1 1781 131 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 2 6220 31 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 3 3387 23 HOMOCYSTEINE ASSOCIATED GENOMIC DNA HYPERMETHYLATION IN PATIENTS WITH CHRONIC ALCOHOLISM. HIGHER PLASMA HOMOCYSTEINE CONCENTRATIONS CAN INFLUENCE GENOMIC DNA METHYLATION IN PERIPHERAL BLOOD CELLS. IN THE PRESENT CONTROLLED STUDY WE OBSERVED A SIGNIFICANT INCREASE (10%) OF GENOMIC DNA METHYLATION IN PATIENTS WITH ALCOHOLISM (T = -3.16, DF = 158, P = 0.002) WHICH WAS SIGNIFICANTLY ASSOCIATED WITH THEIR ELEVATED HOMOCYSTEINE LEVELS (MULTIPLE LINEAR REGRESSION, P < 0.001). SINCE METHYLATION OF DNA IS AN IMPORTANT EPIGENETIC FACTOR IN REGULATION OF GENE EXPRESSION THESE FINDINGS MAY HAVE IMPORTANT IMPLICATIONS FOR A POSSIBLE SUBSEQUENT DERANGEMENT OF EPIGENETIC CONTROL THESE PATIENTS. 2004 4 1193 39 CORRELATION OF CYP2R1 GENE PROMOTER METHYLATION WITH CIRCULATING VITAMIN D LEVELS AMONG HEALTHY ADULTS. BACKGROUND & OBJECTIVES: DESPITE BEING A TROPICAL COUNTRY, VITAMIN D DEFICIENCY IS HIGHLY PREVALENT IN INDIA WITH STUDIES INDICATING 40-99 PER CENT PREVALENCE. APART FROM CALCIUM AND PHOSPHATE METABOLISM, VITAMIN D IS INVOLVED IN CELL CYCLE REGULATION, CARDIOVASCULAR, HEPATOPROTECTION. THE METABOLISM OF VITAMIN D IS REGULATED BY VITAMIN D TOOL GENES (CYP2R1/CYP27B1/CYP24A1/VDR). THE PROMOTER REGIONS OF SOME OF THESE GENES HAVE CPG ISLANDS, MAKING THEM PRONE TO METHYLATION INDUCED GENE SILENCING, WHICH MAY CAUSE A REDUCTION IN CIRCULATING VITAMIN D LEVELS. EPIGENETIC BASIS OF VITAMIN D DEFICIENCY IS YET TO BE STUDIED IN INDIA, AND HENCE, THIS PILOT STUDY WAS AIMED TO ANALYZE WHETHER METHYLATION LEVELS OF CYP2R1 GENE WERE CORRELATED WITH THE LEVELS OF 25(OH)D IN HEALTHY, ADULT INDIVIDUALS IN INDIAN POPULATION. METHODS: IN THIS CROSS-SECTIONAL STUDY, HEALTHY ADULTS OF 18-45 YR OF AGE WITH NO HISTORY OF MALABSORPTION, THYROIDECTOMY, CHRONIC ILLNESS OR THERAPEUTIC VITAMIN D SUPPLEMENTATION WERE RECRUITED. DNA METHYLATION ANALYSIS WAS CARRIED OUT BY METHYLATION SPECIFIC QUANTITATIVE PCR. SERUM CALCIUM, PHOSPHATE AND VITAMIN D LEVELS WERE ALSO QUANTIFIED. STATISTICAL ANALYSIS WAS DONE BY R 4.0.5 SOFTWARE. RESULTS: A TOTAL OF 61 APPARENTLY HEALTHY ADULTS WERE ANALYZED. THE SERUM VITAMIN D LEVELS DID NOT CORRELATE WITH CYP2R1 METHYLATION LEVELS IN OUR STUDY POPULATION. SIGNIFICANT POSITIVE CORRELATION WAS OBSERVED BETWEEN AGE AND SERUM VITAMIN D LEVELS. SIGNIFICANT ASSOCIATION OF GENDER WAS FOUND WITH CYP2R1 METHYLATION LEVELS. INTERPRETATION & CONCLUSIONS: THIS STUDY FOUND NO SIGNIFICANT CORRELATION BETWEEN LEVELS OF CYP2R1 METHYLATION AND CIRCULATING 25(OH)D DEFICIENCY. FURTHER STUDIES ON THE INDIAN POPULATION HAVING A LARGER SAMPLE SIZE INCLUDING ENTIRE VITAMIN D TOOL GENES, AMONG DIFFERENT ETHNIC GROUPS MAY BE CONDUCTED TO ELUCIDATE MOLECULAR ETIOLOGY OF CIRCULATING 25(OH)D DEFICIENCY. THE HIGH PREVALENCE OF NORMAL SERUM CALCIUM AND PHOSPHATE LEVELS AMONG VITAMIN D DEFICIENT SUBJECTS IN THIS STUDY COUPLED WITH THE STRIKINGLY HIGH PREVALENCE OF THE DEFICIENCY AT THE NATIONAL LEVEL, MAY SUGGEST THE NEED TO REVISE THE CUT-OFF CRITERIA FOR VITAMIN D DEFICIENCY IN THE INDIAN POPULATION. 2023 5 3442 39 HYPERMETHYLATION IN THE PROMOTER OF THE MTHFR GENE IS ASSOCIATED WITH DIABETIC COMPLICATIONS AND BIOCHEMICAL INDICATORS. BACKGROUND: DNA METHYLATION IS AN EPIGENETIC MECHANISM FOR REGULATING THE TRANSCRIPTION OF MANY GENES AND HAS BEEN LINKED TO THE DEVELOPMENT OF VARIOUS DISEASES. A PROMISING GENE TO INVESTIGATE IS METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR), SINCE THE ENZYME METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) PROMOTES METHYL RADICAL SYNTHESIS IN THE HOMOCYSTEINE CYCLE AND CAN PROVIDE METHYL GROUPS FOR DNA METHYLATION. IN ADDITION, SEVERAL STUDIES HAVE CORRELATED GENE POLYMORPHISMS OF THIS ENZYME WITH A GREATER RISK OF DIABETES, BUT LITTLE IS KNOWN REGARDING THE RELATIONSHIP BETWEEN EPIGENETIC CHANGES IN THIS GENE AND DIABETES AND ITS COMPLICATIONS. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE RELATIONSHIP BETWEEN METHYLATION PROFILE IN THE MTHFR GENE PROMOTER AND BIOCHEMICAL, INFLAMMATORY AND OXIDATIVE STRESS MARKERS IN INDIVIDUALS WITH TYPE 2 DIABETES (T2DM) WHO HAVE BEEN DIAGNOSED FOR 5-10 YEARS WITH OR WITHOUT DIABETIC RETINOPATHY (DR) AND NEPHROPATHY (DN). METHODS: SPECIFIC PCR FOR METHYLATION (MSP) WAS USED TO ANALYZE MTHFR METHYLATION PROFILE IN LEUCOCYTES DNA. BIOCHEMICAL MARKERS (GLYCEMIA, GLYCATED HEMOGLOBIN, TOTAL CHOLESTEROL, LDL, HDL, TRIGLYCERIDES, SERUM CREATININE), INFLAMMATORY MARKERS (C-REACTIVE PROTEIN AND ALPHA-1 ACID GLYCOPROTEIN) AND OXIDATIVE STRESS (TOTAL ANTIOXIDANT AND MALONALDEHYDE) WERE DETERMINED IN PERIPHERIC BLOOD SAMPLES AND MICROALBUMINURIA IN 24 H URINE SAMPLES. THE X(2) AND MANN-WHITNEY STATISTICAL TESTS WERE PERFORMED AND P < 0.05 WERE CONSIDERED SIGNIFICANT. RESULTS: THE HYPERMETHYLATED PROFILE WAS MOST FREQUENTLY OBSERVED IN INDIVIDUALS WITH RETINOPATHY (P < 0.01) AND WAS ASSOCIATED WITH HIGHER TOTAL CHOLESTEROL AND LDL LEVELS (P = 0.0046, 0.0267, RESPECTIVELY). INDIVIDUALS WITH DN AND HYPERMETHYLATED PROFILES HAD HIGHER LEVELS OF ALPHA-1 ACID GLYCOPROTEIN (P = 0.0080) AND TOTAL ANTIOXIDANT CAPACITY (P = 0.0169) COMPARED TO SUBJECTS WITHOUT COMPLICATIONS. CONCLUSIONS: HYPERMETHYLATION IN THE PROMOTER OF THE MTHFR GENE IS ASSOCIATED WITH THE OCCURRENCE OF DR AND WITH BIOCHEMICAL, INFLAMMATORY AND OXIDATIVE STRESS PARAMETERS IN THE CONTEXT OF CHRONIC COMPLICATIONS. 2017 6 5587 36 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 7 3954 33 LONG INTERSPERSED NUCLEAR ELEMENT-1 METHYLATION STATUS IN THE CIRCULATING DNA FROM BLOOD OF PATIENTS WITH MALIGNANT AND CHRONIC INFLAMMATORY LUNG DISEASES. ALONG WITH OTHER MALIGNANT DISEASES, LUNG CANCER ARISES FROM THE PRECANCEROUS LUNG TISSUE STATE. ABERRANT DNA METHYLATION (HYPERMETHYLATION OF CERTAIN GENES AND HYPOMETHYLATION OF RETROTRANSPOSONS) IS KNOWN AS ONE OF THE DRIVING FORCES OF MALIGNANT CELL TRANSFORMATION. EPIGENETIC CHANGES WERE SHOWN TO BE DETECTABLE IN DNA, CIRCULATING IN THE BLOOD (CIRDNA) OF CANCER PATIENTS, INDICATING THE POSSIBILITY TO USE THEM AS CANCER MARKERS. THE CURRENT STUDY IS THE FIRST TO COMPARE THE LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) METHYLATION LEVEL IN THE BLOOD FROM LUNG CANCER PATIENTS BEFORE TREATMENT VERSUS DIFFERENT CONTROL GROUPS AS HEALTHY SUBJECTS, PATIENTS WITH BRONCHITIS AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THE CONCENTRATION OF LINE-1 METHYLATED FRAGMENTS, REGION 1 (LINE-1 METHYLATED, LINE-1-MET) WAS ESTIMATED BY QUANTITATIVE METHYL-SPECIFIC PCR. THE TOTAL CONCENTRATION OF THE CIRCULATING LINE-1 COPIES WAS MEASURED BY QPCR SPECIFIC FOR LINE-1 REGION 2, WHICH WAS SELECTED DUE TO ITS CPG METHYLATION-INDEPENDENT SEQUENCE (LINE-1-IND). BOTH LINE-1 METHYLATION LEVEL AND LINE-1 METHYLATION INDEX (LINE-1-MET/LINE-1-IND RATIO) WAS DECREASED IN LUNG CANCER PATIENTS COMPARED WITH THE JOINT CONTROL GROUP (HEALTHY SUBJECTS + PATIENTS WITH BRONCHITIS + COPD PATIENTS) (MANN-WHITNEY U-TEST, P = 0.016). WE ALSO FOUND THAT THE TENDENCY OF LINE-1 METHYLATION INDEX DECREASES IN THE CIRDNA FROM LUNG CANCER PATIENTS VERSUS COPD PATIENTS (MANN-WHITNEY U-TEST, P = 0.07). OUR DATA INDICATE THAT THE QUANTITATIVE ANALYSIS OF THE LINE-1 METHYLATION LEVEL IN THE CIRDNA IS VALUABLE FOR DISCRIMINATION OF LUNG CANCER PATIENTS FROM PATIENTS WITH CHRONIC INFLAMMATORY LUNG DISEASES. 2021 8 1855 28 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 9 872 34 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 10 6311 29 THE RELATION BETWEEN DNA METHYLATION PATTERNS AND SERUM CYTOKINE LEVELS IN COMMUNITY-DWELLING ADULTS: A PRELIMINARY STUDY. BACKGROUND: THE LEVELS OF CIRCULATING CYTOKINES FLUCTUATE WITH AGE, ACUTE ILLNESS, AND CHRONIC DISEASE, AND ARE PREDICTIVE OF MORTALITY; THIS IS ALSO TRUE FOR PATTERNS OF DNA (CPG) METHYLATION. GIVEN THAT IMMUNE CELLS ARE PARTICULARLY SENSITIVE TO CHANGES IN THE CONCENTRATION OF CYTOKINES IN THEIR MICROENVIRONMENT, WE HYPOTHESIZED THAT SERUM LEVELS OF TNF, IL-6, IL-8 AND IL-10 WOULD CORRELATE WITH GENOME-WIDE ALTERATIONS IN THE DNA METHYLATION LEVELS OF BLOOD LEUKOCYTES. TO TEST THIS, WE EVALUATED COMMUNITY-DWELLING ADULTS (N = 14; 48-78 YEARS OLD) RECRUITED TO A PILOT STUDY FOR THE CANADIAN LONGITUDINAL STUDY ON AGING (CLSA), EXAMINING DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS USING THE ILLUMINA HUMANMETHYLATION 450 K BEADCHIP. RESULTS: WE SHOW THAT, APART FROM AGE, SERUM IL-10 LEVELS EXHIBITED THE MOST SUBSTANTIAL ASSOCIATION TO DNA METHYLATION PATTERNS, FOLLOWED BY TNF, IL-6 AND IL-8. FURTHERMORE, WHILE THE LEVELS OF THESE CYTOKINES WERE HIGHER IN ELDERLY ADULTS, NO ASSOCIATIONS WITH EPIGENETIC ACCELERATED AGING, DERIVED USING THE EPIGENETIC CLOCK, WERE OBSERVED. CONCLUSIONS: AS A PRELIMINARY STUDY WITH A SMALL SAMPLE SIZE, THE CONCLUSIONS DRAWN FROM THIS WORK MUST BE VIEWED WITH CAUTION; HOWEVER, OUR OBSERVATIONS ARE ENCOURAGING AND CERTAINLY WARRANT MORE SUITABLY POWERED STUDIES OF THIS RELATIONSHIP. 2017 11 1408 36 DIETARY INTAKE IS ASSOCIATED WITH RESPIRATORY HEALTH OUTCOMES AND DNA METHYLATION IN CHILDREN WITH ASTHMA. BACKGROUND: ASTHMA IS AN INCREASINGLY COMMON CHRONIC DISEASE AMONG CHILDREN, AND DATA POINT TOWARD A COMPLEX MECHANISM INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. EPIGENETIC MODIFICATIONS SUCH AS DNA HYPO- OR HYPER-METHYLATION HAVE BEEN SHOWN TO OCCUR IN RESPONSE TO ENVIRONMENTAL EXPOSURES INCLUDING DIETARY NUTRIENTS. METHODS: WITHIN THE CONTEXT OF THE ASTHMA RANDOMIZED TRIAL OF INDOOR WOOD SMOKE (ARTIS) STUDY, WE INVESTIGATED RELATIONSHIPS BETWEEN DIET, ASTHMA HEALTH MEASURES, AND DNA METHYLATION. ASTHMA HEALTH MEASURES INCLUDED A QUALITY OF LIFE INSTRUMENT, DIURNAL PEAK FLOW VARIABILITY (DPFV) AND FORCED EXPIRATORY VOLUME IN THE FIRST SECOND (FEV(1)). DIETARY INTAKE WAS ASSESSED WITH A FOOD FREQUENCY QUESTIONNAIRE. METHYLATION LEVELS OF LINE-1 REPETITIVE ELEMENT AND TWO PROMOTER CPG SITES FOR INTERFERON GAMMA (IFNGAMMA, -186 AND -54) FROM BUCCAL CELL DNA WERE MEASURED USING PYROSEQUENCING ASSAYS. RESULTS: DATA WERE COLLECTED ON 32 CHILDREN WITH ASTHMA LIVING IN WESTERN MONTANA WHO WERE RECRUITED TO THE ARTIS STUDY. SELENIUM AND SEVERAL METHYL DONOR DIETARY NUTRIENTS WERE POSITIVELY ASSOCIATED WITH THE ASTHMA QUALITY OF LIFE MEASURE. INTAKE OF METHYL DONATING NUTRIENTS INCLUDING FOLATE WAS POSITIVELY ASSOCIATED LINE-1 METHYLATION AND NEGATIVELY ASSOCIATED WITH IFNGAMMA CPG-186. HIGHER LEVELS OF LINE-1 METHYLATION WERE ASSOCIATED WITH GREATER DPFV. CONCLUSION: WE IDENTIFIED SEVERAL NUTRIENTS THAT WERE ASSOCIATED WITH IMPROVED QUALITY OF LIFE MEASURES AMONG CHILDREN WITH ASTHMA. THE IFNGAMMA PROMOTER CPG SITE -186 BUT NOT -54 WAS ASSOCIATED WITH THE INTAKE OF SELECTED DIETARY NUTRIENTS. HOWEVER, IN THIS SMALL POPULATION OF CHILDREN WITH ASTHMA, THE IFNGAMMA PROMOTER CPG SITES WERE NOT ASSOCIATED WITH RESPIRATORY HEALTH MEASURES SO IT REMAINS UNCLEAR THROUGH WHICH EPIGENETIC MECHANISM THESE NUTRIENTS ARE IMPACTING THE QUALITY OF LIFE MEASURE. THESE FINDINGS ADD TO THE EVIDENCE THAT DIETARY NUTRIENTS, PARTICULARLY FOODS CONTAINING METHYL DONORS, MAY BE IMPORTANT FOR EPIGENETIC REGULATION AS IT PERTAINS TO THE CONTROL OF ASTHMA. TRIAL REGISTRATION CLINCIALTRIALS.GOV NCT00807183. REGISTERED 10 DECEMBER 2008. 2017 12 3414 34 HSD11B2, RUNX3, AND LINE-1 METHYLATION IN PLACENTAL DNA OF HYPERTENSIVE DISORDERS OF PREGNANCY PATIENTS. HYPERTENSIVE DISORDERS OF PREGNANCY (HDSP) REMAIN LEADING CAUSES OF MATERNAL AND PERINATAL MORBIDITY AND MORTALITY. GROWING EVIDENCE SUGGESTS THE INVOLVEMENT OF EPIGENETIC FACTORS, SUCH AS GENE-SPECIFIC AND GLOBAL DNA METHYLATION CHANGES, BOTH IN THE ETIOLOGY AND AS AN EFFECT OF HDSP. IN THIS STUDY, WE INVESTIGATED THE POTENTIAL ASSOCIATION BETWEEN PLACENTAL DNA METHYLATION STATUS IN SELECTED CPGS OF HSD11B2 CORTISOL LEVEL CONTROLLING GENE, RUNX3 TUMOR SUPPRESSOR GENE, AND LONG INTERSPERSED NUCLEOTIDE ELEMENT-1 (LINE-1) REPETITIVE ELEMENTS AND HDSP-PREECLAMPSIA (PE), GESTATIONAL HYPERTENSION (GH), AND CHRONIC HYPERTENSION (CH). METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) AND PYROSEQUENCING (PSQ) WERE USED TO ANALYZE PLACENTAL DNA METHYLATION. PLASMA AND URINE CORTISOL AND CORTISONE LEVELS WERE MEASURED USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY WITH FLUORESCENCE DETECTION (HPLC-FLD), WHEREAS SERUM PROGESTERONE LEVEL WAS DETERMINED BY ELECTROCHEMILUMINESCENCE IMMUNOASSAY. THE MEAN PERCENTAGE OF HSD11B2, RUNX3, AND LINE-1 METHYLATION WAS NOT ALTERED IN THE PLACENTAS OF PATIENTS WITH HDSP, AS COMPARED TO THE CONTROLS. HOWEVER, AMONG PATIENTS FROM PE, GH, AND CH GROUPS, SEVERAL SIGNIFICANT CORRELATIONS WERE OBSERVED BETWEEN THE METHYLATION STATUS OF HSD11B2, RUNX3, OR LINE-1 AND CHILDREN'S BIRTH WEIGHT, GESTATIONAL AGE AT DELIVERY, MOTHER'S AGE, AND BODY MASS INDEX AS WELL AS HORMONES LEVELS. THESE RESULTS INDICATE LACK OF ASSOCIATION BETWEEN METHYLATION STATUS OF HSD11B2, RUNX3, OR LINE-1 REPETITIVE ELEMENTS AND HDSP. HOWEVER, ASSOCIATION OF THESE PARAMETERS WITH SOME CLINICAL VARIABLES MAY SUGGEST THE ROLE OF PLACENTAL DNA METHYLATION IN FETAL DEVELOPMENT AND SHOULD BE FURTHER EXPLORED. 2017 13 6845 29 [METHYLATION STATUS OF APOPTOSIS GENES AND INTENSITY OF APOPTOTIC DEATH OF PERIPHERAL BLOOD LYMPHOCYTES IN PERSONS CHRONICALLY EXPOSED TO RADIATION]. METHYLATION OF THE CPG ISLANDS OF GENE PROMOTER REGIONS IS THE MOST COMMON EPIGENETIC MODIFICATION INVOLVED IN THE REGULATION OF GENE EXPRESSION. A NUMBER OF STUDIES HAVE SHOWN THAT IONIZING RADIATION CAN CAUSE BOTH HYPER- AND HYPOMETHYLATION OF DNA. ABERRANT METHYLATION AFFECTS CELLULAR PROCESSES AND CAN LEAD TO THE DEVELOPMENT OF VARIOUS PATHOLOGICAL STATES. IN THE LITERATURE, THERE ARE FEW STUDIES ON THE METHYLATION STATUS OF HUMAN DNA A LONG TIME AFTER RADIATION EXPOSURE. HERE, THE METHYLATION LEVEL OF CPG ISLANDS OF THE PROMOTER REGIONS OF APOPTOSIS GENES (BCL2, ATM, MDM2, CDKN1A, STAT3, AND NFKB1), AND ALSO ITS INFLUENCE ON APOPTOSIS OF PERIPHERAL BLOOD LYMPHOCYTES IN CHRONICALLY EXPOSED PERSONS WERE STUDIED. RESIDENTS OF THE SOUTH URAL REGION WHO WERE CHRONICALLY EXPOSED TO RADIATION (AFTER DISCHARGES OF RADIOACTIVE WASTES INTO THE TECHA RIVER BY THE "MAYAK PRODUCTION ASSOCIATION" IN 1949-1956) WERE INCLUDED IN THE STUDY. IT WAS ESTABLISHED THAT THE PROPORTION OF INDIVIDUALS WITH HYPERMETHYLATED BCL2 GENE PROMOTER AMONG THE EXPOSED PEOPLE WAS STATISTICALLY SIGNIFICANTLY HIGHER THAN IN THE CONTROL GROUP. THE PERCENTAGE OF METHYLATION OF THE ATM GENE PROMOTER WEAKLY POSITIVELY CORRELATED WITH DOSE AND AGE CHARACTERISTICS. DIFFERENCES IN THE FREQUENCY OF LYMPHOCYTE APOPTOSIS IN EXPOSED INDIVIDUALS WITH A HYPO- OR HYPERMETHYLATED ATM GENE PROMOTER WERE ALSO ESTABLISHED. THE DATA INDICATE THAT, IN THE LONG-TERM, AFTER CHRONIC LOW INTENSITY RADIATION EXPOSURE AT LOW AND MEDIUM DOSES, EPIGENETIC MODIFICATIONS OF THE GENOME OCCUR, WHICH ARE MANIFESTED AS CHANGES IN METHYLATION OF PROMOTER REGIONS OF BCL2 AND ATM GENES. 2022 14 6547 31 TRANSCRIPTOMICS OF LONG-TERM MEDITATION PRACTICE: EVIDENCE FOR PREVENTION OR REVERSAL OF STRESS EFFECTS HARMFUL TO HEALTH. BACKGROUND AND OBJECTIVES: STRESS CAN OVERLOAD ADAPTIVE MECHANISMS, LEADING TO EPIGENETIC EFFECTS HARMFUL TO HEALTH. RESEARCH ON THE REVERSAL OF THESE EFFECTS IS IN ITS INFANCY. EARLY RESULTS SUGGEST SOME MEDITATION TECHNIQUES HAVE HEALTH BENEFITS THAT GROW WITH REPEATED PRACTICE. THIS STUDY FOCUSED ON POSSIBLE TRANSCRIPTOMIC EFFECTS OF 38 YEARS OF TWICE-DAILY TRANSCENDENTAL MEDITATION((R)) (TM((R))) PRACTICE. MATERIALS AND METHODS: FIRST, USING ILLUMINA((R)) BEADCHIP MICROARRAY TECHNOLOGY, DIFFERENCES IN GLOBAL GENE EXPRESSION IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE SOUGHT BETWEEN HEALTHY PRACTITIONERS AND TIGHTLY MATCHED CONTROLS (N = 12, AGE 65). SECOND, THESE MICROARRAY RESULTS WERE VERIFIED ON A SUBSET OF GENES USING QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) AND WERE VALIDATED USING QPCR IN LARGER TM AND CONTROL GROUPS (N = 45, AGE 63). BIOINFORMATICS INVESTIGATION EMPLOYED INGENUITY((R)) PATHWAY ANALYSIS (IPA((R))), DAVID, GENOMATIX, AND R PACKAGES. RESULTS: THE 200 GENES AND LOCI FOUND TO MEET STRICT CRITERIA FOR DIFFERENTIAL EXPRESSION IN THE MICROARRAY EXPERIMENT SHOWED CONTRASTING PATTERNS OF EXPRESSION THAT DISTINGUISHED THE TWO GROUPS. DIFFERENTIAL EXPRESSION RELATING TO IMMUNE FUNCTION AND ENERGY EFFICIENCY WERE MOST APPARENT. IN THE TM GROUP, RELATIVE TO THE CONTROL, ALL 49 GENES ASSOCIATED WITH INFLAMMATION WERE DOWNREGULATED, WHILE GENES ASSOCIATED WITH ANTIVIRAL AND ANTIBODY COMPONENTS OF THE DEFENSE RESPONSE WERE UPREGULATED. THE LARGEST EXPRESSION DIFFERENCES WERE SHOWN BY SIX GENES RELATED TO ERYTHROCYTE FUNCTION THAT APPEARED TO REFLECT A CONDITION OF LOWER ENERGY EFFICIENCY IN THE CONTROL GROUP. RESULTS SUPPORTING THESE GENE EXPRESSION DIFFERENCES WERE OBTAINED WITH QPCR-MEASURED EXPRESSION BOTH IN THE WELL-MATCHED MICROARRAY GROUPS AND IN THE LARGER, LESS WELL-MATCHED GROUPS. CONCLUSIONS: THESE FINDINGS ARE CONSISTENT WITH PREDICTIONS BASED ON RESULTS FROM EARLIER RANDOMIZED TRIALS OF MEDITATION AND MAY PROVIDE EVIDENCE FOR STRESS-RELATED MOLECULAR MECHANISMS UNDERLYING REDUCTIONS IN ANXIETY, POST-TRAUMATIC STRESS DISORDER (PTSD), CARDIOVASCULAR DISEASE (CVD), AND OTHER CHRONIC DISORDERS AND DISEASES. 2021 15 1503 30 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION. 2009 16 1537 26 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD. 2018 17 4398 33 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 18 2682 40 EVALUATION OF SERUM LINE-1 HYPOMETHYLATION AS A PROGNOSTIC MARKER FOR HEPATOCELLULAR CARCINOMA. BACKGROUND AND STUDY AIMS: GLOBAL HYPOMETHYLATION IS ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN CANCER. DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) MUST BE UNDERSTOOD AS A MULTISTEP PROCESS WITH ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. IN THE LAST DECADES, IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC CHANGES HAVE BEEN RECOGNIZED AS AN IMPORTANT AND ALTERNATIVE MECHANISM IN TUMOURIGENESIS. WE INVESTIGATED THE CLINICAL IMPLICATIONS OF GLOBAL HYPOMETHYLATION IN THE SERA OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC). PATIENTS AND METHODS: PCR WAS USED TO ASSESS THE METHYLATION STATUS OF LONG INTERSPERSED NUCLEAR ELEMENT TYPE 1 (LINE-1) REPETITIVE SEQUENCES IN GENOMIC DNA DERIVED FROM SERA OF 50 PATIENTS WITH HCC, 20 PATIENTS WITH CIRRHOSIS, 20 PATIENTS WITH CHRONIC HEPATITIS C AND 10 HEALTHY SUBJECTS. RESULTS: SERUM GENOME HYPOMETHYLATION WAS SIGNIFICANTLY INCREASED IN PATIENTS WITH HCC (P<0.001). THE LEVELS OF SERUM LINE-1 HYPOMETHYLATION AT INITIAL PRESENTATION CORRELATED SIGNIFICANTLY WITH TUMOUR SIZE, TUMOUR NUMBER AND ALPHA-FOETOPROTEIN LEVEL. MOREOVER HIGH SERUM LINE-1 HYPOMETHYLATION CORRELATES SIGNIFICANTLY WITH POOR SURVIVAL. CONCLUSION: SERUM LINE-1 HYPOMETHYLATION MAY SERVE AS A PROGNOSTIC MARKER FOR PATIENTS WITH HCC. 2011 19 339 34 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 5638 29 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS. 2013