1  6098 105 THE EFFECTS OF VALPROIC ACID ON SKIN HEALING: EXPERIMENTAL STUDY IN RATS. PURPOSE: TO RECOGNIZE THE EFFECTS OF VALPROIC ACID (VPA), AN EPIGENETIC DRUG, ON THE SKIN HEALING PROCESS. METHODS: SIXTY MALE WISTAR RATS WERE DIVIDED INTO TWO GROUPS: THE EXPERIMENT TREATED WITH VPA (100 MG/KG/DAY); AND THE CONTROL, WITH 0.9% SODIUM CHLORIDE BY GAVAGE. SKIN HEALING WAS STUDIED IN THREE MOMENTS (THE THIRD, THE SEVENTH, AND THE 14TH DAY), EVALUATING THE PARAMETERS: INFLAMMATORY REACTION AND ITS INTENSITY (ANTI-LCA), ANGIOGENESIS (ANTI-CD34), COLLAGEN I AND III (ANTI-COLLAGEN I, ANTI-COLLAGEN III AND PICROSIRIUS-RED F3BA) AND MYOFIBROBLASTS (ANTI-ALPHA-AMS). RESULTS: THE INFLAMMATORY REACTION WAS ACUTE OR SUB-ACUTE IN BOTH GROUPS ON THE THIRD DAY. ON THE SEVENTH AND THE 14TH DAY, CHRONIC PREDOMINATED IN THE CONTROL (P=0.006), AND SUB-ACUTE IN THE EXPERIMENT (P=0.020). THERE WAS A GREATER NUMBER OF LEUKOCYTES IN THE GROUP TREATED ONLY ON THE THIRD DAY (P=0.036). THE NUMBER OF VESSELS WAS LOWER IN THE TREATED GROUP AT THE THREE TIMES (P3=0.002, P7<0.001, AND P14=0.027). MYOFIBROBLASTS WERE RARE IN THE THIRD DAY AND MODERATE QUANTITY IN THE REMAINING PERIODS. COLLAGEN I DENSITY WAS HIGHER IN THE CONTROL AT THE THREE TIMES (P<0.001) AND COLLAGEN III IN THE TREATED GROUP (P<0.001). CONCLUSIONS: VPA LED TO A MORE INTENSE INFLAMMATORY REACTION, DECREASED ANGIOGENESIS AND COLLAGEN DEPOSITION, ESPECIALLY TYPE I COLLAGEN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
2  3955  16 LONG MARCH TOWARD SAFE AND EFFECTIVE ANALGESIA BY ENHANCING GENE EXPRESSION OF KCC2: FIRST STEPS TAKEN. LOW INTRANEURONAL CHLORIDE IN SPINAL CORD DORSAL HORN PAIN RELAY NEURONS IS CRITICAL FOR PHYSIOLOGIC TRANSMISSION OF PRIMARY PAIN AFFERENTS BECAUSE LOW INTRANEURONAL CHLORIDE DICTATES WHETHER GABA-ERGIC AND GLYCIN-ERGIC NEUROTRANSMISSION IS INHIBITORY. IF THE NEURONAL CHLORIDE ELEVATES TO PATHOLOGIC LEVELS, THEN SPINAL CORD PRIMARY PAIN RELAY BECOMES LEAKY AND EXHIBITS THE BEHAVIORAL HALLMARKS OF PATHOLOGIC PAIN, NAMELY HYPERSENSITIVITY AND ALLODYNIA. LOW CHLORIDE IN SPINAL CORD DORSAL HORN NEURONS IS MAINTAINED BY PROPER GENE EXPRESSION OF KCC2 AND SUSTAINED PHYSIOLOGIC FUNCTION OF THE KCC2 CHLORIDE EXTRUDING ELECTRONEUTRAL TRANSPORTER. PERIPHERAL NERVE INJURY AND OTHER FORMS OF NEURAL INJURY EVOKE GREATLY DIMINISHED KCC2 GENE EXPRESSION AND SUBSEQUENT CORRUPTION OF INHIBITORY NEUROTRANSMISSION IN THE SPINAL CORD DORSAL HORN, THUS CAUSING DERAILMENT OF THE GATE FUNCTION FOR PAIN. HERE I REVIEW KEY DISCOVERIES THAT HAVE HELPED US UNDERSTAND THESE FUNDAMENTALS, AND FOCUS ON RECENT INSIGHTS RELATING TO THE DISCOVERY OF KCC2 GENE EXPRESSION ENHANCING COMPOUNDS VIA COMPOUND SCREENS IN NEURONS. ONE SUCH STUDY CHARACTERIZED THE KINASE INHIBITOR, KENPAULLONE, MORE IN-DEPTH, REVEALING ITS FUNCTION AS A ROBUST AND LONG-LASTING ANALGESIC IN PRECLINICAL MODELS OF NERVE INJURY AND CANCER BONE PAIN, ALSO ELUCIDATING ITS MECHANISM OF ACTION VIA GSK3BETA INHIBITION, DIMINISHING DELTA-CATENIN PHOSPHORYLATION, AND FACILITATING ITS NUCLEAR TRANSFER AND SUBSEQUENT ENHANCEMENT OF KCC2 GENE EXPRESSION BY DE-REPRESSING KAISO EPIGENETIC TRANSCRIPTIONAL REGULATOR. FUTURE DIRECTIONS RE KCC2 GENE EXPRESSION ENHANCEMENT ARE DISCUSSED, NAMELY COMBINATION WITH OTHER ANALGESICS AND ANALGESIC METHODS, SUCH AS SPINAL CORD STIMULATION AND ELECTROACUPUNCTURE, GENE THERAPY, AND LEVERAGING KCC2 GENE EXPRESSION-ENHANCING NANOMATERIALS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  5328  26 PULSED RADIOFREQUENCY ATTENUATES COMPLETE FREUND'S ADJUVANT-INDUCED EPIGENETIC SUPPRESSION OF POTASSIUM CHLORIDE COTRANSPORTER 2 EXPRESSION. BACKGROUND: PULSED RADIOFREQUENCY (PRF) TREATMENT OFFERS PAIN RELIEF FOR PATIENTS SUFFERING FROM CHRONIC PAIN WHO DO NOT RESPOND WELL TO CONVENTIONAL TREATMENTS. WE TESTED WHETHER PRF TREATMENT ATTENUATED COMPLETE FREUND'S ADJUVANT (CFA)-INDUCED INFLAMMATORY PAIN. EPIGENETIC MODIFICATION OF POTASSIUM-CHLORIDE COTRANSPORTER 2 (KCC2) GENE EXPRESSION WAS EXAMINED TO ELUCIDATE THE POTENTIAL CONTRIBUTING MECHANISM. METHODS: MALE SPRAGUE-DAWLEY RATS WERE INJECTED WITH CFA INTO THE PLANTAR SURFACE OF THE LEFT HIND PAW TO INDUCE INFLAMMATION. PRF (20 MINUTES OF 500-KHZ RF PULSES, DELIVERED AT A RATE OF 2 HZ, MAXIMUM TEMPERATURE 42 MASCULINEC) WAS DELIVERED TO THE L5 AND L6 ANTERIOR PRIMARY RAMUS JUST DISTAL TO THE INTERVERTEBRAL FORAMEN OF ADULT CFA OR SALINE RATS. THE HIND PAW WITHDRAWAL THRESHOLD TO VON FREY FILAMENT STIMULI AND WITHDRAWAL LATENCY TO RADIANT HEAT WERE DETERMINED BEFORE AND AFTER CFA. ACETYL-HISTONE H3 AND H4 WAS DETERMINED BY CHROMATIN IMMUNOPRECIPITATION IN SPINAL DORSAL HORN. KCC2 EXPRESSION WAS DETERMINED BY WESTERN BLOT. INHIBITORY SYNAPTIC FUNCTION WAS EVALUATED BY PATCH CLAMP IN LAMINA II NEURONS. RESULTS: KCC2 GENE EXPRESSION WAS SUPPRESSED THROUGH HISTONE HYPOACETYLATION, RESULTING IN DECREASED EFFICACY OF GABAERGIC SIGNALING IN CFA RATS. PRF INCREASED HISTONE ACETYLATION AND KCC2 EXPRESSION, PARTIALLY RESTORED THE GABA SYNAPTIC FUNCTION, AND RELIEVED SENSITIZED PAIN BEHAVIOR. CONCLUSION: THESE FINDINGS SUGGEST THAT PRF MIGHT BE AN ALTERNATIVE THERAPY FOR INFLAMMATORY PAIN. ONE OF THE UNDERLYING MECHANISMS IS THROUGH MODIFICATION OF KCC2, WHICH IS AN IMPORTANT DETERMINANT FOR THE EFFICACY OF INHIBITORY NEUROTRANSMISSION IN THE SPINAL CORD, AND ITS EXPRESSION LEVELS ARE REGULATED BY HISTONE ACETYLATION EPIGENETICALLY FOLLOWING INFLAMMATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  1215  27 CPG PROMOTER METHYLATION STATUS IS NOT A PROGNOSTIC INDICATOR OF GENE EXPRESSION IN BERYLLIUM CHALLENGE. INDIVIDUALS EXPOSED TO BERYLLIUM (BE) MAY DEVELOP BE SENSITIZATION (BES) AND PROGRESS TO CHRONIC BERYLLIUM DISEASE (CBD). RECENT STUDIES WITH OTHER METAL ANTIGENS SUGGEST EPIGENETIC MECHANISMS MAY BE INVOLVED IN INFLAMMATORY DISEASE PROCESSES, INCLUDING GRANULOMATOUS LUNG DISORDERS AND THAT A NUMBER OF METAL CATIONS ALTER GENE METHYLATION. THE OBJECTIVE OF THIS STUDY WAS TO DETERMINE IF BE CAN EXERT AN EPIGENETIC EFFECT ON GENE EXPRESSION BY ALTERING METHYLATION IN THE PROMOTER REGION OF SPECIFIC GENES KNOWN TO BE INVOLVED IN BE ANTIGEN-MEDIATED GENE EXPRESSION. TO INVESTIGATE THIS OBJECTIVE, THREE MACROPHAGE TUMOR MOUSE CELL LINES KNOWN TO DIFFERENTIALLY PRODUCE TUMOR NECROSIS FACTOR (TNF)-ALPHA, BUT NOT INTERFERON (IFN)-GAMMA, IN RESPONSE TO BE ANTIGEN WERE CULTURED WITH BE OR CONTROLS. FOLLOWING CHALLENGES, ELISA WERE PERFORMED TO QUANTIFY INDUCED TNFALPHA AND IFNGAMMA EXPRESSION. BISULFATE-CONVERTED DNA WAS EVALUATED BY PYROSEQUENCING TO QUANTIFY CPG METHYLATION WITHIN THE PROMOTERS OF TNFALPHA AND IFNGAMMA. BE-CHALLENGED H36.12J CELLS EXPRESSED HIGHER LEVELS OF TNFALPHA COMPARED TO EITHER H36.12E CELLS OR P388D.1 CELLS. HOWEVER, THERE WERE NO VARIATIONS IN TNFALPHA PROMOTER CPG METHYLATION LEVELS BETWEEN CELL LINES AT THE SIX CPG SITES TESTED. H36.12J CELL TNFALPHA EXPRESSION WAS SHOWN TO BE METAL-SPECIFIC BY THE INDUCTION OF SIGNIFICANTLY MORE TNFALPHA WHEN EXPOSED TO BE THAN WHEN EXPOSED TO ALUMINUM SULFATE, OR NICKEL (II) CHLORIDE, BUT NOT WHEN EXPOSED TO COBALT (II) CHLORIDE. HOWEVER, H36.12J CELL METHYLATION LEVELS AT THE SIX CPG SITES EXAMINED IN THE TNFALPHA PROMOTER DID NOT CORRELATE WITH CYTOKINE EXPRESSION DIFFERENCES. NONETHELESS, ALL THREE CELL LINES HAD SIGNIFICANTLY MORE PROMOTER METHYLATION AT THE SIX CPG SITES INVESTIGATED WITHIN THE IFNGAMMA PROMOTER (A GENE THAT IS NOT EXPRESSED) WHEN COMPARED TO THE SIX CPG SITES INVESTIGATED IN THE TNFALPHA PROMOTER, REGARDLESS OF TREATMENT CONDITION (P < 1.17 X 10(-9)). THESE FINDINGS SUGGEST THAT, IN THIS CELL SYSTEM, PROMOTER HYPO-METHYLATION MAY BE NECESSARY TO ALLOW EXPRESSION OF METAL-INDUCED TNFALPHA AND THAT PROMOTER HYPER-METHYLATION IN THE IFNGAMMA PROMOTER MAY INTERFERE WITH EXPRESSION. ALSO, AT THE DOZEN CPG SITES INVESTIGATED IN THE PROMOTER REGIONS OF BOTH GENES, BERYLLIUM HAD NO IMPACT ON PROMOTER METHYLATION STATUS, DESPITE ITS ABILITY TO INDUCE PRO-INFLAMMATORY CYTOKINE EXPRESSION.	2016	

5  6486  17 TP53 AND LIVER CARCINOGENESIS. PRIMARY HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON MALIGNANCIES AND HAS THE FOURTH HIGHEST MORTALITY RATE WORLDWIDE. THE MAJOR RISK FACTORS, INCLUDING CHRONIC INFECTIONS WITH THE HEPATITIS B OR C VIRUS, ARE EXPOSURE TO DIETARY AFLATOXIN B1(AFB1), VINYL CHLORIDE, OR ALCOHOL CONSUMPTION. SOUTHERN CHINA AND SUB-SAHARAN AFRICA HAVE THE HIGHEST DIETARY AFB1 EXPOSURE, MAKING IT AND HEPATITIS B VIRUS (HBV) THE MAJOR CAUSES OF CANCER MORTALITY IN THESE GEOGRAPHIC AREAS. RECENT STUDIES HAVE DISCOVERED GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE MOLECULAR PATHOGENESIS OF HCC, INCLUDING SOMATIC MUTATIONS IN THE P53 TUMOR SUPPRESSOR GENE (TP53). AFB1 INDUCES TYPICAL G:C TO T:A TRANSVERSIONS AT THE THIRD BASE IN CODON 249 OF P53. CHRONIC ACTIVE HEPATITIS B AND C (HCV) INFECTION, AND FURTHER INFLAMMATORY AND OXYRADICAL DISORDERS INCLUDING WILSON DISEASE (WD) OR HEMOCHROMATOSIS, GENERATE REACTIVE OXYGEN/NITROGEN SPECIES THAT CAN DAMAGE DNA AND MUTATE THE P53 GENE. THE X GENE OF HBV (HBX) IS THE MOST COMMON OPEN READING FRAME INTEGRATED INTO THE HOST GENOME IN HCC. THE INTEGRATED HBX IS FREQUENTLY MUTATED AND HAS A DIMINISHED ABILITY TO FUNCTION AS A TRANSCRIPTIONAL COTRANSACTIVATOR AND TO ACTIVATE THE NF-KAPPA B PATHWAY. HOWEVER, THE MUTANT HBX PROTEINS STILL RETAIN THEIR ABILITY TO BIND TO AND ABROGATE P53-MEDIATED APOPTOSIS. IN SUMMARY, BOTH VIRUSES AND CHEMICALS ARE IMPLICATED IN THE ETIOLOGY AND MOLECULAR PATHOGENESIS OF HCC. THE RESULTANT MOLECULAR CHANGES IN THE RAS AND WNT SIGNAL-TRANSDUCTION PATHWAYS, AND THE P53 AND RB TUMOR SUPPRESSOR PATHWAYS SIGNIFICANTLY CONTRIBUTE TO LIVER CARCINOGENESIS	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6   878  21 CHRONIC CADMIUM EXPOSURE AGGRAVATES MALIGNANT PHENOTYPES OF NASOPHARYNGEAL CARCINOMA BY ACTIVATING THE WNT/BETA-CATENIN SIGNALING PATHWAY VIA HYPERMETHYLATION OF THE CASEIN KINASE 1ALPHA PROMOTER. BACKGROUND: OUR PREVIOUS STUDY HAS SHOWN THAT CADMIUM (CD) EXPOSURE IS NOT ONLY A RISK FACTOR FOR NASOPHARYNGEAL CARCINOMA (NPC), BUT ALSO CORRELATED WITH THE CLINICAL STAGE AND LYMPH NODE METASTASIS. HOWEVER, THE UNDERLYING MOLECULAR EVENTS OF CD INVOLVED IN NPC PROGRESSION REMAIN TO BE ELUCIDATED. PURPOSE: THE OBJECTIVE OF THIS STUDY WAS TO DECIPHER HOW CD IMPACTS THE MALIGNANT PHENOTYPES OF NPC CELLS. METHODS: NPC CELL LINES CNE-1 AND CNE-2 WERE CONTINUOUSLY EXPOSED WITH 1 MUM CD CHLORIDE FOR 10 WEEKS, DESIGNATING AS CHRONIC CD TREATED NPC CELLS (CCT-NPC). MTT ASSAY, COLONY FORMATION ASSAY AND XENOGRAFT TUMOR GROWTH WERE USED TO ASSESS CELL VIABILITY IN VITRO AND IN VIVO. TRANSWELL ASSAYS WERE PERFORMED TO DETECT CELL INVASION AND MIGRATION. THE PROTEIN LEVELS OF E-CADHERIN, N-CADHERIN, VIMENTIN AS WELL AS BETA-CATENIN AND CASEIN KINASE 1ALPHA(CK1ALPHA) WERE MEASURED BY WESTERN BLOT. IMMUNOFLUORESCENCE STAINING WAS USED TO OBSERVE THE DISTRIBUTION OF FILAMENT ACTIN (F-ACTIN), BETA-CATENIN AND CK1ALPHA. THE MRNA LEVELS OF DOWNSTREAM TARGET GENES OF BETA-CATENIN WERE DETECTED BY RT-PCR. WNT/BETA-CATENIN SIGNALING ACTIVITY WAS ASSESSED BY TOPFLASH/FOPFLASH DUAL LUCIFERASE REPORT SYSTEM. MS-PCR WAS USED TO DETECT THE METHYLATION STATUS OF CK1ALPHA. FINALLY, THE ACTIVATION OF WNT/BETA-CATENIN PATHWAY AND CELL BIOLOGICAL PROPERTIES WERE EXAMINED FOLLOWING TREATMENT OF CCT-NPC CELLS WITH 5-AZA-2-DEOXY-CYTIDINE(5-AZA-CDR). RESULTS: CCT-NPC CELLS SHOWED AN INCREASE IN CELL PROLIFERATION, COLONY FORMATION, INVASION AND MIGRATION COMPARED TO THE PARENTAL CELLS. CD ALSO INDUCED CYTOSKELETON REORGANIZATION AND EPITHELIAL-TO-MESENCHYMAL TRANSITION. UPREGULATION AND NUCLEAR TRANSLOCATION OF BETA-CATENIN AND INCREASED LUCIFERASE ACTIVITY ACCOMPANIED WITH TRANSCRIPTION OF DOWNSTREAM TARGET GENES WERE FOUND IN CCT-NPC CELLS. TREATMENT OF CCT-CNE1 CELLS WITH 5-AZA-CDR COULD REVERSE THE HYPERMETHYLATION OF CK1ALPHA AND ATTENUATE THE CELL MALIGNANCY. CONCLUSION: THESE RESULTS SUPPORT A ROLE FOR CHRONIC CD EXPOSURE AS A DRIVING FORCE FOR THE MALIGNANT PROGRESSION OF NPC VIA EPIGENETIC ACTIVATION OF THE WNT/BETA-CATENIN PATHWAY.	2019	
                                                                                                                                                                
7  2452  20 EPIGENETIC SUPPRESSION OF POTASSIUM-CHLORIDE CO-TRANSPORTER 2 EXPRESSION IN INFLAMMATORY PAIN INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA). BACKGROUND: MULTIPLE MECHANISMS CONTRIBUTE TO THE STIMULUS-EVOKED PAIN HYPERSENSITIVITY THAT MAY BE EXPERIENCED AFTER PERIPHERAL INFLAMMATION. PERSISTENT PATHOLOGICAL STIMULI IN MANY PAIN CONDITIONS AFFECT THE EXPRESSION OF CERTAIN GENES THROUGH EPIGENETIC ALTERNATIONS. THE MAIN PURPOSE OF OUR STUDY WAS TO INVESTIGATE THE ROLE OF EPIGENETIC MODIFICATION ON POTASSIUM-CHLORIDE CO-TRANSPORTER 2 (KCC2) GENE EXPRESSION IN THE PERSISTENCE OF INFLAMMATORY PAIN. METHODS: PERSISTENT INFLAMMATORY PAIN WAS INDUCED THROUGH THE INJECTION OF COMPLETE FREUND'S ADJUVANT (CFA) IN THE LEFT HIND PAW OF RATS. ACETYL-HISTONE H3 AND H4 LEVEL WAS DETERMINED BY CHROMATIN IMMUNOPRECIPITATION IN THE SPINAL DORSAL HORN. PAIN BEHAVIOUR AND INHIBITORY SYNAPTIC FUNCTION OF SPINAL CORD WERE DETERMINED BEFORE AND AFTER CFA INJECTION. KCC2 EXPRESSION WAS DETERMINED BY REAL TIME RT-PCR AND WESTERN BLOT. INTRATHECAL KCC2 SIRNA (2 MUG PER 10 MUL PER RAT) OR HDAC INHIBITOR (10 MUG PER 10 MUL PER RAT) WAS INJECTED ONCE DAILY FOR 3 DAYS BEFORE CFA INJECTION. RESULTS: PERSISTENT INFLAMMATORY PAIN EPIGENETICALLY SUPPRESSED KCC2 EXPRESSION THROUGH HISTONE DEACETYLASE (HDAC)-MEDIATED HISTONE HYPOACETYLATION, RESULTING IN DECREASED INHIBITORY SIGNALLING EFFICACY. KCC2 KNOCK-DOWN CAUSED BY INTRATHECAL ADMINISTRATION OF KCC2 SIRNA IN NAIVE RATS REDUCED KCC2 EXPRESSION IN THE SPINAL CORD, LEADING TO SENSITIZED PAIN BEHAVIOURS AND IMPAIRED INHIBITORY SYNAPTIC TRANSMISSION IN THEIR SPINAL CORDS. MOREOVER, INTRATHECAL HDAC INHIBITOR INJECTION IN CFA RATS INCREASED KCC2 EXPRESSION, PARTIALLY RESTORING THE SPINAL INHIBITORY SYNAPTIC TRANSMISSION AND RELIEVING THE SENSITIZED PAIN BEHAVIOUR. CONCLUSION: THESE FINDINGS SUGGEST THAT THE TRANSCRIPTION OF SPINAL KCC2 IS REGULATED BY HISTONE ACETYLATION EPIGENETICALLY FOLLOWING CFA. SIGNIFICANCE: PERSISTENT PAIN SUPPRESSES KCC2 EXPRESSION THROUGH HDAC-MEDIATED HISTONE HYPOACETYLATION AND CONSEQUENTLY IMPAIRS THE INHIBITORY FUNCTION OF INHIBITORY INTERNEURONS. DRUGS SUCH AS HDAC INHIBITORS THAT SUPPRESS THE INFLUENCES OF PERSISTENT PAIN ON THE EXPRESSION OF KCC2 MAY SERVE AS A NOVEL ANALGESIC.	2017	
                                                                                                                                                                                                                                                   
8  3267  14 HEPATOCELLULAR CARCINOMA AND POSSIBLE CHEMICAL AND BIOLOGICAL CAUSES: A REVIEW. THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) IS A MULTISTEP PROCESS. IN HCC, PROGRESSIVE AND MORPHOLOGICALLY DISTINCT PRENEOPLASTIC LESIONS/ALTERATIONS ASSOCIATED WITH CHRONIC LIVER INJURY, INFLAMMATION, HEPATOCELLULAR DEGENERATION/REGENERATION, NECROSIS, AND SMALL-CELL DYSPLASIA CAN BE OBSERVED. THE INCIDENCE OF HCC EXHIBITS REGIONAL AND ETHNIC DIFFERENCES. SEVERAL CYTOTOXIC AND DNA-DAMAGING CHEMICALS ARE SUGGESTED TO BE THE UNDERLYING CAUSES OF HCC-FOR EXAMPLE, ACRYLAMIDE, PERFLUOROOCTANOIC ACID (PFOA), POLYCHLORINATED BIPHENYLS (PCBS), BENZO(A)PYRENE (BAP), PERFLUORINATED CHEMICALS (PFCS), VINYL CHLORIDE MONOMER (VCM), AND DIETARY CONTAMINANTS (AFLATOXINS, OCHRATOXINS). ALSO SUGGESTED ARE SUBSTANCES OF ABUSE (ALCOHOL) AND BIOLOGICAL AGENTS, SUCH AS HEPATITIS B AND C AND HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV-1). THESE CAN ACT THROUGH GENETIC AND/OR EPIGENETIC MECHANISMS. THIS REVIEW WILL SHORTLY ADDRESS THE GENETIC AND EPIGENETIC MECHANISMS OF HCC AND FOCUS ON CYTOTOXIC AND DNA-DAMAGING CHEMICALS AND BIOLOGICAL AGENTS, EXPOSURE TO WHICH ARE SUGGESTED TO LEAD TO HCC INITIATION, PROMOTION, AND/OR PROGRESSION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9   865  20 CHRONIC ACRYLAMIDE EXPOSURE IN MALE MICE RESULTS IN ELEVATED DNA DAMAGE IN THE GERMLINE AND HERITABLE INDUCTION OF CYP2E1 IN THE TESTES. ACUTE ACRYLAMIDE EXPOSURE IN MALE RODENTS RESULTS IN REDUCED REPRODUCTIVE PERFORMANCE AND DOMINANT LETHALITY. HOWEVER, THE REPRODUCTIVE EFFECTS OF LOW DOSE CHRONIC EXPOSURE, WHICH BETTER REFLECTS THE NATURE OF HUMAN EXPOSURE, REMAIN FAR LESS CERTAIN. HUMAN DIETARY CONSUMPTION OF ACRYLAMIDE HAS BEEN ESTIMATED AT AN AVERAGE OF 1-4 MICROG/KG BW/DAY. IN ORDER TO SIMULATE THIS EXPOSURE, MALE MICE WERE PROVIDED WITH ACRYLAMIDE (1 MICROG/ML) VIA THEIR DRINKING WATER CONTINUOUSLY FOR SIX MONTHS, WHICH WAS EQUIVALENT TO A HUMAN DOSE OF 10.5 MICROG/ KG BW/DAY. THIS EXPOSURE REGIME INCREASED DNA DAMAGE IN THE SPERMATOZOA, WITHOUT AFFECTING A CONCOMITANT REDUCTION IN OVERALL FERTILITY. THE OFFSPRING OF ACRYLAMIDE TREATED MICE DID NOT HAVE AN INCREASED INCIDENCE OF SKIN PAPILLOMA FORMATION FOLLOWING THE TWO-STAGE TUMOR INDUCTION PROTOCOL. HOWEVER, THE MALE OFFSPRING OF ACRYLAMIDE TREATED FATHERS HAD SIGNIFICANTLY INCREASED LEVELS OF DNA DAMAGE IN THEIR SPERMATOZOA, DESPITE HAVING HAD NO DIRECT TOXICANT EXPOSURE. IT WAS ALSO FOUND THAT THE F0, AND MOST CRUCIALLY, F1 MICE HAD INCREASED LEVELS OF CYP2E1 PROTEIN IN THEIR GERM CELLS. THIS IS SIGNIFICANT AS CYP2E1 IS THE SOLE ENZYME RESPONSIBLE FOR CONVERSION OF ACRYLAMIDE TO ITS HARMFUL METABOLITE GLYCIDAMIDE. THIS ALTERED EXPRESSION MAY BE DUE TO EPIGENETIC ALTERATIONS. ADDITIONALLY, THE F0 AND F1 MICE HAD INCREASED OXIDATIVE ADDUCTS IN THE DNA OF THEIR GERM CELLS, WHICH WAS HYPOTHESIZED TO ARISE AS A BYPRODUCT OF INCREASED CYP2E1 ACTIVITY. THEREFORE, CHRONIC PATERNAL ACRYLAMIDE EXPOSURE IN MICE HAS CONSEQUENCES FOR THEIR OFFSPRING, AND RAISES CONCERNS FOR THE EFFECTS OF ACRYLAMIDE EXPOSURE IN THE HUMAN POPULATION AND THE ACCUMULATED EFFECTS WITH MULTIPLE GENERATIONS OF EXPOSURE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  1800  23 EFFECT OF HISTONE DEACETYLASE INHIBITOR ON ETHANOL WITHDRAWAL-INDUCED HYPERALGESIA IN RATS. BACKGROUND: INCREASED PAIN SENSITIVITY IS OBSERVED FOLLOWING ALCOHOL WITHDRAWAL, AND ATTEMPTS TO ALLEVIATE THIS HYPERALGESIA CAN CONTRIBUTE TO THE CYCLE OF ADDICTION. THE AIM OF THIS STUDY WAS TO DETERMINE IF ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA WAS OBSERVED IN A CHRONIC ETHANOL EXPOSURE MODEL AND IF THIS PAIN WAS AFFECTED BY HISTONE DEACETYLASE INHIBITORS, THUS REVEALING AN EPIGENETIC MECHANISM. METHODS: ADULT MALE SPRAGUE DAWLEY RATS RECEIVED LIEBER-DECARLI LIQUID CONTROL OR ETHANOL (9% V/V) DIET FOR 15 DAYS. MECHANICAL SENSITIVITY WAS MEASURED WITH VON FREY HAIR STIMULATION OF THE HINDPAW DURING ETHANOL ADMINISTRATION AND 24- AND 72-HOUR WITHDRAWAL. RESULTS: ETHANOL WITHDRAWAL PRODUCED SEVERE AND SUSTAINED MECHANICAL HYPERALGESIA, AN EFFECT NOT OBSERVED IN THE CONTROL OR ETHANOL-MAINTAINED GROUPS. FURTHERMORE, THIS HYPERALGESIA WAS ATTENUATED BY THE HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID TREATMENT. CONCLUSIONS: HEIGHTENED PAIN SENSITIVITY WAS OBSERVED FOLLOWING WITHDRAWAL FROM CHRONIC ETHANOL EXPOSURE, AND HISTONE DEACETYLASE INHIBITORS COULD BE NOVEL TREATMENTS FOR THIS ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11  1826  28 EFFECTS OF HISTONE DEACETYLASE INHIBITOR ON EXTRACELLULAR MATRIX PRODUCTION IN HUMAN NASAL POLYP ORGAN CULTURES. BACKGROUND: NASAL POLYPOSIS IS ASSOCIATED WITH A CHRONIC INFLAMMATORY CONDITION OF THE SINONASAL MUCOSA AND INVOLVES MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX (ECM) ACCUMULATION. EPIGENETIC MODULATION BY HISTONE DEACETYLASE (HDAC) INHIBITORS INCLUDING TRICHOSTATIN A (TSA) HAS BEEN REPORTED TO HAVE INHIBITORY EFFECTS ON MYOFIBROBLAST DIFFERENTIATION IN LUNG AND RENAL FIBROBLASTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE INHIBITORY EFFECT OF TSA ON MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION IN NASAL POLYP ORGAN CULTURES. METHODS: NASAL POLYP TISSUES FROM 18 PATIENTS WERE ACQUIRED DURING ENDOSCOPIC SINUS SURGERY. AFTER ORGAN CULTURE, NASAL POLYPS WERE STIMULATED WITH TGF-BETA1 AND THEN TREATED WITH TSA. ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), FIBRONECTIN, AND COLLAGEN TYPE I EXPRESSION LEVELS WERE EXAMINED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (PCR), REAL-TIME PCR, WESTERN BLOT, AND IMMUNOFLUORESCENT STAINING. HDAC2, HDAC4, AND ACETYLATED H4 EXPRESSION LEVELS WERE ASSAYED BY WESTERN BLOT. CYTOTOXICITY WAS ANALYZED BY THE TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE BIOTIN-DUTP NICK END LABELING ASSAY. RESULTS: THE EXPRESSION LEVELS OF ALPHA-SMA, FIBRONECTIN, AND COLLAGEN TYPE 1 WERE INCREASED IN NASAL POLYP AFTER TRANSFORMING GROWTH FACTOR (TGF) BETA1 TREATMENT. TSA-INHIBITED TGF-BETA1 INDUCED THESE GENE AND PROTEIN EXPRESSION LEVELS. FURTHERMORE, TSA SUPPRESSED PROTEIN EXPRESSION LEVELS OF HDAC2 AND HDAC4. HOWEVER, TSA INDUCED HYPERACETYLATION OF HISTONES H4. TREATMENT WITH TGF-BETA1 WITH OR WITHOUT TSA DID NOT HAVE CYTOTOXIC EFFECT. CONCLUSION: THESE FINDINGS PROVIDE NOVEL INSIGHTS INTO THE EPIGENETIC REGULATION IN MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION OF NASAL POLYP. TSA COULD BE A CANDIDATE OF A THERAPEUTIC AGENT FOR REVERSING THE TGF-BETA1-INDUCED ECM SYNTHESIS THAT LEADS TO NASAL POLYP DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12   904  23 CHRONIC EXPOSURE TO CADMIUM INDUCES DIFFERENTIAL METHYLATION IN MICE SPERMATOZOA. CADMIUM EXPOSURE IS UBIQUITOUS AND HAS BEEN LINKED TO DISEASES INCLUDING CANCERS AND REPRODUCTIVE DEFECTS. SINCE CADMIUM IS NONMUTAGENIC, IT IS THOUGHT TO EXERT ITS GENE DYSREGULATORY EFFECTS THROUGH EPIGENETIC REPROGRAMMING. SEVERAL STUDIES HAVE IMPLICATED GERMLINE EXPOSURE TO CADMIUM IN DEVELOPMENTAL REPROGRAMMING. HOWEVER, MOST OF THESE STUDIES HAVE FOCUSED ON MATERNAL EXPOSURE, WHILE THE IMPACT ON SPERM FERTILITY AND DISEASE SUSCEPTIBILITY HAS RECEIVED LESS ATTENTION. IN THIS STUDY, WE USED REDUCED REPRESENTATION BISULFITE SEQUENCING TO COMPREHENSIVELY INVESTIGATE THE IMPACT OF CHRONIC CADMIUM EXPOSURE ON MOUSE SPERMATOZOA DNA METHYLATION. ADULT MALE C57BL/J6 MICE WERE PROVIDED WATER WITH OR WITHOUT CADMIUM CHLORIDE FOR 9 WEEKS. SPERM, TESTES, LIVER, AND KIDNEY TISSUES WERE COLLECTED AT THE END OF THE TREATMENT PERIOD. CADMIUM EXPOSURE WAS CONFIRMED THROUGH GENE EXPRESSION ANALYSIS OF METALLOTHIONEIN-1 AND 2, 2 WELL-KNOWN CADMIUM-INDUCED GENES. ANALYSIS OF SPERM DNA METHYLATION CHANGES REVEALED 1788 DIFFERENTIALLY METHYLATED SITES PRESENT AT REGULATORY REGIONS IN SPERM OF MICE EXPOSED TO CADMIUM COMPARED WITH VEHICLE (CONTROL) MICE. FURTHERMORE, MOST OF THESE DIFFERENTIAL METHYLATION CHANGES POSITIVELY CORRELATED WITH CHANGES IN GENE EXPRESSION AT BOTH THE TRANSCRIPTION INITIATION STAGE AS WELL AS THE SPLICING LEVELS. INTERESTINGLY, THE GENES TARGETED BY CADMIUM EXPOSURE ARE INVOLVED IN SEVERAL CRITICAL DEVELOPMENTAL PROCESSES. OUR RESULTS PRESENT A COMPREHENSIVE ANALYSIS OF THE SPERM METHYLOME IN RESPONSE TO CHRONIC CADMIUM EXPOSURE. THESE DATA, THEREFORE, HIGHLIGHT A FOUNDATIONAL FRAMEWORK TO STUDY GENE EXPRESSION PATTERNS THAT MAY AFFECT FERTILITY IN THE EXPOSED INDIVIDUAL AS WELL AS THEIR OFFSPRING, THROUGH PATERNAL INHERITANCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13  3841  27 IRON SUPPLEMENTATION REVERSES THE REDUCTION OF HYDROXYMETHYLCYTOSINE IN HEPATIC DNA ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION IN RATS. BACKGROUND: ALCOHOL IS KNOWN TO AFFECT TWO EPIGENETIC PHENOMENA, DNA METHYLATION AND DNA HYDROXYMETHYLATION, AND IRON IS A COFACTOR OF TEN-ELEVEN TRANSLOCATION (TET) ENZYMES THAT CATALYZE THE CONVERSION FROM METHYLCYTOSINE TO HYDROXYMETHYLCYTOSINE. IN THE PRESENT STUDY WE AIMED TO DETERMINE THE EFFECTS OF ALCOHOL ON DNA HYDROXYMETHYLATION AND FURTHER EFFECTS OF IRON ON ALCOHOL ASSOCIATED EPIGENETIC CHANGES. METHODS: TWENTY-FOUR MALE SPRAGUE-DAWLEY RATS WERE FED EITHER LIEBER-DECARLI ALCOHOL DIET (36% CALORIES FROM ETHANOL) OR LIEBER-DECARLI CONTROL DIET ALONG WITH OR WITHOUT IRON SUPPLEMENTATION (0.6% CARBONYL IRON) FOR 8 WEEKS. HEPATIC NON-HEME IRON CONCENTRATIONS WERE MEASURED BY COLORIMETRIC ASSAYS. PROTEIN LEVELS OF HEPATIC FERRITIN AND TRANSFERRIN RECEPTOR WERE DETERMINED BY WESTERN BLOTTING. METHYLCYTOSINE, HYDROXYMETHYLCYTOSINE AND UNMODIFIED CYTOSINE IN DNA WERE SIMULTANEOUSLY MEASURED BY LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY METHOD. RESULTS: IRON SUPPLEMENTATION SIGNIFICANTLY INCREASED HEPATIC NON-HEME IRON CONTENTS (P < 0.05) BUT ALCOHOL ALONE DID NOT. HOWEVER, BOTH ALCOHOL AND IRON SIGNIFICANTLY INCREASED HEPATIC FERRITIN LEVELS AND DECREASED HEPATIC TRANSFERRIN RECEPTOR LEVELS (P < 0.05). ALCOHOL REDUCED HEPATIC DNA HYDROXYMETHYLATION (0.21% +/- 0.04% VS. 0.33% +/- 0.04%, P = 0.01) COMPARED TO CONTROL, WHILE IRON SUPPLEMENTATION TO ALCOHOL DIET DID NOT CHANGE DNA HYDROXYMETHYLATION. THERE WAS NO SIGNIFICANT DIFFERENCE IN METHYLCYTOSINE LEVELS, WHILE UNMODIFIED CYTOSINE LEVELS WERE SIGNIFICANTLY INCREASED IN ALCOHOL-FED GROUPS COMPARED TO CONTROL (95.61% +/- 0.08% VS. 95.26% +/- 0.12%, P = 0.03), SUGGESTING THAT ALCOHOL FURTHER INCREASES THE CONVERSION FROM HYDROXYMETHYLCYTOSINE TO UNMODIFIED CYTOSINE. CONCLUSIONS: CHRONIC ALCOHOL CONSUMPTION ALTERS GLOBAL DNA HYDROXYMETHYLATION IN THE LIVER BUT IRON SUPPLEMENTATION REVERSES THE EPIGENETIC EFFECT OF ALCOHOL.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  1122  17 COMPARISON OF GENE EXPRESSION PROFILES IN CHROMATE TRANSFORMED BEAS-2B CELLS. BACKGROUND: HEXAVALENT CHROMIUM [CR(VI)] IS A POTENT HUMAN CARCINOGEN. OCCUPATIONAL EXPOSURE HAS BEEN ASSOCIATED WITH INCREASED RISK OF RESPIRATORY CANCER. MULTIPLE MECHANISMS HAVE BEEN SHOWN TO CONTRIBUTE TO CR(VI) INDUCED CARCINOGENESIS, INCLUDING DNA DAMAGE, GENOMIC INSTABILITY, AND EPIGENETIC MODULATION, HOWEVER, THE MOLECULAR MECHANISM AND DOWNSTREAM GENES MEDIATING CHROMIUM'S CARCINOGENICITY REMAIN TO BE ELUCIDATED. METHODS/RESULTS: WE ESTABLISHED CHROMATE TRANSFORMED CELL LINES BY CHRONIC EXPOSURE OF NORMAL HUMAN BRONCHIAL EPITHELIAL BEAS-2B CELLS TO LOW DOSES OF CR(VI) FOLLOWED BY ANCHORAGE-INDEPENDENT GROWTH. THESE TRANSFORMED CELL LINES NOT ONLY EXHIBITED CONSISTENT MORPHOLOGICAL CHANGES BUT ALSO ACQUIRED ALTERED AND DISTINCT GENE EXPRESSION PATTERNS COMPARED WITH NORMAL BEAS-2B CELLS AND CONTROL CELL LINES (UNTREATED) THAT AROSE SPONTANEOUSLY IN SOFT AGAR. INTERESTINGLY, THE GENE EXPRESSION PROFILES OF SIX CR(VI) TRANSFORMED CELL LINES WERE REMARKABLY SIMILAR TO EACH OTHER YET DIFFERED SIGNIFICANTLY FROM THAT OF EITHER CONTROL CELL LINES OR NORMAL BEAS-2B CELLS. A TOTAL OF 409 DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED IN CR(VI) TRANSFORMED CELLS COMPARED TO CONTROL CELLS. GENES RELATED TO CELL-TO-CELL JUNCTION WERE UPREGULATED IN ALL CR(VI) TRANSFORMED CELLS, WHILE GENES ASSOCIATED WITH THE INTERACTION BETWEEN CELLS AND THEIR EXTRACELLULAR MATRICES WERE DOWN-REGULATED. ADDITIONALLY, EXPRESSION OF GENES INVOLVED IN CELL PROLIFERATION AND APOPTOSIS WERE ALSO CHANGED. CONCLUSION: THIS STUDY IS THE FIRST TO REPORT GENE EXPRESSION PROFILING OF CR(VI) TRANSFORMED CELLS. THE GENE EXPRESSION CHANGES ACROSS INDIVIDUAL CHROMATE EXPOSED CLONES WERE REMARKABLY SIMILAR TO EACH OTHER BUT DIFFERED SIGNIFICANTLY FROM THE GENE EXPRESSION FOUND IN ANCHORAGE-INDEPENDENT CLONES THAT AROSE SPONTANEOUSLY. OUR ANALYSIS IDENTIFIED MANY NOVEL GENE EXPRESSION CHANGES THAT MAY CONTRIBUTE TO CHROMATE INDUCED CELL TRANSFORMATION, AND COLLECTIVELY THIS TYPE OF INFORMATION WILL PROVIDE A BETTER UNDERSTANDING OF THE MECHANISM UNDERLYING CHROMATE CARCINOGENICITY.	2011	
                                                                                                                                                                                                                                                                                                                                                      
15  4303  25 MICRORNA-223 INHIBITS TISSUE FACTOR EXPRESSION IN VASCULAR ENDOTHELIAL CELLS. OBJECTIVE: ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY PROCESS, IN WHICH VASCULAR ENDOTHELIAL CELLS (ECS) BECOME DYSFUNCTIONAL OWING TO THE EFFECTS OF CHEMICAL SUBSTANCES, SUCH AS INFLAMMATORY FACTOR AND GROWTH FACTORS. TISSUE FACTOR (TF) EXPRESSION IS INDUCED BY THE ABOVE CHEMICAL SUBSTANCES IN ACTIVATED ECS. TF INITIATES THROMBOSIS ON DISRUPTED ATHEROSCLEROTIC PLAQUES WHICH PLAYS AN ESSENTIAL ROLE DURING THE ONSET OF ACUTE CORONARY SYNDROMES (ACS). INCREASING EVIDENCES SUGGEST THE IMPORTANT ROLE OF MICRORNAS AS EPIGENETIC REGULATORS OF ATHEROSCLEROTIC DISEASE. THE AIM OF OUR STUDY IS TO IDENTIFY IF MICRORNA-223 (MIR-223) TARGETS TF IN ECS. METHODS AND RESULTS: BIOINFORMATIC ANALYSIS SHOWED THAT TF IS A TARGET CANDIDATE OF MIR-223. WESTERN BLOTTING ANALYSIS REVEALED THAT TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) INCREASED TF EXPRESSION IN AORTA OF C57BL/6J MICE AND CULTURED ECS (EA.HY926 CELLS AND HUVEC) AFTER 4 H TREATMENT. IN TNF-ALPHA TREATED ECS, TF MRNA WAS ALSO INCREASED MEASURED BY REAL-TIME PCR. REAL-TIME PCR RESULTS SHOWED THAT MIR-223 LEVELS WERE DOWNREGULATED IN TNF-ALPHA-TREATED AORTA OF C57BL/6J MICE AND CULTURED ECS. TRANSFECTION OF ECS WITH MIR-223 MIMIC OR MIR-223 INHIBITOR MODIFIED TF EXPRESSION BOTH IN MRNA AND PROTEIN LEVELS. LUCIFERASE ASSAYS CONFIRMED THAT MIR-223 SUPPRESSED TF EXPRESSION BY BINDING TO THE SEQUENCE OF TF 3'-UNTRANSLATED REGIONS (3'UTR). TF PROCOAGULANT ACTIVITY WAS INHIBITED BY OVEREXPRESSING MIR-223 WITH OR WITHOUT TNF-ALPHA STIMULATION. CONCLUSIONS: MIR-223-MEDIATED SUPPRESSION OF TF EXPRESSION PROVIDES A NOVEL MOLECULAR MECHANISM FOR THE REGULATION OF COAGULATION CASCADE, AND SUGGESTS A CLUE AGAINST THROMBOGENESIS DURING THE PROCESS OF ATHEROSCLEROTIC PLAQUE RUPTURE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16  1632  15 DNMTS ARE INVOLVED IN TGF-BETA1-INDUCED EPITHELIAL-MESENCHYMAL TRANSITIONS IN AIRWAY EPITHELIAL CELLS. CHRONIC RHINOSINUSITIS (CRS) PATHOGENESIS IS CLOSELY RELATED TO TISSUE REMODELING, INCLUDING EPITHELIAL-MESENCHYMAL TRANSITION (EMT). EPIGENETIC MECHANISMS PLAY KEY ROLES IN EMT. DNA METHYLATION, MEDIATED BY DNA METHYLTRANSFERASES (DNMTS), IS AN EPIGENETIC MARKER THAT IS CRITICAL TO EMT. THE GOAL OF THIS STUDY WAS TO DETERMINE WHETHER DNMTS WERE INVOLVED IN TGF-BETA1-INDUCED EMT AND ELUCIDATE THE UNDERLYING MECHANISMS IN NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. GLOBAL DNA METHYLATION AND DNMT ACTIVITY WERE QUANTIFIED. DNMT EXPRESSION WAS MEASURED USING REAL-TIME PCR (QRT-PCR) IN HUMAN CRS TISSUES. MRNA AND PROTEIN LEVELS OF DNMTS, E-CADHERIN, VIMENTIN, ALPHA-SMA, AND FIBRONECTIN WERE DETERMINED USING RT-PCR AND WESTERN BLOTTING, RESPECTIVELY. DNMT1, DNMT3A, AND DNMT3B GENE EXPRESSION WERE KNOCKED DOWN USING SIRNA TRANSFECTION. MAPK PHOSPHORYLATION AND EMT-RELATED TRANSCRIPTION FACTOR LEVELS WERE DETERMINED USING WESTERN BLOTTING. SIGNALING PATHWAYS WERE ANALYZED USING SPECIFIC INHIBITORS OF MAPK. WE DEMONSTRATED THESE DATA IN PRIMARY NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. GLOBAL DNA METHYLATION, DNMT ACTIVITY, AND DNMT EXPRESSION INCREASED IN CRS TISSUES. DNMT EXPRESSION WAS POSITIVELY CORRELATED WITH LUND-MCKAY CT SCORES. TGF-BETA1 DOSE-DEPENDENTLY INDUCED DNMT EXPRESSION. FURTHER, 5-AZA INHIBITED TGF-BETA1-INDUCED DNMT, SNAIL, AND SLUG EXPRESSION RELATED TO EMT, AS WELL AS P38 AND JNK PHOSPHORYLATION IN A549 CELLS AND TGF-BETA1-INDUCED DNMT EXPRESSION AND EMT IN PRIMARY NASAL EPITHELIAL CELLS AND AIR-LIQUID INTERFACE CULTURES. TGF-BETA1-INDUCED DNMT EXPRESSION LEADS TO DNA METHYLATION AND EMT VIA P38, JNK, SNAIL, AND SLUG SIGNALING PATHWAYS. INHIBITION OF DNMT SUPPRESSED THE EMT PROCESS AND THEREFORE IS POTENTIALLY A CRS THERAPEUTIC STRATEGY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  4581  17 N-METHYL-D-ASPARTATE 2B RECEPTOR SUBTYPE (NR2B) PROMOTER METHYLATION IN PATIENTS DURING ALCOHOL WITHDRAWAL. NMDA RECEPTORS AND ESPECIALLY THE NR2B RECEPTOR SUBTYPE PLAY A CRUCIAL ROLE DURING CHRONIC ETHANOL CONSUMPTION AND ALCOHOL WITHDRAWAL. THEREFORE, THE NR2B RECEPTOR SUBTYPE EXPRESSION IN PERIPHERAL BLOOD CELLS OF 32 MALE PATIENTS SUFFERING FROM ALCOHOL DEPENDENCY WERE ASSESSED THROUGH QUANTITATIVE RT-PCR AND TO EXPLORE REGULATING EPIGENETIC MECHANISMS, A METHYLATION ANALYSIS WAS CONDUCTED USING BISULFITE SEQUENCING OF A FRAGMENT OF THE NR2B PROMOTER REGION. THE EXPRESSION OF THE NR2B RECEPTOR INCREASED SIGNIFICANTLY DURING THE FIRST 24 H OF WITHDRAWAL TREATMENT (DAY 1; T = 4.1, P = 0.001), AND ALSO ON AND DAY 3 (T = 2.4; P = 0.029). THE SEVERITY OF ALCOHOL DRINKING PATTERN, MEASURED BY LIFETIME DRINKING AND DAILY ETHANOL INTAKE, WAS NEGATIVELY CORRELATED WITH THE METHYLATION OF A DEFINED CLUSTER OF FIVE CPG-SITES WITHIN THE NR2B PROMOTER (LIFETIME DRINKING: SPEARMAN'S RHO = -0.55; P = 0.013; DAILY ETHANOL INTAKE: RHO = -0.46; P = 0.043). THESE FINDINGS MIGHT EXPLAIN THE OBSERVATION OF AN IMPACT OF ALCOHOL CONSUMPTION PATTERNS ON THE GRAVITY OF WITHDRAWAL SYMPTOMS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18  4819  22 OCCURRENCE OF TOXICITY AND CELL PROLIFERATION AFTER A SINGLE GAVAGE ADMINISTRATION OF CHLOROFORM TO MALE F344 RATS. CHLOROFORM, AN INDUSTRIAL SOLVENT AND ONE OF THE MOST COMMON ENVIRONMENTAL CONTAMINANTS WHICH PRODUCES CARCINOGENIC EFFECTS IN THE LIVER AND KIDNEY OF RODENTS, IS NOT GENOTOXIC IN MOST TRADITIONAL BACTERIAL AND MAMMALIAN TEST SYSTEMS. ITS CARCINOGENIC POTENTIAL APPEARS ATTRIBUTABLE TO THE SUSTAINED CELL TURNOVER (REGENERATIVE HYPERPLASIA) WHICH RESULTS FROM CHRONIC CHLOROFORM TOXICITY. IN THIS PRESENT STUDY, CELL PROLIFERATION (REPLICATIVE DNA SYNTHESIS, RDS) AND HISTOPATHOLOGICAL CHANGES IN HEPATOCYTES AND RENAL TUBULAR EPITHELIAL CELLS WERE ASSESSED IN MALE F344 RATS FOLLOWING A SINGLE GAVAGE CHLOROFORM EXPOSURE (50, 150 OR 500 MG/KG). IN ADDITION, BIOCHEMICAL PARAMETERS (BUN, GOT, LDH AND NAG) WERE EXAMINED USING PLASMA AND URINE SAMPLES. CELL PROLIFERATION AND HISTOPATHOLOGICAL CHANGES (E.G. HYPERTROPHY, NECROSIS, VACUOLATION) WERE ONLY SEEN AT THE DOSE OF 500 MG/KG IN THE LIVER AND KIDNEY. AT THE SAME DOSE, ALL BIOCHEMICAL MARKERS WERE INCREASED AT THE 24 TO 48 HR TIME POINTS. THESE RESULTS OBTAINED ARE THUS IN LINE WITH EARLIER FINDINGS POINTING TO EPIGENETIC CARCINOGENICITY.	1998	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19  1393  20 DIAGNOSTIC VALUE OF THE HYPOMETHYLATION OF THE WISP1 PROMOTER IN PATIENTS WITH HEPATOCELLULAR CARCINOMA ASSOCIATED WITH HEPATITIS B VIRUS. WNT1-INDUCIBLE SIGNALING PATHWAY PROTEIN 1 (WISP1) REGULATES CELL PROLIFERATION, DIFFERENTIATION, ADHESION, MIGRATION AND SURVIVAL. ABNORMAL WISP1 EXPRESSION IS ASSOCIATED WITH THE CARCINOGENESIS OF HEPATOCELLULAR CARCINOMA (HCC). ABERRANT DNA METHYLATION IS ONE OF THE MAJOR EPIGENETIC ALTERATIONS IN HCC. HOWEVER, THE METHYLATION STATUS OF THE WISP1 PROMOTER IS STILL UNCLEAR. WE THEREFORE AIMED TO DETERMINE THE METHYLATION STATUS OF THE WISP1 PROMOTER AND EVALUATE ITS CLINICAL VALUE IN HCC. THE STUDY ENROLLED 251 PARTICIPANTS, INCLUDING 123 PARTICIPANTS WITH HCC, 90 PARTICIPANTS WITH CHRONIC HEPATITIS B (CHB) AND 38 HEALTHY CONTROLS (HCS). WISP1 METHYLATION STATUS, MRNA LEVELS AND PLASMA SOLUBLE WISP1 WERE DETECTED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), QUANTITATIVE REAL-TIME PCR (RT-QPCR) AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. WE FOUND THAT THE METHYLATION FREQUENCY OF WISP1 IN PATIENTS WITH HCC WAS SIGNIFICANTLY LOWER THAN THAT IN PATIENTS WITH CHB AND HCS, WHILE THE RELATIVE EXPRESSION LEVELS OF WISP1 MRNA WERE MARKEDLY HIGHER IN PATIENTS WITH HCC THAN IN PATIENTS WITH CHB AND HCS. FURTHERMORE, THE PLASMA SOLUBLE WISP1 IN PATIENTS WITH HCC WAS OBVIOUSLY LOWER THAN IN THAT IN PATIENTS WITH CHB AND HCS. ALPHA-FETOPROTEIN (AFP) IS A WIDELY RECOGNIZED BIOMARKER TO DIAGNOSE HCC WHICH LACKS ENOUGH SENSITIVITY AND SPECIFICITY. WISP1 PROMOTER METHYLATION STATUS COMBINED WITH AFP SIGNIFICANTLY IMPROVED THE DIAGNOSTIC ABILITY IN DISCRIMINATING HCC FROM CHB COMPARED WITH AFP OR WISP1 METHYLATION STATUS ALONE. IN CONCLUSION, HYPOMETHYLATION OF THE WISP1 GENE PROMOTER MAY SERVE AS A NONINVASIVE BIOMARKER FOR DETECTING HBV-ASSOCIATED HCC.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20  4008  23 LOW DOSE OF URANIUM INDUCES MULTIGENERATIONAL EPIGENETIC EFFECTS IN RAT KIDNEY. PURPOSE: A PROTOCOL OF CHRONIC EXPOSURE TO LOW DOSE OF URANIUM WAS ESTABLISHED IN ORDER TO DISTINGUISH THE SEXUAL DIFFERENCES AND THE DEVELOPMENTAL PROCESS THAT ARE CRITICAL WINDOWS FOR EPIGENETIC EFFECTS OVER GENERATIONS. METHODS: BOTH MALE AND FEMALE RATS WERE CONTAMINATED THROUGH THEIR DRINKING WATER WITH A NON-TOXIC SOLUTION OF URANYL NITRATE FOR 9 MONTHS. THE EXPOSED GENERATION (F0) AND THE FOLLOWING TWO GENERATIONS (F1 AND F2) WERE EXAMINED. CLINICAL MONITORING, GLOBAL DNA METHYLATION PROFILE AND DNA METHYLTRANSFERASES (DNMTS) GENE EXPRESSION WERE ANALYZED IN KIDNEYS. RESULTS: WHILE THE BODY WEIGHT OF F1 MALES INCREASED, A SMALL DECREASE IN KIDNEY AND BODY WEIGHT WAS OBSERVED IN F2 MALES. IN ADDITION, GLOBAL DNA HYPERMETHYLATION PROFILE IN KIDNEY CELLS WAS OBSERVED IN F1 AND F2 MALES. QPCR RESULTS REVEAL A SIGNIFICANT INCREASE OF METHYLTRANSFERASE GENES EXPRESSION (DNMT1 AND DNMT3A) FOR F2 FEMALES. CONCLUSIONS: IN THE FIELD OF PUBLIC HEALTH POLICY AND TO RAISE ATTENTION TO GENERATIONAL EFFECTS FOR THE RISK ASSESSMENT OF THE ENVIRONMENTAL EXPOSURES, LOW DOSES OF URANIUM DO NOT IMPLY CLINICAL EFFECTS ON ADULT EXPOSED RATS. HOWEVER, OUR RESULTS CONFIRM THE IMPORTANCE OF THE DEVELOPMENTAL WINDOWS' SENSITIVITY IN ADDITION TO THE SEXUAL DIMORPHISMS OF THE OFFSPRING.	2018