1  3619 139 IN VIVO ACUTE ON CHRONIC ETHANOL EFFECTS IN LIVER: A MOUSE MODEL EXHIBITING EXACERBATED INJURY, ALTERED METABOLIC AND EPIGENETIC RESPONSES. CHRONIC ALCOHOLICS WHO ALSO BINGE DRINK (I.E., ACUTE ON CHRONIC) ARE PRONE TO AN EXACERBATED LIVER INJURY BUT ITS MECHANISM IS NOT UNDERSTOOD. WE THEREFORE INVESTIGATED THE IN VIVO EFFECTS OF CHRONIC AND BINGE ETHANOL INGESTION AND COMPARED TO CHRONIC ETHANOL FOLLOWED BY THREE REPEAT BINGE ETHANOL ON THE LIVER OF MALE C57/BL6 MICE FED ETHANOL IN LIQUID DIET (4%) FOR FOUR WEEKS FOLLOWED BY BINGE ETHANOL (INTRAGASTRIC ADMINISTRATION, 3.5 G/KG BODY WEIGHT, THREE DOSES, 12H APART). CHRONIC FOLLOWED BY BINGE ETHANOL EXACERBATED FAT ACCUMULATION, NECROSIS, DECREASE IN HEPATIC SAM AND SAM:SAH RATIO, INCREASE IN ADENOSINE LEVELS, AND ELEVATED CYP2E1 LEVELS. HISTONE H3 LYSINE ACETYLATION (H3ACK9), DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10), AND PHOSPHORYLATED H2AX INCREASED AFTER BINGE WHEREAS PHOSPHORYLATION OF HISTONE H3 SER 10 (H3S10) AND H3 SER 28 (H3S28) INCREASED AFTER CHRONIC ETHANOL-BINGE. HISTONE H3 LYSINE 4 AND 9 DIMETHYLATION INCREASED WITH A MARKED DIMETHYLATION IN H3K9 IN CHRONIC ETHANOL BINGE GROUP. TRIMETHYLATED HISTONE H3 LEVELS DID NOT CHANGE. NUCLEAR LEVELS OF HISTONE ACETYL TRANSFERASE GCN5 AND HISTONE DEACETYLASE HDAC3 WERE ELEVATED WHEREAS PHOSPHO-CREB DECREASED IN A DISTINCTIVE MANNER. TAKEN TOGETHER, ACUTE ON CHRONIC ETHANOL INGESTION CAUSED AMPLIFICATION OF LIVER INJURY AND ELICITED CHARACTERISTIC PROFILES OF HISTONE MODIFICATIONS, METABOLIC ALTERATIONS, AND CHANGES IN NUCLEAR PROTEIN LEVELS. THESE FINDINGS DEMONSTRATE THAT CHRONIC ETHANOL EXPOSURE RENDERS LIVER MORE SUSCEPTIBLE TO REPEAT ACUTE/BINGE ETHANOL INDUCED ACCELERATION OF ALCOHOLIC LIVER DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2  5609  44 S-ADENOSYLMETHIONINE DECREASES THE PEAK BLOOD ALCOHOL LEVELS 3 H AFTER AN ACUTE BOLUS OF ETHANOL BY INDUCING ALCOHOL METABOLIZING ENZYMES IN THE LIVER. INTRODUCTION: AN ALCOHOL BOLUS CAUSES THE BLOOD ALCOHOL LEVEL (BAL) TO PEAK AT 1-2 H POST INGESTION. THE ETHANOL ELIMINATION RATE IS REGULATED BY ALCOHOL METABOLIZING ENZYMES, PRIMARILY ALCOHOL DEHYDROGENASE (ADH1), ACETALDEHYDE DEHYDROGENASE (ALDH), AND CYTOCHROME P450 (CYP2E1). RECENTLY, S-ADENOSYLMETHIONINE (SAME) WAS FOUND TO REDUCE ACUTE BALS 3 H AFTER AN ALCOHOL BOLUS. THE QUESTION, THEN, WAS: WHAT IS THE MECHANISM INVOLVED IN THIS REDUCTION OF BAL BY FEEDING SAME? TO ANSWER THIS QUESTION, WE INVESTIGATED THE CHANGES IN ETHANOL METABOLIZING ENZYMES AND THE EPIGENETIC CHANGES THAT REGULATE THE EXPRESSION OF THESE ENZYMES DURING ACUTE BINGE DRINKING AND CHRONIC DRINKING. METHODS: RATS WERE FED A BOLUS OF ETHANOL WITH OR WITHOUT SAME, AND WERE SACRIFICED AT 3 H OR 12 H AFTER THE BOLUS. RESULTS: RT-PCR AND WESTERN BLOT ANALYSES SHOWED THAT SAME SIGNIFICANTLY INDUCED ADH1 LEVELS IN THE 3 H LIVER SAMPLES. HOWEVER, SAME DID NOT AFFECT THE CHANGES IN ADH1 PROTEIN LEVELS 12 H POST BOLUS. SINCE SAME IS A METHYL DONOR, IT WAS POSTULATED THAT THE ADH1 GENE EXPRESSION UP REGULATION AT 3 H WAS DUE TO A HISTONE MODIFICATION INDUCED BY METHYLATION FROM METHYL TRANSFERASES. DIMETHYLATED HISTONE 3 LYSINE 4 (H3K4ME2), A MODIFICATION RESPONSIBLE FOR GENE EXPRESSION ACTIVATION, WAS FOUND TO BE SIGNIFICANTLY INCREASED BY SAME AT 3 H POST BOLUS. CONCLUSION: THESE RESULTS CORRELATED WITH THE LOW BAL FOUND AT 3 H POST BOLUS, AND SUPPORT THE CONCEPT THAT SAME INCREASED THE GENE EXPRESSION TO INCREASE THE ELIMINATION RATE OF ETHANOL IN BINGE DRINKING BY INCREASING H3K4ME2.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  2120  69 EPIGENETIC HISTONE MODIFICATIONS IN A CLINICALLY RELEVANT RAT MODEL OF CHRONIC ETHANOL-BINGE-MEDIATED LIVER INJURY. PURPOSE: ETHANOL BINGE AUGMENTS LIVER INJURY AFTER CHRONIC ETHANOL CONSUMPTION IN HUMANS, BUT THE MECHANISM BEHIND THE ENHANCED LIVER INJURY BY ETHANOL BINGE IS NOT KNOWN. IN THIS STUDY WE USED A CLINICALLY RELEVANT RAT MODEL IN WHICH LIVER INJURY IS AMPLIFIED BY BINGE AFTER CHRONIC ETHANOL TREATMENT AND INVESTIGATED THE IMPORTANCE OF HISTONE MODIFICATIONS. METHODS: EIGHT-WEEK-OLD SPRAGUE-DAWLEY RATS WERE FED ETHANOL IN A LIQUID DIET FOR 4 WEEKS. CONTROL RATS WERE FED AN ISOCALORIC LIQUID DIET. THIS WAS FOLLOWED BY THREE BINGE ADMINISTRATIONS OF ETHANOL (INTRAGASTRIC 5 G/KG BODY WEIGHT, 12 H APART). IN THE CONTROL, ETHANOL WAS REPLACED BY WATER. FOUR HOURS AFTER THE LAST BINGE ADMINISTRATION, LIVER SAMPLES WERE ANALYZED FOR HISTONE MODIFICATIONS AND PARAMETERS OF LIVER INJURY. RESULTS: CHRONIC ETHANOL ADMINISTRATION ALONE CAUSED AN INCREASE IN HISTONE H3 SER10 AND SER28 (H3S10 OR S28) PHOSPHORYLATION, AND BINGE ETHANOL REDUCED THEIR LEVELS. LEVELS OF DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10) INCREASED AFTER ACUTE BINGE ETHANOL AND REMAINED SAME AFTER CHRONIC ETHANOL BINGE. IN CONTRAST, HISTONE H3 LYSINE-9 ACETYLATION (H3ACK9) WAS NOT INCREASED AFTER CHRONIC ETHANOL BUT INCREASED SIGNIFICANTLY AFTER ACUTE BINGE AND CHRONIC ETHANOL BINGE. INCREASE IN HISTONE ACETYLATION WAS ACCOMPANIED BY INCREASED PHOSPHO-ERK1/2 IN THE NUCLEAR EXTRACTS. INCREASED ACETYLATION AFTER CHRONIC ETHANOL BINGE WAS ALSO ACCOMPANIED BY INCREASED PROTEIN LEVELS OF GCN5 HISTONE ACETYL TRANSFERASE AND A MODEST INCREASE IN HDAC3 IN THE NUCLEUS. HISTONE LYSINE-9 DIMETHYLATION WAS SIGNIFICANTLY INCREASED AFTER CHRONIC ETHANOL BINGE. CHRONIC ETHANOL BINGE ALSO RESULTED IN A DECREASE IN THE SAM:SAH RATIO WITH A RELATIVE DECREASE OF SAM LEVELS AND A CORRESPONDING INCREASE IN SAH LEVELS. CONCLUSIONS: ETHANOL BINGE AFTER CHRONIC ETHANOL ALTERED THE PROFILE OF SITE-SPECIFIC HISTONE MODIFICATIONS AND MAY UNDERLIE THE MECHANISM OF AUGMENTED LIVER INJURY BY CHRONIC-ETHANOL-BINGE-TREATED RATS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4  2907  42 GENE EXPRESSION MODIFICATIONS IN THE LIVER CAUSED BY BINGE DRINKING AND S-ADENOSYLMETHIONINE FEEDING. THE ROLE OF EPIGENETIC CHANGES. CHRONIC ETHANOL INGESTION, ACHIEVED BY FEEDING ETHANOL AT A CONSTANT RATE USING INTRAGASTRIC TUBE FEEDING, ALTERS THE EXPRESSION OF GENES IN THE LIVER. THIS IS DONE BY EPIGENETIC MECHANISMS, WHICH DEPEND ON THE BLOOD ALCOHOL LEVELS AT THE TIME OF KILLING. HOWEVER, ACUTE BOLUS FEEDING OF ETHANOL CHANGES GENE EXPRESSION WITHOUT LASTING EPIGENETIC CHANGES. THIS OCCURS WITH HISTONE 3 METHYLATION AND ACETYLATION MODIFICATIONS. THE GENE EXPRESSION RESPONSE TO AN ACUTE BOLUS OF ETHANOL MIGHT BE MODIFIED BY FEEDING S-ADENOSYLMETHIONINE (SAME), A METHYL DONOR. IN THE PRESENT STUDY, RATS WERE GIVEN A BOLUS OF ETHANOL (6 G/KG BODY WEIGHT (BW), SAME (1 G/KG BW), ETHANOL + SAME, OR ISOCALORIC GLUCOSE. THE GROUP OF RATS (N = 3) WERE KILLED AT 3 AND 12 H POST BOLUS, AND GENE MICROARRAY ANALYSIS WAS PERFORMED ON THEIR LIVER CELLS. SAME REDUCED THE 3 H BLOOD ETHANOL LEVELS AND INCREASED THE ALT LEVELS AT 3 H. VENN DIAGRAMS SHOWED THAT ALCOHOL CHANGED THE EXPRESSION OF 646 GENES AT 3 H POST BOLUS AND 586 GENES AT 12 H. SAME CHANGED THE EXPRESSION OF 1,012 GENES WHEN FED WITH ETHANOL 3 H POST ETHANOL BOLUS AND 554 GENES AT 12 H POST ETHANOL BOLUS. SAME ALONE CHANGED THE EXPRESSION OF 1,751 GENES AT 3 H AND 1,398 AT 12 H. THERE WERE MORE CHANGES IN GENE EXPRESSION AT 3 H THAN AT 12 H POST ETHANOL WHEN ETHANOL ALONE WAS COMPARED TO THE DEXTROSE CONTROL. THE SAME WAS TRUE WHEN SAME WAS COMPARED TO SAME + ETHANOL. ETHANOL UP REGULATED GENE EXPRESSION IN MOST FUNCTIONAL PATHWAYS AT 3 H. HOWEVER, WHEN SAME WAS FED WITH ETHANOL AT 3 H, MOST PATHWAYS WERE DOWN REGULATED. AT 12 H, HOWEVER, WHEN ETHANOL WAS FED, THE PATHWAYS WERE HALF UP REGULATED AND HALF DOWN REGULATED. THE SAME WAS TRUE WHEN SAME + ETHANOL WAS FED. THE EXPRESSION OF EPIGENETICALLY IMPORTANT GENES, SUCH AS BHMT AND FOXN3, WAS UP REGULATED 3 H POST ALCOHOL BOLUS. AT 3 H, SAME DOWN REGULATED THE EXPRESSION OF GENES, SUCH AS BHMT, MAT2A, JUN, TNFRS9, AHCY 1, TGFBR1 AND 2, AND PCAF. AT 12 H, THE INSULIN SIGNALING PATHWAYS WERE HALF DOWN REGULATED BY ETHANOL, WHICH WAS PARTLY PREVENTED BY SAME. THE MAPK PATHWAY WAS UP REGULATED BY ETHANOL, BUT SAME DID NOT PREVENT THIS. IN CONCLUSION, PROFOUND CHANGES IN GENE EXPRESSION EVOLVED BETWEEN 3 H AND 12 POST ETHANOL BOLUS. SAME DOWN REGULATED THESE CHANGES IN GENE EXPRESSION AT 3 H, AND LESS SO AT 12 H.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5   872  40 CHRONIC ALCOHOL EXPOSURE DIFFERENTIALLY ALTERS ONE-CARBON METABOLISM IN RAT LIVER AND BRAIN. BACKGROUND: EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION PLAY AN IMPORTANT ROLE IN REGULATING THE PATHOPHYSIOLOGY OF ALCOHOLISM. CHRONIC ALCOHOL EXPOSURE LEADS TO BEHAVIORAL CHANGES AS WELL AS DECREASED EXPRESSION OF GENES ASSOCIATED WITH SYNAPTIC PLASTICITY. IN THE LIVER, IT HAS BEEN DOCUMENTED THAT CHRONIC ALCOHOL EXPOSURE IMPAIRS METHIONINE SYNTHASE (MS) ACTIVITY LEADING TO A DECREASE IN S-ADENOSYL METHIONINE/S-ADENOSYL HOMOCYSTEINE (SAM/SAH) RATIO WHICH RESULTS IN DNA HYPOMETHYLATION; HOWEVER, IT IS NOT KNOWN WHETHER SIMILAR ALTERATIONS OF SAM AND SAH LEVELS ARE ALSO PRODUCED IN BRAIN. METHODS: MALE ADULT SPRAGUE DAWLEY RATS WERE FED CHRONICALLY WITH LIEBER-DECARLI ETHANOL (ETOH) (9% V/V) OR CONTROL DIET. THE ETOH-DIET-FED RATS WERE WITHDRAWN FOR 0 AND 24 HOURS. THE CEREBELLUM AND LIVER TISSUES WERE DISSECTED AND USED TO INVESTIGATE CHANGES IN ONE-CARBON METABOLISM, SAM, AND SAH LEVELS. RESULTS: WE FOUND THAT CHRONIC ETOH EXPOSURE DECREASED SAM LEVELS, SAM/SAH RATIO, MS, METHYLENE TETRAHYDROFOLATE REDUCTASE, AND BETAINE HOMOCYSTEINE METHYLTRANSFERASE (BHMT) EXPRESSION AND INCREASED METHIONINE ADENOSYLTRANSFERASE-2B (MAT2B) BUT NOT MAT2A EXPRESSION IN THE LIVER. IN CONTRAST, CHRONIC ETOH EXPOSURE DECREASED SAH LEVELS, INCREASED SAM/SAH RATIO AND THE EXPRESSION OF MAT2A AND S-ADENOSYL HOMOCYSTEINE HYDROLASE, WHILE THE LEVELS OF SAM OR BHMT EXPRESSION IN CEREBELLUM REMAINED UNALTERED. HOWEVER, IN BOTH LIVER AND CEREBELLUM, CHRONIC ETOH EXPOSURE DECREASED THE EXPRESSION OF MS AND INCREASED MAT2B EXPRESSION. ALL CHRONIC ETOH-INDUCED CHANGES OF ONE-CARBON METABOLISM IN CEREBELLUM, BUT NOT LIVER, RETURNED TO NEAR-NORMAL LEVELS DURING ETOH WITHDRAWAL. CONCLUSIONS: THESE RESULTS INDICATE A DECREASED "METHYLATION INDEX" IN LIVER AND AN INCREASED "METHYLATION INDEX" IN CEREBELLUM. THE OPPOSING CHANGES OF THE "METHYLATION INDEX" SUGGEST ALTERED DNA METHYLATION IN LIVER AND CEREBELLUM, THUS IMPLICATING ONE-CARBON METABOLISM IN THE PATHOPHYSIOLOGY OF ALCOHOLISM.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6   894  36 CHRONIC ETHANOL FEEDING ALTERS HEPATOCYTE MEMORY WHICH IS NOT ALTERED BY ACUTE FEEDING. BACKGROUND: GENE EXPRESSION CHANGES IN THE LIVER AFTER ACUTE BINGE DRINKING MAY DIFFER FROM THE CHANGES SEEN IN CHRONIC ETHANOL FEEDING IN THE RAT. THE CHANGES IN GENE EXPRESSION AFTER CHRONIC ETHANOL FEEDING MAY SENSITIZE THE LIVER TO ALCOHOL-INDUCED LIVER DAMAGE, WHICH IS NOT SEEN AFTER ACUTE BINGE DRINKING. METHODS: TO TEST THIS HYPOTHESIS, GENE MICROARRAY ANALYSIS WAS PERFORMED ON THE LIVERS OF RATS (N = 3) FED AN ACUTE BINGE DOSE OF ETHANOL (6 G/KG BODY WT) AND KILLED AT 3 AND 12 HOURS AFTER ETHANOL BY GAVAGE. THE GENE MICROARRAYS WERE COMPARED WITH THOSE MADE ON THE LIVER OF RATS FROM A PREVIOUS STUDY, IN WHICH THE RATS WERE FED ETHANOL BY INTRAGASTRIC TUBE FOR 1 MONTH (36% OF CALORIES DERIVED FROM ETHANOL). RESULTS: MICROARRAY ANALYSIS DATA VARIED BETWEEN THE ACUTE AND CHRONIC MODELS IN SEVERAL IMPORTANT RESPECTS. GROWTH FACTORS INCREASED MAINLY IN THE CHRONIC ALCOHOL FED RAT. CHANGES IN ENZYMES INVOLVED IN OXIDATIVE STRESS WERE NOTED ONLY WITH CHRONIC ETHANOL FEEDING. GENE EXPRESSION OF FAT METABOLISM WAS INCREASED ONLY WITH CHRONIC ETHANOL FEEDING. MOST IMPORTANTLY, EPIGENETIC RELATED ENZYMES AND ACETYLATION AND METHYLATION OF HISTONES CHANGED ONLY AFTER CHRONIC ETHANOL FEEDING. CONCLUSIONS: THE RESULTS SUPPORT THE CONCEPT THAT CHRONIC ETHANOL INGESTION INDUCES ALTERED GENE EXPRESSION AS A RESULT OF CHANGES IN EPIGENETIC MECHANISMS, WHERE ACETYLATION AND METHYLATION OF HISTONES WERE ALTERED.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  2792  30 FAT10 IS AN EPIGENETIC MARKER FOR LIVER PRENEOPLASIA IN A DRUG-PRIMED MOUSE MODEL OF TUMORIGENESIS. THERE IS CLINICAL EVIDENCE THAT CHRONIC LIVER DISEASES IN WHICH MDBS (MALLORY DENK BODIES) FORM PROGRESS TO HEPATOCELLULAR CARCINOMA. THE PRESENT STUDY PROVIDES EVIDENCE THAT LINKS MDB FORMATION INDUCED BY CHRONIC DRUG INJURY, WITH PRENEOPLASIA AND LATER TO THE FORMATION OF TUMORS, WHICH DEVELOP LONG AFTER DRUG WITHDRAWAL. EVIDENCE INDICATED THAT THIS LINK WAS DUE TO AN EPIGENETIC CELLULAR MEMORY INDUCED BY CHRONIC DRUG INGESTION. MICROARRAY ANALYSIS SHOWED THAT THE EXPRESSIONS OF MANY MARKERS OF PRENEOPLASIA (UBD, ALPHA FETOPROTEIN, KLF6 AND GLUTATHIONE-S-TRANSFERASE MU2) WERE INCREASED TOGETHER WHEN THE DRUG DDC WAS REFED. THESE CHANGES WERE SUPPRESSED BY S-ADENOSYLMETHIONINE FEEDING, INDICATING THAT THE DRUG WAS AFFECTING DNA AND HISTONES METHYLATION IN AN EPIGENETIC MANNER. THE LINK BETWEEN MDB FORMATION AND NEOPLASIA FORMATION WAS LIKELY DUE TO THE OVER EXPRESSION OF UBD (ALSO CALLED FAT10), WHICH IS UP REGULATED IN 90% OF HUMAN HEPATOCELLULAR CARCINOMAS. IMMUNOHISTOCHEMICAL STAINING OF DRUG-PRIMED MOUSE LIVERS SHOWED THAT FAT10 POSITIVE LIVER CELLS PERSISTED UP TO 4 MONTHS AFTER DRUG WITHDRAWAL AND THEY WERE STILL FOUND IN THE LIVERS OF MICE, 14 MONTHS AFTER DRUG WITHDRAWAL. THE REFEEDING OF DDC INCREASED THE PERCENT OF FAT10 HEPATOCYTES.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8  1140  26 CONCENTRATION OF FOLIC ACID (FA) IN SERUM OF JAPANESE PREGNANT WOMEN. OBJECTIVES EXPOSURE TO INORGANIC ARSENIC (IAS) IS A WORLD-WIDE HEALTH CONCERN. WE REPORTED THAT JAPANESE CHILDREN AND PREGNANT WOMEN ARE EXPOSED TO MODERATE LEVELS OF IAS THROUGH FOOD. REDUCING IAS CONTAMINATION FROM FOODS OF HIGH IAS IS AN IMPORTANT ISSUE UNIQUE IN JAPAN. INTEGRATED IAS IS METHYLATED TO LESS TOXIC ORGANIC FORMS, AND S-ADENOSYL-L-METHYONINE (SAM), A COMMON METHYL-DONOR OF DNA AND HISTONES, IS UTILIZED IN THIS PROCESS. CHRONIC CONSUMPTION OF SAM BY IAS METABOLISM DUE TO EXPOSURE TO IAS MIGHT ALTER THE EPIGENETIC MODIFICATION OF GENOME. THE SAM BIOSYNTHESIS PATHWAY IS DEPENDENT ON FOLATE CYCLE, AND IT IS POSSIBLE THAT INGESTION OF SUFFICIENT FOLIC ACID (FA) IS PROTECTIVE TO IAS INDUCED TOXICITY. METHODS IN THE COURSE OF OUR CROSS-SECTIONAL BODY BURDEN ANALYSES OF PB AND IAS IN JAPANESE CHILDREN AND PREGNANT WOMEN, TERMED "PBAS STUDY", FA CONCENTRATION IN SERUM OF 104 PREGNANT WOMEN WAS MEASURED. RESULTS MEAN (+/-SEM) OF SERUM FA CONCENTRATION WAS 15.8 +/- 1.3 (NG/ML). THERE ARE SIGNIFICANT NUMBER OF PEOPLE SHOWING VERY HIGH FA (>30 NG/ ML), AND LARGE FRACTION OF THEM WERE TAKING SUPPLEMENTS DAILY. CONCLUSIONS THESE RESULTS SUGGESTED THAT LEVEL OF FA INGESTION OF JAPANESE PREGNANT WOMEN IS HIGH FOR SUPPORTING NORMAL FETAL DEVELOPMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9  1781  31 EFFECT OF 1 YEAR B AND D VITAMIN SUPPLEMENTATION ON LINE-1 REPETITIVE ELEMENT METHYLATION IN OLDER SUBJECTS. BACKGROUND: DISTURBED DNA METHYLATION IS CAUSALLY RELATED TO CHRONIC DISEASES LIKE CANCER AND ATHEROSCLEROSIS. B VITAMINS ARE COFACTORS REQUIRED FOR METHYL GROUP SYNTHESIS AND MAY THEREFORE AFFECT DNA METHYLATION. VITAMIN D HAS EPIGENETIC EFFECTS. WE TESTED IF B AND D VITAMIN SUPPLEMENTATION HAS AN EFFECT ON GENOMIC LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) METHYLATION AND THE METABOLITES S-ADENOSYLMETHIONINE (SAM) AND S-ADENOSYLHOMOCYSTEINE (SAH). METHODS: FIFTY SUBJECTS (MEDIAN AGE 68.0 YEARS) WERE SUPPLEMENTED WITH A DAILY ORAL DOSE OF B VITAMINS (500 MICROG FOLIC ACID, 500 MICROG VITAMIN B12 AND 50 MG VITAMIN B6), 1200 IU VITAMIN D AND 456 MG CALCIUM. FASTING BLOOD SAMPLES WERE COLLECTED BEFORE AND AFTER 1 YEAR OF SUPPLEMENTATION. LINE-1 METHYLATION WAS DETERMINED IN GENOMIC DNA FROM BLOOD CELLS AS A SURROGATE FOR WHOLE GENOME METHYLATION. IN ADDITION, SAM, SAH AND TOTAL HOMOCYSTEINE (THCY) WERE MEASURED IN PLASMA SAMPLES. RESULTS: PLASMA HOMOCYSTEINE DECREASED SIGNIFICANTLY AFTER SUPPLEMENTATION (12.8 VS. 9.1 MICROMOL/L; P<0.05), WHEREAS SAM, SAH, THE SAM/SAH RATIO AND LINE-1 METHYLATION DID NOT CHANGE SIGNIFICANTLY. LINE-1 METHYLATION WAS NOT SIGNIFICANTLY CORRELATED WITH SAH, HOMOCYSTEINE OR B VITAMINS. CONCLUSIONS: LONG-TERM VITAMIN B SUPPLEMENTATION HAD NO EFFECT ON LINE-1 METHYLATION IN BLOOD CELLS NOR ON PLASMA LEVELS OF SAM AND SAH. VITAMIN B AND D SUPPLEMENTATION SEEMS TO HAVE NO EFFECT ON DNA METHYLATION, ESPECIALLY IN CASES WHERE NO SEVERE DEFICIENCY EXISTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  6310  37 THE REGULATION OF NON-CODING RNA EXPRESSION IN THE LIVER OF MICE FED DDC. MALLORY-DENK BODIES (MDBS) ARE FOUND IN THE LIVER OF PATIENTS WITH ALCOHOLIC AND CHRONIC NONALCOHOLIC LIVER DISEASE, AND HEPATOCELLULAR CARCINOMA (HCC). DIETHYL 1,4-DIHYDRO-2,4,6,-TRIMETHYL-3,5-PYRIDINEDICARBOXYLATE (DDC) IS USED AS A MODEL TO INDUCE THE FORMATION OF MDBS IN MOUSE LIVER. PREVIOUS STUDIES IN THIS LABORATORY SHOWED THAT DDC INDUCED EPIGENETIC MODIFICATIONS IN DNA AND HISTONES. THE COMBINATION OF THESE MODIFICATIONS CHANGES THE PHENOTYPE OF THE MDB FORMING HEPATOCYTES, AS INDICATED BY THE MARKER FAT10. THESE EPIGENETIC MODIFICATIONS ARE PARTIALLY PREVENTED BY ADDING TO THE DIET S-ADENOSYLMETHIONINE (SAME) OR BETAINE, BOTH METHYL DONORS. THE EXPRESSION OF THREE IMPRINTED NCRNA GENES WAS FOUND TO CHANGE IN MDB FORMING HEPATOCYTES, WHICH IS THE SUBJECT OF THIS REPORT. NCRNA EXPRESSION WAS QUANTITATED BY REAL-TIME PCR AND RNA FISH IN LIVER SECTIONS. MICROARRAY ANALYSIS SHOWED THAT THE EXPRESSION OF THREE NCRNAS WAS REGULATED BY DDC: UP REGULATION OF H19, ANTISENSE IGF2R (AIR), AND DOWN REGULATION OF GTL2 (ALSO CALLED MEG3). S-ADENOSYLMETHIONINE (SAME) FEEDING PREVENTED THESE CHANGES. BETAINE, ANOTHER METHYL GROUP DONOR, PREVENTED ONLY H19 AND AIR UP REGULATION INDUCED BY DDC, ON MICROARRAYS. THE RESULTS OF THE SAME AND BETAINE GROUPS WERE CONFIRMED BY REAL-TIME PCR, EXCEPT FOR AIR EXPRESSION. AFTER 1 MONTH OF DRUG WITHDRAWAL, THE EXPRESSION OF THE THREE NCRNAS TENDED TOWARD CONTROL LEVELS OF EXPRESSION. LIVER TUMORS THAT DEVELOPED ALSO SHOWED UP REGULATION OF H19 AND AIR. THE RNA FISH APPROACH SHOWED THAT THE MDB FORMING CELLS' PHENOTYPE CHANGED THE LEVEL OF EXPRESSION OF AIR, H19 AND GTL2, COMPARED TO THE SURROUNDING CELLS. FURTHERMORE, OVER EXPRESSION OF H19 AND AIR WAS DEMONSTRATED IN TUMORS FORMED IN MICE WITHDRAWN FOR 9 MONTHS. THE DYSREGULATION OF NCRNA IN MDB FORMING LIVER CELLS HAS BEEN OBSERVED FOR THE FIRST TIME IN DRUG-PRIMED MICE ASSOCIATED WITH LIVER PRENEOPLASTIC FOCI AND TUMORS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11   853  30 CHOLINE, OTHER METHYL-DONORS AND EPIGENETICS. CHOLINE DIETARY INTAKE VARIES SUCH THAT MANY PEOPLE DO NOT ACHIEVE ADEQUATE INTAKES. DIET INTAKE OF CHOLINE CAN MODULATE METHYLATION BECAUSE, VIA BETAINE HOMOCYSTEINE METHYLTRANSFERASE (BHMT), THIS NUTRIENT (AND ITS METABOLITE, BETAINE) REGULATE THE CONCENTRATIONS OF S-ADENOSYLHOMOCYSTEINE AND S-ADENOSYLMETHIONINE. SOME OF THE EPIGENETIC MECHANISMS THAT MODIFY GENE EXPRESSION WITHOUT MODIFYING THE GENETIC CODE DEPEND ON THE METHYLATION OF DNA OR OF HISTONES; AND DIET AVAILABILITY OF CHOLINE AND OTHER METHYL-GROUP DONORS INFLUENCES BOTH OF THESE METHYLATIONS. EXAMPLES OF METHYL-DONOR MEDIATED EPIGENETIC EFFECTS INCLUDE THE CHANGES IN COAT COLOR AND BODY WEIGHT IN OFFSPRING WHEN PREGNANT AGOUTI MICE ARE FED HIGH CHOLINE, HIGH METHYL DIETS; THE CHANGES IN TAIL KINKING IN OFFSPRING WHEN PREGNANT AXIN(FU) MICE ARE FED HIGH CHOLINE, HIGH METHYL DIETS; THE CHANGES IN CDKN3 METHYLATION AND ALTERED BRAIN DEVELOPMENT THAT OCCURS IN OFFSPRING WHEN PREGNANT RODENTS ARE FED LOW CHOLINE DIETS. WHEN CHOLINE METABOLISM IS DISRUPTED BY DELETING THE GENE BHMT, DNA METHYLATION IS AFFECTED (ESPECIALLY IN A REGION OF CHROMOSOME 13), EXPRESSION OF SPECIFIC GENES IS SUPPRESSED, AND LIVER CANCERS DEVELOP. BETTER UNDERSTANDING OF HOW NUTRIENTS SUCH AS CHOLINE AND METHYL-DONORS INFLUENCE EPIGENETIC PROGRAMS HAS IMPORTANCE FOR OUR UNDERSTANDING OF NOT ONLY DEVELOPMENTAL ABNORMALITIES BUT ALSO FOR UNDERSTANDING THE ORIGINS OF CHRONIC DISEASES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12   558  33 B-VITAMIN DEPENDENT METHIONINE METABOLISM AND ALCOHOLIC LIVER DISEASE. CONVINCING EVIDENCE LINKS ABERRANT B-VITAMIN DEPENDENT HEPATIC METHIONINE METABOLISM TO THE PATHOGENESIS OF ALCOHOLIC LIVER DISEASE (ALD). THIS REVIEW FOCUSES ON THE ESSENTIAL ROLES OF FOLATE AND VITAMINS B6 AND B12 IN HEPATIC METHIONINE METABOLISM, THE CAUSES OF THEIR DEFICIENCIES AMONG CHRONIC ALCOHOLIC PERSONS, AND HOW THEIR DEFICIENCIES TOGETHER WITH CHRONIC ALCOHOL EXPOSURE IMPACT ON ABERRANT METHIONINE METABOLISM IN THE PATHOGENESIS OF ALD. FOLATE IS THE DIETARY TRANSMETHYLATION DONOR FOR THE PRODUCTION OF S-ADENOSYLMETHIONINE (SAM), WHICH IS THE SUBSTRATE FOR ALL METHYLTRANSFERASES THAT REGULATE GENE EXPRESSIONS IN PATHWAYS OF LIVER INJURY, AS WELL AS A REGULATOR OF THE TRANSSULFURATION PATHWAY THAT IS ESSENTIAL FOR PRODUCTION OF GLUTATHIONE (GSH), THE PRINCIPAL ANTIOXIDANT FOR DEFENSE AGAINST OXIDATIVE LIVER INJURY. VITAMIN B12 REGULATES TRANSMETHYLATION REACTIONS FOR SAM PRODUCTION AND VITAMIN B6 REGULATES TRANSSULFURATION REACTIONS FOR GSH PRODUCTION. FOLATE DEFICIENCY ACCELERATES THE EXPERIMENTAL DEVELOPMENT OF ALD IN ETHANOL-FED ANIMALS WHILE REDUCING LIVER SAM LEVELS WITH RESULTANT ABNORMAL GENE EXPRESSION AND DECREASED PRODUCTION OF ANTIOXIDANT GSH. THROUGH ITS EFFECTS ON FOLATE METABOLISM, REDUCED SAM ALSO IMPAIRS NUCLEOTIDE BALANCE WITH RESULTANT INCREASED DNA STRAND BREAKS, OXIDATION, HEPATOCELLULAR APOPTOSIS, AND RISK OF CARCINOGENESIS. THE REVIEW ENCOMPASSES REFERENCED STUDIES ON MECHANISMS FOR PERTURBATIONS OF METHIONINE METABOLISM IN ALD, EVIDENCE FOR ALTERED GENE EXPRESSIONS AND THEIR EPIGENETIC REGULATION IN THE PATHOGENESIS OF ALD, AND CLINICAL STUDIES ON POTENTIAL PREVENTION AND TREATMENT OF ALD BY CORRECTION OF METHIONINE METABOLISM WITH SAM.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13  1030  34 CIRCULATING PLASMA MICRORNAS DYSREGULATION AND METABOLIC ENDOTOXEMIA INDUCED BY A HIGH-FAT HIGH-SATURATED DIET. HIGH-FAT DIET INCREASE TWO TO THREE TIMES THE PLASMA LIPOPOLYSACCHARIDE (LPS) LEVELS AND INDUCE SUBCLINICAL INFLAMMATION. DIET CAN MODIFY GENE EXPRESSION DUE TO EPIGENETIC PROCESSES RELATED TO MICRORNAS (MIRNAS). MICRORNAS (MIRNAS) PLAY IMPORTANT ROLE IN THE POST-TRANSCRIPTIONAL MECHANISMS INVOLVED IN REGULATION OF EXPRESSION OF GENES RELATED TO THE INFLAMMATORY RESPONSE. ALSO, DIET CAN INDIRECTLY INDUCE POST-TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION BY MIRNAS, WHICH MAY AFFECT THE RISK FOR THE DEVELOPMENT OF CHRONIC DISEASES. OBJECTIVE: THIS STUDY INVESTIGATED THE EFFECT OF HIGH-FAT HIGH-SATURATED MEAL INGESTION ON PLASMA MIRNA EXPRESSION AND LPS LEVELS DURING THE POSTPRANDIAL PERIOD IN HEALTHY WOMEN. METHODS: AN INTERVENTIONAL STUDY WAS CARRIED OUT IN WHICH A HIGH-FAT BREAKFAST (1067.45 KCAL), COMPOSED MAINLY OF SATURATED FATTY ACIDS (56 G), AND 500 ML OF WATER, WAS OFFERED. BLOOD SAMPLES WERE COLLECTED AT BASELINE AND 1, 3 AND 5 H AFTER MEAL INTAKE. THE STUDIED POPULATION CONSISTED OF HEALTHY WOMEN (N = 11), AGED BETWEEN 20 AND 40 YEARS, AND BODY MASS INDEX (BMI) BETWEEN 18.5 AND 25 KG/M(2). PLASMA LEVELS OF LIPID PROFILE, CYTOKINES, ADHESION MOLECULES, AND LPS WERE MEASURED AT THE 3 TIME POINTS. A PROFILE OF 752 HUMAN PLASMA MIRNA EXPRESSION WAS ANALYZED BY REAL-TIME PCR ASSAY. THESE ANALYZES WERE PERFORMED FOR ALL BLOOD COLLECTION TIME-POINTS. RESULTS: EXPRESSION PROFILE ANALYSIS REVEALED 33 DIFFERENTIALLY EXPRESSED PLASMA CIRCULATING MIRNAS COMPARED TO THAT OF THE CONTROL GROUP. MIR-145-5P AND MIR-200 WERE DIFFERENTIALLY MODULATED IN ALL TIME-POINTS POST MEAL CONSUMPTION. IN ADDITION, THERE WAS A SIGNIFICANT INCREASE IN PLASMA LPS, TRIGLYCERIDES, MYRISTIC AND PALMITIC SATURATED FATTY ACIDS LEVELS AT THE 3 TIME-POINTS IN COMPARISON WITH THE CONTROL BASAL LEVELS. WE ALSO OBSERVED INCREASED LEVELS OF THE PLASMA TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) CYTOKINE AND THE VASCULAR CELL ADHESION MOLECULE 1 (VCAM-1) LEVELS AFTER 5 H POST MEAL INGESTION. CONCLUSION: INGESTION OF HIGH-FAT HIGH-SATURATED MEAL WAS ABLE TO INDUCE METABOLIC ENDOTOXEMIA AND INCREASE THE EXPRESSION OF PRO-INFLAMMATORY MOLECULES SUCH AS TNF-ALPHA AND VCAM-1, AS WELL AS MODULATING CIRCULATING MIRNAS POSSIBLY CONTROLLING INFLAMMATORY AND LIPID METABOLISM PROTEINS AT THE POSTPRANDIAL PERIOD.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  4683  33 NEW PERSPECTIVES ON FOLATE TRANSPORT IN RELATION TO ALCOHOLISM-INDUCED FOLATE MALABSORPTION--ASSOCIATION WITH EPIGENOME STABILITY AND CANCER DEVELOPMENT. FOLATES ARE MEMBERS OF THE B-CLASS OF VITAMINS, WHICH ARE REQUIRED FOR THE SYNTHESIS OF PURINES AND PYRIMIDINES, AND FOR THE METHYLATION OF ESSENTIAL BIOLOGICAL SUBSTANCES, INCLUDING PHOSPHOLIPIDS, DNA, AND NEUROTRANSMITTERS. FOLATES CANNOT BE SYNTHESIZED DE NOVO BY MAMMALS; HENCE, AN EFFICIENT INTESTINAL ABSORPTION PROCESS IS REQUIRED. INTESTINAL FOLATE TRANSPORT IS CARRIER-MEDIATED, PH-DEPENDENT AND ELECTRONEUTRAL, WITH SIMILAR AFFINITY FOR OXIDIZED AND REDUCED FOLIC ACID DERIVATIVES. THE VARIOUS TRANSPORTERS, I.E. REDUCED FOLATE CARRIER, PROTON-COUPLED FOLATE TRANSPORTER, FOLATE-BINDING PROTEIN, AND ORGANIC ANION TRANSPORTERS, ARE INVOLVED IN THE FOLATE TRANSPORT PROCESS IN VARIOUS TISSUES. ANY IMPAIRMENT IN UPTAKE OF FOLATE CAN LEAD TO A STATE OF FOLATE DEFICIENCY, THE MOST PREVALENT VITAMIN DEFICIENCY IN WORLD, AFFECTING 10% OF THE POPULATION IN THE USA. SUCH IMPAIRMENTS IN FOLATE TRANSPORT OCCUR IN A VARIETY OF CONDITIONS, INCLUDING CHRONIC USE OF ETHANOL, SOME INBORN HEREDITARY DISORDERS, AND CERTAIN DISEASES. AMONG THESE, ETHANOL INGESTION HAS BEEN THE MAJOR CONTRIBUTOR TO FOLATE DEFICIENCY. ETHANOL-ASSOCIATED FOLATE DEFICIENCY CAN DEVELOP BECAUSE OF DIETARY INADEQUACY, INTESTINAL MALABSORPTION, ALTERED HEPATOBILIARY METABOLISM, ENHANCED COLONIC METABOLISM, AND INCREASED RENAL EXCRETION. ETHANOL REDUCES THE INTESTINAL AND RENAL UPTAKE OF FOLATE BY ALTERING THE BINDING AND TRANSPORT KINETICS OF FOLATE TRANSPORT SYSTEMS. ALSO, ETHANOL REDUCES THE EXPRESSION OF FOLATE TRANSPORTERS IN BOTH INTESTINE AND KIDNEY, AND THIS MIGHT BE A CONTRIBUTING FACTOR FOR FOLATE MALABSORPTION, LEADING TO FOLATE DEFICIENCY. THE MAINTENANCE OF INTRACELLULAR FOLATE HOMEOSTASIS IS ESSENTIAL FOR THE ONE-CARBON TRANSFER REACTIONS NECESSARY FOR DNA SYNTHESIS AND BIOLOGICAL METHYLATION REACTIONS. DNA METHYLATION IS AN IMPORTANT EPIGENETIC DETERMINANT IN GENE EXPRESSION, IN THE MAINTENANCE OF DNA INTEGRITY AND STABILITY, IN CHROMOSOMAL MODIFICATIONS, AND IN THE DEVELOPMENT OF MUTATIONS. ETHANOL, A TOXIN THAT IS CONSUMED REGULARLY, HAS BEEN FOUND TO AFFECT THE METHYLATION OF DNA. IN ADDITION TO ITS EFFECT ON DNA METHYLATION DUE TO FOLATE DEFICIENCY, ETHANOL COULD DIRECTLY EXERT ITS EFFECT THROUGH ITS INTERACTION WITH ONE-CARBON METABOLISM, IMPAIRMENT OF METHYL GROUP SYNTHESIS, AND AFFECTING THE ENZYMES REGULATING THE SYNTHESIS OF S-ADENOSYLMETHIONINE, THE PRIMARY METHYL GROUP DONOR FOR MOST BIOLOGICAL METHYLATION REACTIONS. THUS, ETHANOL PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF SEVERAL DISEASES THROUGH ITS POTENTIAL ABILITY TO MODULATE THE METHYLATION OF BIOLOGICAL MOLECULES. THIS REVIEW DISCUSSES THE UNDERLYING MECHANISM OF FOLATE MALABSORPTION IN ALCOHOLISM, THE MECHANISM OF METHYLATION-ASSOCIATED SILENCING OF GENES, AND HOW THE INTERACTION BETWEEN ETHANOL AND FOLATE DEFICIENCY AFFECTS THE METHYLATION OF GENES, THEREBY MODULATING EPIGENOME STABILITY AND THE RISK OF CANCER.	2009	

15  2156  42 EPIGENETIC MECHANISMS ARE INVOLVED IN THE REGULATION OF ETHANOL CONSUMPTION IN MICE. BACKGROUND: REPEATED ALCOHOL EXPOSURE IS KNOWN TO INCREASE SUBSEQUENT ETHANOL CONSUMPTION IN MICE. HOWEVER, THE UNDERLYING MECHANISMS HAVE NOT BEEN FULLY ELUCIDATED. ONE POSTULATED MECHANISM INVOLVES EPIGENETIC MODIFICATIONS, INCLUDING HISTONE MODIFICATIONS AND DNA METHYLATION OF RELEVANT GENES SUCH AS NR2B OR BDNF. METHODS: TO INVESTIGATE THE ROLE OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF ALCOHOL DRINKING BEHAVIOR, AN ESTABLISHED CHRONIC INTERMITTENT ETHANOL EXPOSURE REINFORCED ETHANOL DRINKING MOUSE MODEL WITH VAPOR INHALATION OVER TWO 9-DAY TREATMENT REGIMENS WAS USED. THE DNA METHYLTRANSFERASE INHIBITOR, 5-AZACYTIDINE OR THE HISTONE DEACETYLASE INHIBITOR, TRICHOSTATIN A WAS ADMINISTERED (INTRAPERITONEALLY) TO C57BL/6 MICE 30 MIN BEFORE DAILY EXPOSURE TO CHRONIC INTERMITTENT ETHANOL. CHANGES IN ETHANOL CONSUMPTION WERE MEASURED USING THE 2-BOTTLE CHOICE TEST. RESULTS: THE RESULTS INDICATED THAT SYSTEMIC ADMINISTRATION OF TRICHOSTATIN A (2.5 MICROG/G) FACILITATED CHRONIC INTERMITTENT ETHANOL-INDUCED ETHANOL DRINKING, BUT SYSTEMIC ADMINISTRATION OF 5-AZACYTIDINE (2 MICROG/G) DID NOT CAUSE THE SAME EFFECT. HOWEVER, WHEN 5-AZACYTIDINE WAS ADMINISTERED BY INTRACEREBROVENTRICULAR INJECTION, IT FACILITATED CHRONIC INTERMITTENT ETHANOL-INDUCED ETHANOL DRINKING. FURTHERMORE, THE INCREASED DRINKING CAUSED BY CHRONIC INTERMITTENT ETHANOL WAS PREVENTED BY INJECTION OF A METHYL DONOR, S-ADENOSYL-L-METHIONINE. TO PROVIDE EVIDENCE THAT CHRONIC INTERMITTENT ETHANOL- OR TRICHOSTATIN A-INDUCED DNA DEMETHYLATION AND HISTONE MODIFICATIONS OF THE NR2B PROMOTER MAY UNDERLIE THE ALTERED ETHANOL CONSUMPTION, WE EXAMINED EPIGENETIC MODIFICATIONS AND NR2B EXPRESSION IN THE PREFRONTAL CORTEX OF THESE MICE. CHRONIC INTERMITTENT ETHANOL OR TRICHOSTATIN A DECREASED DNA METHYLATION AND INCREASED HISTONE ACETYLATION IN THE NR2B GENE PROMOTER, AS WELL AS MRNA LEVELS OF NR2B IN THESE MICE. CONCLUSIONS: TAKEN TOGETHER, THESE RESULTS INDICATE THAT EPIGENETIC MODIFICATIONS ARE INVOLVED IN REGULATING ETHANOL DRINKING BEHAVIOR, PARTIALLY THROUGH ALTERING NR2B EXPRESSION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16   614  44 BINGE ALCOHOL-INDUCED MICROVESICULAR LIVER STEATOSIS AND INJURY ARE ASSOCIATED WITH DOWN-REGULATION OF HEPATIC HDAC 1, 7, 9, 10, 11 AND UP-REGULATION OF HDAC 3. BACKGROUND: BINGE, AS WELL AS CHRONIC, ALCOHOL CONSUMPTION AFFECTS GLOBAL HISTONE ACETYLATION LEADING TO CHANGES IN GENE EXPRESSION. IT IS BECOMING INCREASINGLY EVIDENT THAT THESE HISTONE-ASSOCIATED EPIGENETIC MODIFICATIONS PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF ALCOHOL-MEDIATED HEPATIC INJURY. METHODS: C57BL/6 MICE WERE GAVAGED 3 TIMES (12-HOUR INTERVALS) WITH ETHANOL (ETOH; 4.5 G/KG). HEPATIC HISTONE DEACETYLASE (HDAC) MRNAS WERE ASSESSED BY QRT-PCR. TOTAL HDAC ACTIVITY WAS ESTIMATED BY A COLORIMETRIC HDAC ACTIVITY/INHIBITION ASSAY. HISTONE ACETYLATION LEVELS WERE EVALUATED BY WESTERN BLOT. LIVER STEATOSIS AND INJURY WERE EVALUATED BY HISTOPATHOLOGY, PLASMA AMINOTRANSFERASE (ALT) ACTIVITY, AND LIVER TRIGLYCERIDE ACCUMULATION. EXPRESSION OF FATTY ACID SYNTHASE (FAS) AND CARNITINE PALMITOYL TRANSFERASE 1A (CPT1A) WAS ALSO EXAMINED. HDAC 9 ASSOCIATION WITH FAS PROMOTER WAS ANALYZED. RESULTS: BINGE ALCOHOL EXPOSURE RESULTED IN ALTERATIONS OF HEPATIC HDAC MRNA LEVELS. DOWN-REGULATION OF HDAC CLASS I (HDAC 1), CLASS II (HDAC 7, 9, 10), AND CLASS IV (HDAC 11) AND UP-REGULATION OF HDAC CLASS I (HDAC 3) GENE EXPRESSION WERE OBSERVED. CORRESPONDENT TO THE DECREASE IN HDAC ACTIVITY, AN INCREASE IN HEPATIC HISTONE ACETYLATION WAS OBSERVED. THESE MOLECULAR EVENTS WERE ASSOCIATED WITH MICROVESICULAR HEPATIC STEATOSIS AND INJURY CHARACTERIZED BY INCREASED HEPATIC TRIGLYCERIDES (48.02 +/- 3.83 VS. 19.90 +/- 3.48 MG/G LIVER, P < 0.05) AND ELEVATED PLASMA ALT ACTIVITY (51.98 +/- 6.91 VS. 20.8 +/- 0.62 U/L, P < 0.05). HEPATIC STEATOSIS WAS ASSOCIATED WITH AN INCREASE IN FAS AND A DECREASE IN CPT1A MRNA AND PROTEIN EXPRESSION. FAS PROMOTER ANALYSIS REVEALED THAT BINGE ETOH TREATMENT DECREASED HDAC 9 OCCUPANCY AT THE FAS PROMOTER RESULTING IN ITS TRANSCRIPTIONAL ACTIVATION. CONCLUSIONS: DEREGULATION OF HEPATIC HDAC EXPRESSION LIKELY PLAYS A MAJOR ROLE IN THE BINGE ALCOHOL-INDUCED HEPATIC STEATOSIS AND LIVER INJURY BY AFFECTING LIPOGENESIS AND FATTY ACID BETA-OXIDATION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  3841  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  2590  38 EPIGENETICS OF PROTEASOME INHIBITION IN THE LIVER OF RATS FED ETHANOL CHRONICALLY. AIM: TO EXAMINE THE EFFECTS OF ETHANOL-INDUCED PROTEASOME INHIBITION, AND THE EFFECTS OF PROTEASOME INHIBITION IN THE REGULATION OF EPIGENETIC MECHANISMS. METHODS: RATS WERE FED ETHANOL FOR 1 MO USING THE TSUKAMOTO-FRENCH MODEL AND WERE COMPARED TO RATS GIVEN THE PROTEASOME INHIBITOR PS-341 (BORTEZOMIB, VELCADE(TM)) BY INTRAPERITONEAL INJECTION. MICROARRAY ANALYSIS AND REAL TIME PCR WERE PERFORMED AND PROTEASOME ACTIVITY ASSAYS AND WESTERN BLOT ANALYSIS WERE PERFORMED USING ISOLATED NUCLEI. RESULTS: CHRONIC ETHANOL FEEDING CAUSED A SIGNIFICANT INHIBITION OF THE UBIQUITIN PROTEASOME PATHWAY IN THE NUCLEUS, WHICH LED TO CHANGES IN THE TURNOVER OF TRANSCRIPTIONAL FACTORS, HISTONE-MODIFYING ENZYMES, AND, THEREFORE, AFFECTED EPIGENETIC MECHANISMS. CHRONIC ETHANOL FEEDING WAS RELATED TO AN INCREASE IN HISTONE ACETYLATION, AND IT IS HYPOTHESIZED THAT THE PROTEASOME PROTEOLYTIC ACTIVITY REGULATED HISTONE MODIFICATIONS BY CONTROLLING THE STABILITY OF HISTONE MODIFYING ENZYMES, AND, THEREFORE, REGULATED THE CHROMATIN STRUCTURE, ALLOWING EASY ACCESS TO CHROMATIN BY RNA POLYMERASE, AND, THUS, PROPER GENE EXPRESSION. PROTEASOME INHIBITION BY PS-341 INCREASED HISTONE ACETYLATION SIMILAR TO CHRONIC ETHANOL FEEDING. IN ADDITION, PROTEASOME INHIBITION CAUSED DRAMATIC CHANGES IN HEPATIC REMETHYLATION REACTIONS AS THERE WAS A SIGNIFICANT DECREASE IN THE ENZYMES RESPONSIBLE FOR THE REGENERATION OF S-ADENOSYLMETHIONINE, AND, IN PARTICULAR, A SIGNIFICANT DECREASE IN THE BETAINE-HOMOCYSTEINE METHYLTRANSFERASE ENZYME. THIS SUGGESTED THAT HYPOMETHYLATION WAS ASSOCIATED WITH PROTEASOME INHIBITION, AS INDICATED BY THE DECREASE IN HISTONE METHYLATION. CONCLUSION: THE ROLE OF PROTEASOME INHIBITION IN REGULATING EPIGENETIC MECHANISMS, AND ITS LINK TO LIVER INJURY IN ALCOHOLIC LIVER DISEASE, IS THUS A PROMISING APPROACH TO STUDY LIVER INJURY DUE TO CHRONIC ETHANOL CONSUMPTION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
19  6220  28 THE KIDNEY IS THE MAJOR SITE OF S-ADENOSYLHOMOCYSTEINE DISPOSAL IN HUMANS. S-ADENOSYLHOMOCYSTEINE (SAH), THE METABOLIC PRECURSOR OF HOMOCYSTEINE IN THE BODY, IS A POTENT INHIBITOR OF METHYLATION REACTIONS. SEVERAL METHYLATION REACTIONS PLAY A MAJOR ROLE IN EPIGENETIC REGULATION OF PROTEIN EXPRESSION, ATHEROSCLEROSIS, AND CANCER DEVELOPMENT. HERE WE STUDIED THE MECHANISMS RESPONSIBLE FOR THE MAINTENANCE OF CIRCULATING SAH LEVELS BY MEASUREMENT OF THE ARTERIO-VENOUS DIFFERENCES ACROSS THE KIDNEY, SPLANCHNIC ORGANS, AND THE LUNG IN HUMANS. THE LUNGS DID NOT REMOVE OR ADD ANY CIRCULATING SAH, WHEREAS THE LIVER RELEASED IT INTO THE HEPATIC VEINS. THE KIDNEY EXTRACTED 40% OF SAH AND THE SAH ARTERIO-VENOUS DIFFERENCE ACROSS THE KIDNEY WAS DIRECTLY AND SIGNIFICANTLY RELATED TO ITS ARTERIAL LEVELS. THUS, THE KIDNEY PLAYS A MAJOR ROLE IN MAINTAINING SAH LEVELS AND MAY, INDIRECTLY, CONTROL TISSUE TRANSMETHYLATION REACTIONS. OUR FINDINGS OF A PIVOTAL ROLE FOR THE HUMAN KIDNEY IN SULFUR AMINO ACID METABOLISM MAY ALSO ACCOUNT FOR THE INCREASED PLASMA LEVELS OF SAH IN PATIENTS WITH CHRONIC KIDNEY DISEASES.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20  1800  28 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