM ACTIVITY HAS BEEN LINKED TO EPIGENETIC MECHANISMS BASED ON TRANSMETHYLATION PATHWAYS. PREVIOUS DRUG DISCOVERY RESEARCH HAS TARGETED ADK INHIBITION AS A THERAPEUTIC APPROACH TO MANAGE EPILEPSY, PAIN, AND INFLAMMATION. THESE EFFORTS GENERATED MULTIPLE CLASSES OF HIGHLY POTENT AND SELECTIVE INHIBITORS. HOWEVER, CLINICAL DEVELOPMENT OF EARLY ADK INHIBITORS WAS STOPPED DUE TO APPARENT MECHANISTIC TOXICITY AND THE LACK OF SUITABLE TRANSLATIONAL MARKERS. NEW INSIGHTS REGARDING THE POTENTIAL ROLE OF THE NUCLEAR ADK ISOFORM (ADK-LONG) IN THE EPIGENETIC MODULATION OF MALADAPTIVE DNA METHYLATION OFFERS THE POSSIBILITY OF IDENTIFYING NOVEL ADK-ISOFORM SELECTIVE INHIBITORS AND NEW INTERVENTIONAL STRATEGIES THAT ARE INDEPENDENT OF ADO RECEPTOR ACTIVATION. 2021 16 5153 24 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION. 2019 17 6351 35 THE ROLE OF EPIGENOMICS IN MAPPING POTENTIAL PRECURSORS FOR FOOT AND ANKLE TENDINOPATHY: A SYSTEMATIC REVIEW. TENDINOPATHY OF THE FOOT AND ANKLE IS A COMMON CLINICAL PROBLEM FOR WHICH THE EXACT ETIOLOGY IS POORLY UNDERSTOOD. THE FIELD OF EPIGENETICS HAS BEEN A RECENT FOCUS OF THIS INVESTIGATION. THE PURPOSE OF THIS ARTICLE WAS TO REVIEW THE GENOMIC ADVANCES IN FOOT AND ANKLE TENDINOPATHY THAT COULD POTENTIALLY BE USED TO STRATIFY DISEASE RISK AND CREATE PREVENTATIVE OR THERAPEUTIC AGENTS. A MULTI-DATABASE SEARCH OF PUBMED, COCHRANE, GOOGLE SCHOLAR, AND CLINICALTRIALS.GOV FROM JANUARY 1, 2000 TO JULY 1, 2022 WAS PERFORMED. A TOTAL OF 18 ARTICLES MET INCLUSION AND EXCLUSION CRITERIA FOR THIS REVIEW. THE MAJORITY OF SUCH RESEARCH UTILIZED CASE-CONTROL CANDIDATE GENE ASSOCIATION TO IDENTIFY DIFFERENT GENETIC RISK FACTORS ASSOCIATED WITH CHRONIC TENDINOPATHY. POLYMORPHISMS IN COLLAGEN GENES COL5A1, COL27A1, AND COL1A1 WERE NOTED AT A SIGNIFICANTLY HIGHER FREQUENCY IN ACHILLES TENDINOPATHY VERSUS CONTROL GROUPS. OTHER ALLELIC VARIATIONS THAT WERE OBSERVED AT AN INCREASED INCIDENCE IN ACHILLES TENDINOPATHY WERE TNC AND CASP8. THE EXTRACELLULAR MATRIX (ECM) DEMONSTRATED MACROSCOPIC CHANGES IN ACHILLES TENDINOPATHY, INCLUDING AN INCREASE IN AGGRECAN AND BIGLYCAN MRNA EXPRESSION, AND INCREASED EXPRESSION OF MULTIPLE MATRIX METALLOPROTEINASES. CYTOKINE EXPRESSION WAS ALSO INFLUENCED IN PATHOLOGY AND ABERRANTLY DEMONSTRATED DYNAMIC RESPONSE TO MECHANICAL LOAD. THE PATHOLOGIC ACCUMULATION OF ECM PROTEINS AND CYTOKINE EXPRESSION ALTERS THE ADAPTIVE RESPONSE NORMAL TENDON HAS TO PHYSIOLOGIC STRESS, FURTHER PROPAGATING THE RISK FOR TENDINOPATHY. BY IDENTIFYING AND UNDERSTANDING THE EPIGENETIC MEDIATORS THAT LEAD TO TENDINOPATHY, THERAPEUTIC AGENTS CAN BE DEVELOPED TO TARGET THE EXACT UNDERLYING ETIOLOGY AND MINIMIZE SIDE EFFECTS.LEVEL OF EVIDENCE: LEVEL IV: SYSTEMATIC REVIEW OF LEVEL II-IV STUDIES. 2023 18 5353 33 RE-EVALUATION OF POLIHEXANIDE USE IN WOUND ANTISEPSIS IN ORDER TO CLARIFY AMBIGUITIES OF TWO ANIMAL STUDIES. OBJECTIVE: DUE TO CLASSIFICATION OF THE AGENT POLIHEXANIDE (PHMB) IN CATEGORY 2 'MAY CAUSE CANCER' BY THE COMMITTEE FOR RISK ASSESSMENT OF THE EUROPEAN CHEMICALS AGENCY IN 2011, THE USERS OF WOUND ANTISEPTICS MAY BE HIGHLY CONFUSED. IN 2017, THIS STATEMENT WAS UPDATED, DEFINING PHMB UP TO 0.1% AS A PRESERVATIVE SAFE IN ALL COSMETIC PRODUCTS. IN THE INTEREST OF PATIENT SAFETY, A SCIENTIFIC CLARIFICATION OF THE POTENTIAL CARCINOGENICITY OF PHMB IS NECESSARY. METHODS: A MULTIDISCIPLINARY TEAM (MDT) OF MICROBIOLOGISTS, SURGEONS, DERMATOLOGISTS AND BIOCHEMISTS CONDUCTED A BENEFIT-RISK ASSESSMENT TO CLARIFY THE HAZARD OF ANTISEPTIC USE OF PHMB. RESULTS: IN TWO ANIMAL STUDIES, FROM WHICH THE ASSESSMENT OF A CARCINOGENIC RISK WAS DERIVED, PHMB WAS ADMINISTERED ORALLY OVER TWO YEARS IN EXTREMELY HIGH CONCENTRATIONS FAR ABOVE THE NO(A)EL (NO-OBSERVED-(ADVERSE-) EFFECT LEVEL) IN RATS AND MICE. FEEDING IN THE NO(A)EL RANGE RESULTED IN NO ABNORMAL EFFECTS. IN ONE MALE IN THE HIGHEST DOSE GROUP OF 4000PPM PHMB, AN ADENOCARCINOMA WAS FOUND, WHICH THE AUTHOR ATTRIBUTED TO CHRONIC INFLAMMATION OF THE COLON WITH SYSTEMIC ATYPICAL EXPOSURE. THE INCREASING INCIDENCE OF HEMANGIOSARCOMAS HIGHLY PROBABLY RESULTED FROM INCREASED ENDOTHELIAL PROLIFERATION, TRIGGERED BY THE EXCEEDINGLY HIGH DOSAGE FED, BECAUSE PHMB IS NOT GENOTOXIC AND THERE IS NO EVIDENCE FOR EPIGENETIC EFFECTS. DISCUSSION: IT IS WELL KNOWN THAT PHMB IS NOT ABSORBED WHEN APPLIED TOPICALLY. CONSIDERING THE ABSENCE OF GENOTOXICITY AND EPIGENETIC EFFECTS TOGETHER WITH THE INTERPRETATION OF THE ANIMAL STUDIES, IT IS THE CONSENSUS OF THE MULTIDISCIPLINARY EXPERTS THAT A CARCINOGENIC RISK FROM PHMB-USE FOR WOUND ANTISEPSIS CAN BE RULED OUT. CONCLUSION: ON THIS BASIS AND CONSIDERING THEIR EFFECTIVENESS, TOLERABILITY AND CLINICAL EVIDENCE, THE INDICATIONS FOR PHMB BASED WOUND ANTISEPTICS ARE JUSTIFIED. 2019 19 5636 37 SERELAXIN ALLEVIATES CARDIAC FIBROSIS THROUGH INHIBITING ENDOTHELIAL-TO-MESENCHYMAL TRANSITION VIA RXFP1. RATIONALE: CARDIAC FIBROSIS IS AN INTEGRAL CONSTITUENT OF EVERY FORM OF CHRONIC HEART DISEASE, AND PERSISTENCE OF FIBROSIS REDUCES TISSUE COMPLIANCE AND ACCELERATES THE PROGRESSION TO HEART FAILURE. RELAXIN-2 IS A HUMAN HORMONE, WHICH HAS VARIOUS PHYSIOLOGICAL FUNCTIONS SUCH AS MEDIATING RENAL VASODILATION IN PREGNANCY. ITS RECOMBINANT FORM SERELAXIN HAS RECENTLY BEEN TESTED IN CLINICAL TRIALS AS A THERAPY FOR ACUTE HEART FAILURE BUT DID NOT MEET ITS PRIMARY ENDPOINTS. THE AIM OF THIS STUDY IS TO EXAMINE WHETHER SERELAXIN HAS AN ANTI-FIBROTIC EFFECT IN THE HEART AND THEREFORE COULD BE BENEFICIAL IN CHRONIC HEART FAILURE. METHODS: WE UTILIZED TWO DIFFERENT CARDIAC FIBROSIS MOUSE MODELS (ASCENDING AORTIC CONSTRICTION (AAC) AND ANGIOTENSIN II (ATII) ADMINISTRATION VIA OSMOTIC MINIPUMPS) TO ASSESS THE ANTI-FIBROTIC POTENTIAL OF SERELAXIN. HISTOLOGICAL ANALYSIS, IMMUNOFLUORESCENCE STAINING AND MOLECULAR ANALYSIS WERE PERFORMED TO ASSESS THE FIBROSIS LEVEL AND INDICATE ENDOTHELIAL CELLS WHICH ARE UNDERGOING ENDMT. IN VITRO TGFBETA1-INDUCED ENDOTHELIAL-TO-MESENCHYMAL TRANSITION (ENDMT) ASSAYS WERE PERFORMED IN HUMAN CORONARY ARTERY ENDOTHELIAL CELLS AND MOUSE CARDIAC ENDOTHELIAL CELLS (MCECS) AND WERE EXAMINED USING MOLECULAR METHODS. CHROMATIN IMMUNOPRECIPITATION-QPCR ASSAY WAS UTILIZED TO IDENTIFY THE SERELAXIN EFFECT ON CHROMATIN REMODELING IN THE RXFP1 PROMOTER REGION IN MCECS. RESULTS: OUR RESULTS DEMONSTRATE A SIGNIFICANT AND DOSE-DEPENDENT ANTI-FIBROTIC EFFECT OF SERELAXIN IN THE HEART IN BOTH MODELS. WE FURTHER SHOW THAT SERELAXIN MEDIATES THIS EFFECT, AT LEAST IN PART, THROUGH INHIBITION OF ENDMT THROUGH THE ENDOTHELIAL RELAXIN FAMILY PEPTIDE RECEPTOR 1 (RXFP1). WE FURTHER DEMONSTRATE THAT SERELAXIN ADMINISTRATION IS ABLE TO INCREASE ITS OWN RECEPTOR EXPRESSION (RXFP1) THROUGH EPIGENETIC REGULATION IN FORM OF HISTONE MODIFICATIONS BY ATTENUATING TGFBETA-PSMAD2/3 SIGNALING IN ENDOTHELIAL CELLS. CONCLUSIONS: THIS STUDY IS THE FIRST TO IDENTIFY THAT SERELAXIN INCREASES THE EXPRESSION OF ITS OWN RECEPTOR RXFP1 AND THAT THIS MEDIATES THE INHIBITION OF ENDMT AND CARDIAC FIBROSIS, SUGGESTING THAT SERELAXIN MAY HAVE A BENEFICIAL EFFECT AS ANTI-FIBROTIC THERAPY IN CHRONIC HEART FAILURE. 2020 20 3465 36 HYPOTHESIS: REGULATION OF NEUROPLASTICITY MAY INVOLVE I-MOTIF AND G-QUADRUPLEX DNA FORMATION MODULATED BY EPIGENETIC MECHANISMS. RECENT STUDIES DEMONSTRATED THE EXISTENCE IN VIVO OF VARIOUS FUNCTIONAL DNA STRUCTURES THAT DIFFER FROM THE DOUBLE HELIX. THE G-QUADRUPLEX (G4) AND INTERCALATED MOTIF (I-MOTIF OR IM) DNA STRUCTURES ARE FORMED AS KNOTS WHERE, CORRESPONDINGLY, GUANINES OR CYTOSINES ON THE SAME STRAND OF DNA BIND TO EACH OTHER. THERE ARE GROUNDS TO BELIEVE THAT G4 AND IM SEQUENCES PLAY A SIGNIFICANT ROLE IN REGULATING GENE EXPRESSION CONSIDERING THEIR TENDENCY TO BE FOUND IN OR NEAR REGULATORY SITES (SUCH AS PROMOTERS, ENHANCERS, AND TELOMERES) AS WELL AS THE CORRELATION BETWEEN THE PREVALENCE OF G4 OR IM CONFORMATIONS AND SPECIFIC PHASES OF CELL CYCLE. NOTABLY, G4 AND IM CAPABLE SEQUENCES TEND TO BE FOUND ON THE OPPOSITE STRANDS OF THE SAME DNA SITE WITH AT MOST ONE OF THE TWO STRUCTURES FORMED AT ANY GIVEN TIME. THE RECENT EVIDENCE THAT K(+), MG(2+) CONCENTRATIONS DIRECTLY AFFECT IM FORMATION (AND LIKELY G4 FORMATION INDIRECTLY) LEAD US TO BELIEVE THAT THESE STRUCTURES MAY PLAY A MAJOR ROLE IN SYNAPTIC PLASTICITY OF NEURONS, AND, THEREFORE, IN A VARIETY OF CENTRAL NERVOUS SYSTEM (CNS) FUNCTIONS INCLUDING MEMORY, LEARNING, HABITUAL BEHAVIORS, PAIN PERCEPTION AND OTHERS. FURTHERMORE, EPIGENETIC MECHANISMS, WHICH HAVE AN IMPORTANT ROLE IN SYNAPTIC PLASTICITY AND MEMORY FORMATION, WERE ALSO SHOWN TO INFLUENCE FORMATION AND STABILITY OF G4S AND IMS. OUR HYPOTHESIS IS THAT NON-CANONICAL DNA AND RNA STRUCTURES COULD BE AN INTEGRAL PART OF NEUROPLASTICITY CONTROL VIA GENE EXPRESSION REGULATION AT THE LEVEL OF TRANSCRIPTION, TRANSLATION AND SPLICING. WE PROPOSE THAT THE REGULATORY ACTIVITY OF DNA IM AND G4 STRUCTURES IS MODULATED BY DNA METHYLATION/DEMETHYLATION OF THE IM AND/OR G4 SEQUENCES, WHICH FACILITATES THE SWITCH BETWEEN CANONICAL AND NON-CANONICAL CONFORMATION. OTHER NEURONAL MECHANISMS INTERACTING WITH THE FORMATION AND REGULATORY ACTIVITY OF NON-CANONICAL DNA AND RNA STRUCTURES, PARTICULARLY G4, IM AND TRIPLEXES, MAY INVOLVE MICRORNAS AS WELL AS ION AND PROTON FLUXES. WE ARE PROPOSING EXPERIMENTS IN ACUTE BRAIN SLICES AND IN VIVO TO TEST OUR HYPOTHESIS. THE PROPOSED STUDIES WOULD PROVIDE NEW INSIGHTS INTO FUNDAMENTAL NEURONAL MECHANISMS IN HEALTH AND DISEASE AND POTENTIALLY OPEN NEW AVENUES FOR TREATING MENTAL HEALTH DISORDERS. 2019