1   853 117 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2   872  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3  4214  43 METHIONINE METABOLISM IN YUCATAN MINIATURE SWINE. METHIONINE IS AN ESSENTIAL AMINO ACID WHICH WHEN NOT INCORPORATED INTO PROTEIN, CAN BE CONVERTED TO S-ADENOSYLMETHIONINE, THE UNIVERSAL METHYL DONOR IN OVER 200 TRANSMETHYLATION REACTIONS, WHICH INCLUDE CREATINE AND PHOSPHATIDYLCHOLINE (PC) SYNTHESIS, AS WELL AS DEOXYRIBONUCLEIC ACID (DNA) METHYLATION. FOLLOWING TRANSMETHYLATION, HOMOCYSTEINE IS FORMED, WHICH CAN BE CONVERTED TO CYSTEINE VIA TRANSSULFURATION OR REMETHYLATED TO METHIONINE BY RECEIVING A METHYL GROUP FROM FOLATE OR BETAINE. CHANGES TO METHYL GROUP AVAILABILITY IN UTERO CAN LEAD TO PERMANENT CHANGES IN EPIGENETIC PATTERNS OF DNA METHYLATION, WHICH HAS BEEN IMPLICATED IN "FETAL PROGRAMMING", A PHENOMENON ASSOCIATED WITH POOR NUTRITION DURING FETAL DEVELOPMENT THAT RESULTS IN LOW BIRTH WEIGHT AND DISEASE IN LATER LIFE. IT HAS BEEN SHOWN THAT PROGRAMMING CAN ALSO OCCUR IN THE NEONATE. OUR GLOBAL OBJECTIVE WAS TO UNDERSTAND HOW THE VARIABILITY OF NUTRIENTS INVOLVED IN METHIONINE METABOLISM CAN AFFECT METHIONINE AND METHYL GROUP AVAILABILITY. WE HYPOTHESIZE THAT NUTRIENTS THAT CONVERGE ON METHIONINE METABOLISM CAN AFFECT METHIONINE AVAILABILITY FOR ITS VARIOUS FUNCTIONS. IN THIS THESIS, WE USED INTRAUTERINE GROWTH RESTRICTED (IUGR) PIGLETS TO INVESTIGATE WHETHER A GLOBAL NUTRITIONAL INSULT IN UTERO CAN LEAD TO A PERTURBED METHIONINE METABOLISM. OUR RESULTS DEMONSTRATE THAT IUGR PIGLETS HAVE A LOWER CAPACITY TO DISPOSE OF HOMOCYSTEINE VIA BOTH TRANSSULFURATION AND REMETHYLATION PATHWAYS, AS WELL AS A LOWER INCORPORATION OF METHYL GROUPS INTO PC. THE SECOND OBJECTIVE OF THIS THESIS WAS TO DETERMINE WHETHER VARIATION IN METHIONINE SUPPLY AND DEMAND CAN AFFECT METHIONINE AVAILABILITY. WE DEMONSTRATED THAT STIMULATING EITHER ACUTE OR CHRONIC CREATINE SYNTHESIS LEADS TO LOWER METHYL INCORPORATION INTO PROTEIN AND PC IN PIGS. FURTHERMORE, WHEN METHIONINE IS LIMITING, SUPPLEMENTATION WITH EITHER FOLATE OR BETAINE LEADS TO HIGHER METHIONINE AVAILABILITY FOR PROTEIN SYNTHESIS. FINALLY, BECAUSE CREATINE IS INCREASINGLY BEING UTILIZED AS AN ERGOGENIC AND NEUROPROTECTIVE SUPPLEMENT, WE WANTED TO DETERMINE WHETHER PROVISION OF THE CREATINE PRECURSOR, GUANIDINOACETATE (GAA), COULD EFFECTIVELY INCREASE TISSUE CREATINE STORES. WE SHOWED THAT 2.5 WEEKS OF SUPPLEMENTATION WITH GAA IS MORE EFFECTIVE THAN CREATINE AT INCREASING HEPATIC AND MUSCLE CREATINE STORES. THE RESULTS OF THIS THESIS DEMONSTRATE THAT THE PRESENCE OF IUGR, AN INCREASED DEMAND FOR CREATINE SYNTHESIS, OR THE SUPPLEMENTATION WITH REMETHYLATION NUTRIENTS CAN EACH AFFECT METHIONINE AVAILABILITY; ALL ARE IMPORTANT WHEN CONSIDERING NEONATAL NUTRIENT REQUIREMENTS. FURTHERMORE, ALTHOUGH GAA IS EFFECTIVE AT INCREASING LEVELS OF TISSUE CREATINE, HIGHER GAA METHYLATION CAN LIMIT METHIONINE AVAILABILITY FOR GROWTH AND SYNTHESIS OF PC.	2016	

4  6310  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5  4086  37 MATERNAL OBESITY DISRUPTS THE METHIONINE CYCLE IN BABOON PREGNANCY. MATERNAL INTAKE OF DIETARY METHYL-MICRONUTRIENTS (E.G. FOLATE, CHOLINE, BETAINE AND VITAMIN B-12) DURING PREGNANCY IS ESSENTIAL FOR NORMAL MATERNAL AND FETAL METHIONINE METABOLISM, AND IS CRITICAL FOR IMPORTANT METABOLIC PROCESSES INCLUDING THOSE INVOLVED IN DEVELOPMENTAL PROGRAMMING. MATERNAL OBESITY AND NUTRIENT EXCESS DURING PREGNANCY INFLUENCE DEVELOPMENTAL PROGRAMMING POTENTIALLY PREDISPOSING ADULT OFFSPRING TO A VARIETY OF CHRONIC HEALTH PROBLEMS. IN THE PRESENT STUDY, WE HYPOTHESIZED THAT MATERNAL OBESITY WOULD DYSREGULATE THE MATERNAL AND FETAL METHIONINE CYCLE. TO TEST THIS HYPOTHESIS, WE DEVELOPED A NULLIPAROUS BABOON OBESITY MODEL FED A HIGH FAT, HIGH ENERGY DIET (HF-HED) PRIOR TO AND DURING GESTATION, AND EXAMINED METHIONINE CYCLE BIOMARKERS (E.G., CIRCULATING CONCENTRATIONS OF HOMOCYSTEINE, METHIONINE, CHOLINE, BETAINE, KEY AMINO ACIDS, FOLATE, AND VITAMIN B-12). ANIMALS WERE GROUP HOUSED ALLOWING FULL PHYSICAL ACTIVITY AND SOCIAL INTERACTION. MATERNAL PREPREGNANCY PERCENT BODY FAT WAS 5% IN CONTROLS AND 19% IN HF-HED MOTHERS, WHILE FETAL WEIGHT WAS 16% LOWER IN OFFSPRING OF HF-HED MOTHERS AT TERM. MATERNAL AND FETAL HOMOCYSTEINE WERE HIGHER, WHILE MATERNAL AND FETAL VITAMIN B-12 AND BETAINE WERE LOWER IN THE HF-HED GROUP. ELEVATIONS IN CIRCULATING MATERNAL FOLATE WERE EVIDENT IN THE HF-HED GROUP INDICATING IMPAIRED FOLATE METABOLISM (METHYL-TRAP) AS A CONSEQUENCE OF MATERNAL VITAMIN B-12 DEPLETION. FINALLY, FETAL METHIONINE, GLYCINE, SERINE, AND TAURINE WERE LOWER IN THE HF-HED FETUSES. THESE DATA SHOW THAT MATERNAL OBESITY DISTURBS THE METHIONINE CYCLE IN PRIMATE PREGNANCY, PROVIDING A MECHANISM FOR THE EPIGENETIC CHANGES OBSERVED AMONG OBESE PREGNANT WOMEN AND SUGGESTING DIAGNOSTIC AND THERAPEUTIC OPPORTUNITIES IN HUMAN PREGNANCIES COMPLICATED BY OBESITY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6  2792  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7   558  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8  1855  29 ELEVATION IN S-ADENOSYLHOMOCYSTEINE AND DNA HYPOMETHYLATION: POTENTIAL EPIGENETIC MECHANISM FOR HOMOCYSTEINE-RELATED PATHOLOGY. CHRONIC NUTRITIONAL DEFICIENCIES IN FOLATE, CHOLINE, METHIONINE, VITAMIN B-6 AND/OR VITAMIN B-12 CAN PERTURB THE COMPLEX REGULATORY NETWORK THAT MAINTAINS NORMAL ONE-CARBON METABOLISM AND HOMOCYSTEINE HOMEOSTASIS. GENETIC POLYMORPHISMS IN THESE PATHWAYS CAN ACT SYNERGISTICALLY WITH NUTRITIONAL DEFICIENCIES TO ACCELERATE METABOLIC PATHOLOGY ASSOCIATED WITH OCCLUSIVE HEART DISEASE, BIRTH DEFECTS AND DEMENTIA. A MAJOR UNANSWERED QUESTION IS WHETHER HOMOCYSTEINE IS CAUSALLY INVOLVED IN DISEASE PATHOGENESIS OR WHETHER HOMOCYSTEINEMIA IS SIMPLY A PASSIVE AND INDIRECT INDICATOR OF A MORE COMPLEX MECHANISM. S-ADENOSYLMETHIONINE AND S-ADENOSYLHOMOCYSTEINE (SAH), AS THE SUBSTRATE AND PRODUCT OF METHYLTRANSFERASE REACTIONS, ARE IMPORTANT METABOLIC INDICATORS OF CELLULAR METHYLATION STATUS. CHRONIC ELEVATION IN HOMOCYSTEINE LEVELS RESULTS IN PARALLEL INCREASES IN INTRACELLULAR SAH AND POTENT PRODUCT INHIBITION OF DNA METHYLTRANSFERASES. SAH-MEDIATED DNA HYPOMETHYLATION AND ASSOCIATED ALTERATIONS IN GENE EXPRESSION AND CHROMATIN STRUCTURE MAY PROVIDE NEW HYPOTHESES FOR PATHOGENESIS OF DISEASES RELATED TO HOMOCYSTEINEMIA.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9  1781  24 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  4747  25 NOVEL MODULATORS OF HEPATOSTEATOSIS, INFLAMMATION AND FIBROGENESIS. ALCOHOLIC STEATOSIS, INSTEAD OF BEING INNOCUOUS, PLAYS A CRITICAL ROLE IN LIVER INFLAMMATION AND FIBROGENESIS. THE SEVERITY OF FATTY LIVER IS GOVERNED BY THE CONCERTED BALANCE BETWEEN LIPID TRANSPORT, SYNTHESIS, AND DEGRADATION. WHEREAS SCAVENGER RECEPTOR CLASS B, TYPE I (SR-B1) IS CRITICAL FOR REVERSE CHOLESTEROL UPTAKE BY THE LIVER, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA) COACTIVATOR-1ALPHA AND -BETA (PGC1ALPHA AND PGC1BETA) ARE CRITICAL FOR LIPID DEGRADATION AND SYNTHESIS, RESPECTIVELY. BECAUSE BETAINE IS A LIPOTROPIC AGENT, WE HAVE EVALUATED ITS EFFECTS ON ALCOHOLIC STEATOSIS. BETAINE EFFECTIVELY PREVENTED CHRONIC ALCOHOL-MEDIATED (I) IMPAIRED SR-B1 GLYCOSYLATION, PLASMA MEMBRANE LOCALIZATION, AND CONSEQUENT IMPAIRED CHOLESTEROL TRANSPORT; AND (II) UP REGULATION OF PGC-1BETA, STEROL REGULATORY ELEMENT-BINDING PROTEIN 1C AND DOWNSTREAM LIPOGENIC GENES WITH CONCOMITANT INCREASED LIVER CHOLESTEROL, TRIGLYCERIDES AND HEPATIC LIPID SCORE. SIMILARLY, BECAUSE OF ITS ANTI-INFLAMMATORY AND ANTI-FIBROTIC EFFECTS IN OTHER ORGANS, WE EVALUATED THE PROTECTIVE EFFECTS OF THYMOSIN BETA4 (TBETA4) AGAINST CARBON TETRACHLORIDE (CCL4)-INDUCED HEPATOTOXICITY IN RAT. TBETA4 PREVENTED CCL4-INDUCED (I) NECROSIS, INFLAMMATORY INFILTRATION AND UP-REGULATION OF ALPHA1(2)COLLAGEN, ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), PLATELET DERIVED GROWTH FACTOR BETA (PDGF-BETA) RECEPTOR AND FIBRONECTIN MRNA EXPRESSION; (II) DOWN-REGULATION OF ADIPOGENIC GENE, PPARGAMMA AND THE UP-REGULATION OF EPIGENETIC REPRESSOR GENE, METHYL CPG BINDING PROTEIN 2 (MECP2) MRNA LEVELS, SUGGESTING THAT THE ANTI-FIBROGENIC ACTIONS OF TBETA4 INVOLVE THE PREVENTION OF TRANS-DIFFERENTIATION OF QUIESCENT HEPATIC STELLATE CELLS INTO MYO-FIBROBLASTS LARGELY BY UP-REGULATING PPARGAMMA AND BY DOWN-REGULATING MECP2 GENES. WE THEREFORE CONCLUDE THAT BETAINE AND TBETA4 CAN EFFECTIVELY PROTECT AGAINST ALCOHOLIC HEPATOSTEATOSIS AND HEPATIC FIBROGENESIS, RESPECTIVELY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11  3133  26 GLOBAL DNA HYPOMETHYLATION AND ITS CORRELATION TO THE BETAINE LEVEL IN PERIPHERAL BLOOD OF PATIENTS WITH SCHIZOPHRENIA. ACCUMULATING EVIDENCE SUGGESTS THAT ABERRANT EPIGENETIC REGULATION IS INVOLVED IN THE PATHOPHYSIOLOGY OF MAJOR PSYCHIATRIC DISORDERS SUCH AS SCHIZOPHRENIA (SZ) AND BIPOLAR DISORDER (BD). WE PREVIOUSLY SHOWED THAT THE PLASMA LEVEL OF BETAINE (N,N,N-TRIMETHYLGLYCINE), A METHYL-GROUP DONOR, WAS SIGNIFICANTLY DECREASED IN PATIENTS WITH FIRST EPISODE SCHIZOPHRENIA (FESZ). IN THIS STUDY, WE IDENTIFIED DECREASE OF GLOBAL DNA METHYLATION LEVEL IN FESZ (N = 24 PATIENTS VS N = 42 CONTROLS), AND FOUND THAT GLOBAL DNA METHYLATION LEVEL WAS INVERSELY CORRELATED WITH SCORES ON THE GLOBAL ASSESSMENT OF FUNCTIONING (GAF) SCALE, AND POSITIVELY CORRELATED WITH PLASMA BETAINE LEVEL. NOTABLY, CORRELATIONS BETWEEN LEVELS OF BETAINE AND ITS METABOLITES (N,N-DIMETHYLGLYCINE AND SARCOSINE, N-METHYLGLYCINE) WERE LOWER OR LOST IN FESZ PLASMA, BUT REMAINED HIGH IN CONTROLS. WE FURTHER EXAMINED GLOBAL DNA METHYLATION LEVELS IN PATIENTS WITH CHRONIC SZ (N = 388) AND BD (N = 414) AS WELL AS CONTROLS (N = 430), AND CONFIRMED SIGNIFICANT HYPOMETHYLATION AND DECREASED BETAINE LEVEL IN SZ. WE ALSO FOUND THAT PATIENTS WITH BD TYPE I, BUT NOT THOSE WITH BD TYPE II, SHOWED SIGNIFICANT GLOBAL HYPOMETHYLATION. THESE RESULTS SUGGEST THAT GLOBAL HYPOMETHYLATION ASSOCIATED WITH DECREASED BETAINE LEVEL IN BLOOD CELLS IS COMMON TO SZ AND BD, AND MAY REFLECT COMMON PATHOPHYSIOLOGY SUCH AS PSYCHOTIC SYMPTOMS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12  6361  36 THE ROLE OF INNATE IMMUNITY IN THE PATHOGENESIS OF PRENEOPLASIA IN DRUG-INDUCED CHRONIC HEPATITIS BASED ON A MOUSE MODEL. INNATE IMMUNITY FACTORS SUCH AS CONVERSION OF THE 26S PROTEASOME TO FORM THE IMMUNOPROTEASOME AND THE TOLL-LIKE RECEPTOR SIGNALING PATHWAYS ARE ACTIVATED IN CHRONIC HEPATITIS INDUCED BY THE CARCINOGENIC DRUG DDC. OVER TIME, PRENEOPLASTIC HEPATOCYTE PHENOTYPES APPEAR IN THE LIVER PARENCHYMA. THESE CHANGED HEPATOCYTES EXPAND IN NUMBER BECAUSE THEY HAVE A GROWTH ADVANTAGE OVER NORMAL HEPATOCYTES WHEN RESPONDING TO CHRONIC LIVER INJURY. THE CHANGED HEPATOCYTES CAN BE IDENTIFIED USING IMMUNOFLUORESCENT ANTIBODIES TO PRENEOPLASTIC CELLS E.G. FAT10/UBD, A2 MACROGLOBULIN, GLUTATHIONE TRANSPEPTIDASE, ALPHA FETOPROTEIN, GLYCIPAN 3, FAS, AND GAMMA GLUTAMYL TRANSPEPTIDASE. THE FORMATION OF THE PRENEOPLASTIC CELLS OCCURS CONCOMITANT WITH ACTIVATION OF THE TOLL-LIKE RECEPTOR SIGNALING PATHWAYS AND THE TRANSFORMATION OF THE 26S PROTEASOME TO FORM THE IMMUNOPROTEASOME. THIS TRANSFORMATION IS IN RESPONSE TO INTERFERON STIMULATING RESPONSE ELEMENT ON THE PROMOTER OF THE FAT10/UBD GENE. NFKAPPAB, ERK, P38 AND JNK ARE ALSO UP REGULATED. SPECIFIC INHIBITORS BLOCK THESE RESPONSES IN VITRO IN A MOUSE TUMOR CELL LINE EXPOSED TO INTERFERON GAMMA. MALLORY-DENK BODIES FORM IN THESE PRENEOPLASTIC CELLS, BECAUSE OF THE DEPLETION OF THE 26S PROTEASOME DUE TO FORMATION OF THE IMMUNOPROTEASOME. THUS, MDB FORMING CELLS ARE ALSO MARKERS OF THE PRENEOPLASTIC HEPATOCYTES. THE UBD POSITIVE PRENEOPLASTIC CELLS REGRESS WHEN THE LIVER INJURY INDUCED CHRONIC HEPATITIS SUBSIDES. WHEN THE DRUG DDC IS REFED TO MICE AND CHRONIC HEPATITIS IS ACTIVATED, THE PRENEOPLASTIC CELL POPULATION EXPANDS AND MALLORY-DENK BODIES RAPIDLY REFORM. THIS RESPONSE IS REMEMBERED BY THE PRENEOPLASTIC CELLS FOR AT LEAST FOUR MONTHS INDICATING THAT AN EPIGENETIC CELLULAR MEMORY HAS FORMED IN THE PRENEOPLASTIC CELLS. THIS PROLIFERATIVE RESPONSE IS PREVENTED BY FEEDING METHYL DONORS SUCH AS S-ADENOSYLMETHIONINE OR BETAINE. DRUG FEEDING REDUCES THE METHYLATION OF H(3) K4, 9, AND 27 AND THIS RESPONSE IS PREVENTED BY FEEDING THE METHYL DONORS. AFTER 8 TO 15MONTHS OF DRUG WITHDRAWAL IN MICE THE PRENEOPLASTIC LIVER CELLS PERSIST AS SINGLE OR SMALL CLUSTERS OF CELLS IN THE LIVER LOBULES. MULTIPLE LIVER TUMORS FORM, SOME OF WHICH ARE HEPATOCELLULAR CARCINOMAS. THE TUMORS IMMUNOSTAIN POSITIVELY FOR THE SAME PRENEOPLASTIC MARKERS AS THE PRENEOPLASTIC CELLS. SIMILAR CELLS ARE IDENTIFIED IN HUMAN CIRRHOSIS AND HEPATOCELLULAR CARCINOMA INDICATING THE RELEVANCE OF THE DRUG MODEL DESCRIBED HERE TO THE PRENEOPLASTIC CHANGES ASSOCIATED WITH HUMAN CHRONIC HEPATITIS AND HEPATOCELLULAR CARCINOMA.	2011	
                                                                                                                                                          
13  4069  30 MATERNAL CHRONIC FOLATE SUPPLEMENTATION AMELIORATES BEHAVIOR DISORDERS INDUCED BY PRENATAL HIGH-FAT DIET THROUGH METHYLATION ALTERATION OF BDNF AND GRIN2B IN OFFSPRING HIPPOCAMPUS. SCOPE: MATERNAL CONSUMPTION OF A HIGH-FAT DIET (HFD) DURING PREGNANCY INCREASES THE RISK OF BEHAVIORAL PROBLEMS. FOLATE PLAYS AN IMPORTANT ROLE IN NEUROPLASTICITY AND THE PRESERVATION OF NEURONAL INTEGRITY. THIS STUDY AIMS AT DETERMINING THE INFLUENCE OF DIETS SUPPLEMENTED WITH FOLATE ON OFFSPRING BEHAVIOR, AND THE MECHANISMS INVOLVED. METHODS AND RESULTS: FEMALE MICE WERE FED A CONTROL DIET, AN HFD, CONTROL DIET SUPPLEMENTED WITH FOLATE, OR AN HFD SUPPLEMENTED WITH FOLATE FOR 5 WEEKS BEFORE MATING. OPEN FIELD TASK AND ELEVATED PLUS MAZE ARE USED TO EVALUATE THE OFFSPRING BEHAVIORS. RESULTS SHOWED THAT OFFSPRING COGNITIVE PERFORMANCE AND ANXIETY-RELATED BEHAVIORS, INCLUDING THOSE RELATED TO OPEN FIELD EXPLORATION AND ELEVATED PLUS MAZE, WERE SIGNIFICANTLY IMPROVED WHEN DAMS WERE TREATED WITH FOLATE IN PREGNANCY. MOREOVER, THE MATERNAL FOLATE SUPPLEMENT DECREASED BDNF AND GRIN2B METHYLATION AND UPREGULATED THEIR EXPRESSIONS IN THE BRAIN OF OFFSPRING, WHICH WERE ASSOCIATED WITH DECREASING THE EXPRESSION OF DNA METHYLTRANSFERASES COMPARED WITH THOSE DAMS WERE TREATED ONLY HFD IN PREGNANCY. CONCLUSION: MATERNAL FOLATE SUPPLEMENTATION AMELIORATES BEHAVIOR DISORDERS INDUCED BY PRENATAL HIGH-FAT DIET. THE BENEFICIAL EFFECTS WERE ASSOCIATED WITH METHYLATION AND EXPRESSION ALTERATION OF BDNF AND GRIN2B GENES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14  4398  31 MODULATION OF DNA METHYLTRANSFERASE PROFILE BY METHYL DONOR STARVATION FOLLOWED BY GAMMA IRRADIATION. DNA METHYLATION IS AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, WHICH PLAYS AN ESSENTIAL ROLE IN MAINTAINING CELLULAR FUNCTION. ROLE OF ONE-CARBON TRANSFER AGENTS/METHYL DONORS NAMELY FOLATE, CHOLINE AND METHIONINE IN DNA METHYLATION HAS BEEN THE SUBJECT OF EXTENSIVE INVESTIGATION. THE METHYLATION PATTERN OF DNA IS ESTABLISHED DURING EMBRYOGENESIS BY DNA METHYLTRANSFERASE 3 (DNMT3) AND IS SUBSEQUENTLY MAINTAINED BY MAINTENANCE METHYLATION ACTIVITY OF THE ENZYME DNA METHYLTRANSFERASE 1 (DNMT1). IONIZING RADIATION IS KNOWN TO EXTENSIVELY DAMAGE THE DNA. SUFFICIENT DIETARY AVAILABILITY OF METHYL DONORS IS KNOWN TO CONTRIBUTE TOWARDS ONE-CARBON TRANSFER MEDIATED REPAIR OF DAMAGED DNA WHERE FOLATE IS INVOLVED IN NUCLEOTIDE BASE SYNTHESIS. IN THE PRESENT STUDY, MODIFICATION IN ACTIVITIES OF DNMT1 AND DNMT3 BY METHYL DONOR STARVATION FOLLOWED BY GAMMA-IRRADIATION WAS OBSERVED. ASSAYS WERE BASED ON THE CATALYTIC TRANSFER OF (3)H-METHYL GROUPS FROM S-ADENOSYL-L: -METHIONINE TO A DNA SUBSTRATE. EXPERIMENTS SHOWED A DOSE AND METHYL DONORS STARVATION DEPENDENT ATTENUATION IN DNMT1 ACTIVITY. ATTENUATION OF DNMT1 ACTIVITY WAS MOST SIGNIFICANT FOR DIET DEPRIVED OF ALL THE THREE-METHYL DONORS. NO SIGNIFICANT CHANGE IN NUCLEAR OR CYTOPLASMIC DNMT3 ACTIVITY WAS OBSERVED WHEN EITHER OR ALL THE THREE POSSIBLE SOURCE OF DIETARY METHYL GROUP SUPPLY WERE REMOVED. IONIZING RADIATION AND METHYL DONOR DEFICIENCY WERE OBSERVED TO ACT SYNERGISTICALLY TOWARDS INHIBITING DNMT1 ACTIVITY. PRESENT RESULTS SUGGESTED POSSIBILITY OF INTERACTION AMONG FOLATE, METHIONINE AND CHOLINE DEFICIENCY TO POTENTIATE SYMPTOMS OF IONIZING RADIATION STRESS. THESE ENZYMATIC MODIFICATIONS MIGHT CONTRIBUTE TO ALTERED DNA METHYLATION AFTER CHRONIC FEEDING OF METHYL DONOR FREE DIETS FOLLOWED BY GAMMA IRRADIATION. THESE RESULTS SUGGESTED THAT DIETARY AVAILABILITY OF METHYL DONORS AND GAMMA-RADIATION STRESS MIGHT SIGNIFICANTLY ALTER THE DNMT1 PROFILE.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15  6717  35 VITAMIN B SUPPLEMENTATION AND NUTRITIONAL INTAKE OF METHYL DONORS IN PATIENTS WITH CHRONIC KIDNEY DISEASE: A CRITICAL REVIEW OF THE IMPACT ON EPIGENETIC MACHINERY. CARDIOVASCULAR MORBIDITY AND MORTALITY ARE SEVERAL-FOLD HIGHER IN PATIENTS WITH ADVANCED CHRONIC KIDNEY DISEASE (CKD) AND END-STAGE RENAL DISEASE (ESRD) THAN IN THE GENERAL POPULATION. HYPERHOMOCYSTEINEMIA HAS UNDOUBTEDLY A CENTRAL ROLE IN SUCH A PROMINENT CARDIOVASCULAR BURDEN. THE LEVELS OF HOMOCYSTEINE ARE REGULATED BY METHYL DONORS (FOLATE, METHIONINE, CHOLINE, BETAINE), AND COFACTORS (VITAMIN B6, VITAMIN B12,). UREMIA-INDUCED HYPERHOMOCYSTEINEMIA HAS AS ITS MAIN TARGETS DNA METHYLTRANSFERASES, AND THIS LEADS TO AN ALTERED EPIGENETIC CONTROL OF GENES REGULATED THROUGH METHYLATION. IN RENAL PATIENTS, THE EPIGENETIC LANDSCAPE IS STRICTLY CORRELATED WITH THE UREMIC PHENOTYPE AND DEPENDENT ON DIETARY INTAKE OF MICRONUTRIENTS, INFLAMMATION, GUT MICROBIOME, INFLAMMATORY STATUS, OXIDATIVE STRESS, AND LIFESTYLE HABITS. ALL THESE FACTORS ARE KEY CONTRIBUTORS IN METHYLOME MAINTENANCE AND IN THE MODULATION OF GENE TRANSCRIPTION THROUGH DNA HYPO- OR HYPERMETHYLATION IN CKD. THIS IS AN OVERVIEW OF THE EPIGENETIC CHANGES RELATED TO DNA METHYLATION IN PATIENTS WITH ADVANCED CKD AND ESRD. WE EXPLORED THE CURRENTLY AVAILABLE DATA ON THE MOLECULAR DYSREGULATIONS RESULTING FROM ALTERED GENE EXPRESSION IN UREMIA. SPECIAL ATTENTION WAS PAID TO THE EFFICACY OF B-VITAMINS SUPPLEMENTATION AND DIETARY INTAKE OF METHYL DONORS ON HOMOCYSTEINE LOWERING AND CARDIOVASCULAR PROTECTION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  5587  34 ROLE OF S-ADENOSYLHOMOCYSTEINE IN CARDIOVASCULAR DISEASE AND ITS POTENTIAL EPIGENETIC MECHANISM. TRANSMETHYLATION REACTIONS UTILIZE S-ADENOSYLMETHIONINE (SAM) AS A METHYL DONOR AND ARE CENTRAL TO THE REGULATION OF MANY BIOLOGICAL PROCESSES: MORE THAN FIFTY SAM-DEPENDENT METHYLTRANSFERASES METHYLATE A BROAD SPECTRUM OF CELLULAR COMPOUNDS INCLUDING DNA, HISTONES, PHOSPHOLIPIDS AND OTHER SMALL MOLECULES. COMMON TO ALL SAM-DEPENDENT TRANSMETHYLATION REACTIONS IS THE RELEASE OF THE POTENT INHIBITOR S-ADENOSYLHOMOCYSTEINE (SAH) AS A BY-PRODUCT. SAH IS REVERSIBLY HYDROLYZED TO ADENOSINE AND HOMOCYSTEINE BY SAH HYDROLASE. HYPERHOMOCYSTEINEMIA IS AN INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR DISEASE. HOWEVER, A MAJOR UNANSWERED QUESTION IS IF HOMOCYSTEINE IS CAUSALLY INVOLVED IN DISEASE PATHOGENESIS OR SIMPLY A PASSIVE AND INDIRECT INDICATOR OF A MORE COMPLEX MECHANISM. A CHRONIC ELEVATION IN HOMOCYSTEINE LEVELS RESULTS IN A PARALLEL INCREASE IN INTRACELLULAR OR PLASMA SAH, WHICH IS A MORE SENSITIVE BIOMARKER OF CARDIOVASCULAR DISEASE THAN HOMOCYSTEINE AND SUGGESTS THAT SAH IS A CRITICAL PATHOLOGICAL FACTOR IN HOMOCYSTEINE-ASSOCIATED DISORDERS. PREVIOUS REPORTS INDICATE THAT SUPPLEMENTATION WITH FOLATE AND B VITAMINS EFFICIENTLY LOWERS HOMOCYSTEINE LEVELS BUT NOT PLASMA SAH LEVELS, WHICH POSSIBLY EXPLAINS THE FAILURE OF HOMOCYSTEINE-LOWERING VITAMINS TO REDUCE VASCULAR EVENTS IN SEVERAL RECENT CLINICAL INTERVENTION STUDIES. FURTHERMORE, MORE STUDIES ARE FOCUSING ON THE ROLE AND MECHANISMS OF SAH IN DIFFERENT CHRONIC DISEASES RELATED TO HYPERHOMOCYSTEINEMIA, SUCH AS CARDIOVASCULAR DISEASE, KIDNEY DISEASE, DIABETES, AND OBESITY. THIS REVIEW SUMMARIZES THE CURRENT ROLE OF SAH IN CARDIOVASCULAR DISEASE AND ITS EFFECT ON SEVERAL RELATED RISK FACTORS. IT ALSO EXPLORES POSSIBLE THE MECHANISMS, SUCH AS EPIGENETICS AND OXIDATIVE STRESS, OF SAH. THIS ARTICLE IS PART OF A DIRECTED ISSUE ENTITLED: EPIGENETIC DYNAMICS IN DEVELOPMENT AND DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17  5131  30 POSTWEANING DIETARY FOLATE DEFICIENCY PROVIDED THROUGH CHILDHOOD TO PUBERTY PERMANENTLY INCREASES GENOMIC DNA METHYLATION IN ADULT RAT LIVER. FOLATE PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF SEVERAL CHRONIC DISEASES BY ITS POTENTIAL ABILITY TO MODULATE DNA METHYLATION. WE HYPOTHESIZED THAT THE POSTWEANING PERIOD MIGHT BE A HIGHLY SUSCEPTIBLE PERIOD TO DIETARY FOLATE INTERVENTION FOR DNA METHYLATION PATTERNING. WE DETERMINED THE EFFECTS OF TIMING AND DURATION OF DIETARY FOLATE INTERVENTION PROVIDED DURING THE POSTWEANING PERIOD ON GENOMIC DNA METHYLATION IN ADULT RAT LIVER. IN STUDY 1, WEANLING RATS WERE RANDOMIZED TO RECEIVE AN AMINO ACID-DEFINED DIET CONTAINING 0 (DEFICIENT), 2 (CONTROL), OR 8 (SUPPLEMENTED) MG FOLIC ACID/KG UNTIL 8 WK OF AGE, AFTER WHICH ALL THE RATS WERE FED THE CONTROL DIET UNTIL 30 WK OF AGE. IN STUDY 2, WEANLING RATS WERE FED THE CONTROL DIET UNTIL 8 WK OF AGE AND THEN RANDOMIZED TO RECEIVE THE DIET CONTAINING 0, 2, OR 8 MG FOLIC ACID/KG UNTIL 30 WK OF AGE. IN STUDY 3, WEANLING RATS WERE RANDOMIZED TO RECEIVE THESE DIETS UNTIL 30 WK OF AGE. DIETARY FOLATE DEFICIENCY, BUT NOT SUPPLEMENTATION, PROVIDED DURING THE POSTWEANING PERIOD THROUGH CHILDHOOD TO PUBERTY SIGNIFICANTLY INCREASED GENOMIC DNA METHYLATION BY 34-48% (P < 0.04) IN RAT LIVER THAT PERSISTED INTO ADULTHOOD FOLLOWING A RETURN TO THE CONTROL DIET AT PUBERTY. IN CONTRAST, DIETARY FOLATE DEFICIENCY OR SUPPLEMENTATION CONTINUALLY IMPOSED AT WEANING OR AT PUBERTY DID NOT SIGNIFICANTLY AFFECT GENOMIC DNA METHYLATION IN ADULT RAT LIVER. OUR DATA SUGGEST THAT EARLY FOLATE NUTRITION DURING POSTNATAL DEVELOPMENT PLAYS AN IMPORTANT ROLE IN EPIGENETIC PROGRAMMING THAT CAN HAVE A PERMANENT EFFECT IN ADULTHOOD.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18  1140  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19   339  36 ALTERATIONS IN HOMOCYSTEINE METABOLISM AMONG ALCOHOL DEPENDENT PATIENTS--CLINICAL, PATHOBIOCHEMICAL AND GENETIC ASPECTS. ADDICTION RESEARCH FOCUSING ON HOMOCYSTEINE METABOLISM AND ITS ASSOCIATION WITH ASPECTS OF ALCOHOL DEPENDENCE HAS REVEALED IMPORTANT FINDINGS. RECENT LITERATURE ON THIS TOPIC HAS BEEN TAKEN INTO ACCOUNT FOR THE REVIEW PROVIDED. METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) IS A KEY ENZYME IN THE HOMOCYSTEINE METABOLISM. PLASMA HOMOCYSTEINE LEVELS ARE INFLUENCED BY THE SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) MTHFR C677T. BESIDES GENETIC FACTORS, ENVIRONMENTAL FACTORS HAVE AN IMPACT ON HOMOCYSTEINE PLASMA LEVELS TOO. THUS, CHRONIC ALCOHOL INTAKE IS ASSOCIATED WITH ELEVATED HOMOCYSTEINE PLASMA CONCENTRATIONS. ELEVATION OF PLASMA HOMOCYSTEINE CONCENTRATION IS CONSIDERED AS A PREDICTOR FOR THE OCCURRENCE OF ALCOHOL WITHDRAWAL SEIZURES AND--AS HOMOCYSTEINE IS A CARDIOVASCULAR RISK FACTOR--MIGHT CONTRIBUTE TO THE HIGHER RISK FOR MYOCARDIAL INFARCTION AMONG ALCOHOL DEPENDENT PATIENTS. HOMOCYSTEINE ACTS AS AN N-METHYL-D-ASPARTATE (NMDA) RECEPTOR AGONIST AND HAS EXCITOTOXIC EFFECTS. FURTHERMORE, IT HAS BEEN DEMONSTRATED THAT HOMOCYSTEINE HAS NEUROTOXIC EFFECTS ESPECIALLY ON DOPAMINERGIC NEURONS. AS THE REWARDING EFFECTS OF ALCOHOL ARE MEDIATED BY THE DOPAMINERGIC SYSTEM, A HOMOCYSTEINE-DEPENDENT IMPAIRMENT OF THE REWARD SYSTEM POSSIBLY LEADS TO AN ALTERED DRINKING BEHAVIOUR ACCORDING TO THE DEFICIT HYPOTHESIS OF ADDICTION. HOMOCYSTEINE IS INVOLVED IN THE METABOLISM OF METHYL GROUPS AND DNA-METHYLATION PLAYS A ROLE IN REGULATION OF GENE EXPRESSION. THEREFORE IT HAS BEEN SUGGESTED THAT HOMOCYSTEINE IS AN IMPORTANT EPIGENETIC FACTOR. IT REMAINS TO BE DETERMINED WHETHER ALCOHOL DEPENDENT PATIENTS BENEFIT FROM HOMOCYSTEINE LOWERING STRATEGIES, E.G., VIA SUPPLEMENTATION OF FOLATE, VITAMIN B6 AND B12. IN THIS RESPECT IT IS NOT CLEAR YET, IF A SUPPLEMENTATION THERAPY CAN REDUCE THE RISK FOR THE OCCURRENCE OF ALCOHOL WITHDRAWAL SEIZURES.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20  1833  33 EFFECTS OF METHYL DONOR DIETS ON INCISIONAL PAIN IN MICE. BACKGROUND: DIETARY SUPPLEMENTATION WITH METHYL DONORS CAN INFLUENCE THE PROGRAMMING OF EPIGENETIC PATTERNS RESULTING IN PERSISTENT ALTERATIONS IN DISEASE SUSCEPTIBILITY AND BEHAVIOR. HOWEVER, THE DIETARY EFFECTS OF METHYL DONORS ON PAIN HAVE NOT BEEN EXPLORED. IN THIS STUDY, WE EVALUATED THE EFFECTS OF DIETARY METHYL DONOR CONTENT ON PAIN RESPONSES IN MICE. METHODS: MALE AND FEMALE C57BL/6J MICE WERE TREATED WITH HIGH OR LOW METHYL DONOR DIETS EITHER IN THE PERINATAL PERIOD OR AFTER WEANING. MECHANICAL AND THERMAL NOCICEPTIVE SENSITIVITY WERE MEASURED BEFORE AND AFTER INCISION. RESULTS: MICE FED HIGH OR LOW METHYL DONOR DIETS DISPLAYED EQUAL WEIGHT GAIN OVER THE COURSE OF THE EXPERIMENTS. WHEN EXPOSED TO THESE DIETARY MANIPULATIONS IN THE PERINATAL PERIOD, ONLY MALE OFFSPRING OF DAMS FED A HIGH METHYL DONOR DIET DISPLAYED INCREASED MECHANICAL ALLODYNIA. HINDPAW INCISION IN THESE ANIMALS CAUSED ENHANCED NOCICEPTIVE SENSITIZATION, BUT DIETARY HISTORY DID NOT AFFECT THE DURATION OF SENSITIZATION. FOR MICE EXPOSED TO HIGH OR LOW METHYL DONOR DIETS AFTER WEANING, NO SIGNIFICANT DIFFERENCES WERE OBSERVED IN MECHANICAL OR THERMAL NOCICEPTIVE SENSITIVITY EITHER AT BASELINE OR IN RESPONSE TO HINDPAW INCISION. CONCLUSIONS: PERINATAL DIETARY FACTORS SUCH AS METHYL DONOR CONTENT MAY IMPACT PAIN EXPERIENCES IN LATER LIFE. THESE EFFECTS, HOWEVER, MAY BE SPECIFIC TO SEX AND PAIN MODALITY.	2013