1 558 113 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 2 6726 47 VITAMIN-DEPENDENT METHIONINE METABOLISM AND ALCOHOLIC LIVER DISEASE. EMERGING EVIDENCE INDICATES THAT ETHANOL-INDUCED ALTERATIONS IN HEPATIC METHIONINE METABOLISM PLAY A CENTRAL ROLE IN THE PATHOGENESIS OF ALCOHOLIC LIVER DISEASE (ALD). BECAUSE MALNUTRITION IS A UNIVERSAL CLINICAL FINDING IN THIS DISEASE AND HEPATIC METHIONINE METABOLISM IS DEPENDENT UPON DIETARY FOLATE AND VITAMINS B-6 AND B-12, ALD CAN BE CONSIDERED AN INDUCED NUTRITIONAL DISORDER THAT IS CONDITIONED BY ALCOHOL ABUSE. THE PRESENT REVIEW DESCRIBES THE ETIOLOGIES OF THESE 3 VITAMIN DEFICIENCIES IN ALD AND HOW THEY INTERACT WITH CHRONIC ETHANOL EXPOSURE TO ALTER HEPATIC METHIONINE METABOLISM. SUBSEQUENT SECTIONS FOCUS ON MOLECULAR MECHANISMS FOR THE INTERACTIONS OF ABERRANT METHIONINE METABOLISM WITH ETHANOL IN THE PATHOGENESIS OF ALD, IN PARTICULAR THE ROLE OF S-ADENOSYLMETHIONINE (SAM) IN REGULATING THE EPIGENETIC EXPRESSIONS OF GENES RELEVANT TO PATHWAYS OF LIVER INJURY. THE REVIEW WILL CONCLUDE WITH DESCRIPTIONS OF STUDIES ON THE EFFICACY OF SAM IN THE TREATMENT OF ALD AND WITH DISCUSSION OF POTENTIALLY FRUITFUL FUTURE AVENUES OF RESEARCH. 2011 3 318 45 ALCOHOL-INDUCED EPIGENETIC CHANGES IN CANCER. CHRONIC, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH SERIOUS NEGATIVE HEALTH EFFECTS, INCLUDING THE DEVELOPMENT OF SEVERAL CANCER TYPES. ONE OF THE PATHWAYS AFFECTED BY ALCOHOL TOXICITY IS THE ONE-CARBON METABOLISM. THE ALCOHOL-INDUCED IMPAIRMENT OF THIS METABOLIC PATHWAY RESULTS IN EPIGENETIC CHANGES ASSOCIATED WITH CANCER DEVELOPMENT. THESE EPIGENETIC CHANGES ARE INDUCED BY FOLATE DEFICIENCY AND BY PRODUCTS OF THE ETHANOL METABOLISM. THE CHANGES INDUCED BY LONG-TERM HEAVY ETHANOL CONSUMPTION RESULT IN ELEVATIONS OF HOMOCYSTEINE AND S-ADENOSYL-HOMOCYSTEINE (SAH) AND REDUCTIONS IN S-ADENOSYLMETHIONINE (SAM) AND ANTIOXIDANT GLUTATHIONE (GSH) LEVELS, LEADING TO ABNORMAL PROMOTER GENE HYPERMETHYLATION, GLOBAL HYPOMETHYLATION, AND METABOLIC INSUFFICIENCY OF ANTIOXIDANT DEFENSE MECHANISMS. IN ADDITION, REACTIVE OXYGEN SPECIES (ROS) GENERATED DURING THE ETHANOL METABOLISM INDUCE ALTERATIONS IN DNA METHYLATION PATTERNS THAT PLAY A CRITICAL ROLE IN CANCER DEVELOPMENT. SPECIFIC EPIGENETIC CHANGES IN ESOPHAGEAL, HEPATIC, AND COLORECTAL CANCERS HAVE BEEN DETECTED IN BLOOD SAMPLES AND PROPOSED TO BE USED CLINICALLY AS EPIGENETIC BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS OF THESE CANCERS. ALSO, GENETIC VARIANTS OF GENES INVOLVED IN ONE-CARBON METABOLISM AND ETHANOL METABOLISM WERE FOUND TO MODULATE THE RELATIONSHIP BETWEEN ALCOHOL-INDUCED EPIGENETIC CHANGES AND CANCER RISK. FURTHERMORE, ALCOHOL METABOLISM PRODUCTS HAVE BEEN ASSOCIATED WITH AN INCREASE IN NADH LEVELS, WHICH LEAD TO HISTONE MODIFICATIONS AND CHANGES IN GENE EXPRESSION THAT IN TURN INFLUENCE CANCER SUSCEPTIBILITY. CHRONIC EXCESSIVE USE OF ALCOHOL ALSO AFFECTS SELECTED MEMBERS OF THE FAMILY OF MICRORNAS, AND AS MIRNAS COULD ACT AS EPIGENETIC REGULATORS, THIS MAY PLAY AN IMPORTANT ROLE IN CARCINOGENESIS. IN CONCLUSION, TARGETING ALCOHOL-INDUCED EPIGENETIC CHANGES IN SEVERAL CANCER TYPES COULD MAKE AVAILABLE CLINICAL TOOLS FOR THE DIAGNOSIS, PROGNOSIS, AND TREATMENT OF THESE CANCERS, WITH AN IMPORTANT ROLE IN PRECISION MEDICINE. 2018 4 1855 34 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 5 4683 46 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 6 5587 41 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 6717 36 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 8 315 42 ALCOHOL, DNA METHYLATION, AND CANCER. CANCER IS ONE OF THE MOST SIGNIFICANT DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION, AND CHRONIC DRINKING IS A STRONG RISK FACTOR FOR CANCER, PARTICULARLY OF THE UPPER AERODIGESTIVE TRACT, LIVER, COLORECTUM, AND BREAST. SEVERAL FACTORS CONTRIBUTE TO ALCOHOL-INDUCED CANCER DEVELOPMENT (I.E., CARCINOGENESIS), INCLUDING THE ACTIONS OF ACETALDEHYDE, THE FIRST AND PRIMARY METABOLITE OF ETHANOL, AND OXIDATIVE STRESS. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT ABERRANT PATTERNS OF DNA METHYLATION, AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, ALSO COULD BE PART OF THE PATHOGENETIC MECHANISMS THAT LEAD TO ALCOHOL-INDUCED CANCER DEVELOPMENT. THE EFFECTS OF ALCOHOL ON GLOBAL AND LOCAL DNA METHYLATION PATTERNS LIKELY ARE MEDIATED BY ITS ABILITY TO INTERFERE WITH THE AVAILABILITY OF THE PRINCIPAL BIOLOGICAL METHYL DONOR, S-ADENOSYLMETHIONINE (SAME), AS WELL AS PATHWAYS RELATED TO IT. SEVERAL MECHANISMS MAY MEDIATE THE EFFECTS OF ALCOHOL ON DNA METHYLATION, INCLUDING REDUCED FOLATE LEVELS AND INHIBITION OF KEY ENZYMES IN ONE-CARBON METABOLISM THAT ULTIMATELY LEAD TO LOWER SAME LEVELS, AS WELL AS INHIBITION OF ACTIVITY AND EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION (I.E., DNA METHYLTRANSFERASES). FINALLY, VARIATIONS (I.E., POLYMORPHISMS) OF SEVERAL GENES INVOLVED IN ONE-CARBON METABOLISM ALSO MODULATE THE RISK OF ALCOHOL-ASSOCIATED CARCINOGENESIS. 2013 9 313 27 ALCOHOL METABOLISM AND EPIGENETICS CHANGES. METABOLITES, INCLUDING THOSE GENERATED DURING ETHANOL METABOLISM, CAN IMPACT DISEASE STATES BY BINDING TO TRANSCRIPTION FACTORS AND/OR MODIFYING CHROMATIN STRUCTURE, THEREBY ALTERING GENE EXPRESSION PATTERNS. FOR EXAMPLE, THE ACTIVITIES OF ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS DNA AND HISTONE METHYLATION AND HISTONE ACETYLATION, ARE INFLUENCED BY THE LEVELS OF METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD), ADENOSINE TRIPHOSPHATE (ATP), AND S-ADENOSYLMETHIONINE (SAM). CHRONIC ALCOHOL CONSUMPTION LEADS TO SIGNIFICANT REDUCTIONS IN SAM LEVELS, THEREBY CONTRIBUTING TO DNA HYPOMETHYLATION. SIMILARLY, ETHANOL METABOLISM ALTERS THE RATIO OF NAD+ TO REDUCED NAD (NADH) AND PROMOTES THE FORMATION OF REACTIVE OXYGEN SPECIES AND ACETATE, ALL OF WHICH IMPACT EPIGENETIC REGULATORY MECHANISMS. IN ADDITION TO ALTERED CARBOHYDRATE METABOLISM, INDUCTION OF CELL DEATH, AND CHANGES IN MITOCHONDRIAL PERMEABILITY TRANSITION, THESE METABOLISM-RELATED CHANGES CAN LEAD TO MODULATION OF EPIGENETIC REGULATION OF GENE EXPRESSION. UNDERSTANDING THE NATURE OF THESE EPIGENETIC CHANGES WILL HELP RESEARCHERS DESIGN NOVEL MEDICATIONS TO TREAT OR AT LEAST AMELIORATE ALCOHOL-INDUCED ORGAN DAMAGE. 2013 10 339 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 11 4897 41 OXIDATIVE STRESS IN ALCOHOL-RELATED LIVER DISEASE. ALCOHOL CONSUMPTION IS ONE OF THE LEADING CAUSES OF THE GLOBAL BURDEN OF DISEASE AND RESULTS IN HIGH HEALTHCARE AND ECONOMIC COSTS. HEAVY ALCOHOL MISUSE LEADS TO ALCOHOL-RELATED LIVER DISEASE, WHICH IS RESPONSIBLE FOR A SIGNIFICANT PROPORTION OF ALCOHOL-ATTRIBUTABLE DEATHS GLOBALLY. OTHER THAN REDUCING ALCOHOL CONSUMPTION, THERE ARE CURRENTLY NO EFFECTIVE TREATMENTS FOR ALCOHOL-RELATED LIVER DISEASE. OXIDATIVE STRESS REFERS TO AN IMBALANCE IN THE PRODUCTION AND ELIMINATION OF REACTIVE OXYGEN SPECIES AND ANTIOXIDANTS. IT PLAYS IMPORTANT ROLES IN SEVERAL ASPECTS OF ALCOHOL-RELATED LIVER DISEASE PATHOGENESIS. HERE, WE REVIEW HOW CHRONIC ALCOHOL USE RESULTS IN OXIDATIVE STRESS THROUGH INCREASED METABOLISM VIA THE CYTOCHROME P450 2E1 SYSTEM PRODUCING REACTIVE OXYGEN SPECIES, ACETALDEHYDE AND PROTEIN AND DNA ADDUCTS. THESE TRIGGER INFLAMMATORY SIGNALING PATHWAYS WITHIN THE LIVER LEADING TO EXPRESSION OF PRO-INFLAMMATORY MEDIATORS CAUSING HEPATOCYTE APOPTOSIS AND NECROSIS. REACTIVE OXYGEN SPECIES EXPOSURE ALSO RESULTS IN MITOCHONDRIAL STRESS WITHIN HEPATOCYTES CAUSING STRUCTURAL AND FUNCTIONAL DYSREGULATION OF MITOCHONDRIA AND UPREGULATING APOPTOTIC SIGNALING. THERE IS ALSO EVIDENCE THAT OXIDATIVE STRESS AS WELL AS THE DIRECT EFFECT OF ALCOHOL INFLUENCES EPIGENETIC REGULATION. INCREASED GLOBAL HISTONE METHYLATION AND ACETYLATION AND SPECIFIC HISTONE ACETYLATION INHIBITS ANTIOXIDANT RESPONSES AND PROMOTES EXPRESSION OF KEY PRO-INFLAMMATORY GENES. THIS REVIEW HIGHLIGHTS ASPECTS OF THE ROLE OF OXIDATIVE STRESS IN DISEASE PATHOGENESIS THAT WARRANT FURTHER STUDY INCLUDING MITOCHONDRIAL STRESS AND EPIGENETIC REGULATION. IMPROVED UNDERSTANDING OF THESE PROCESSES MAY IDENTIFY NOVEL TARGETS FOR THERAPY. 2020 12 2833 25 FOLATE AND DNA METHYLATION: A REVIEW OF MOLECULAR MECHANISMS AND THE EVIDENCE FOR FOLATE'S ROLE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION CRITICAL TO NORMAL GENOME REGULATION AND DEVELOPMENT. THE VITAMIN FOLATE IS A KEY SOURCE OF THE ONE CARBON GROUP USED TO METHYLATE DNA. BECAUSE NORMAL MAMMALIAN DEVELOPMENT IS DEPENDENT ON DNA METHYLATION, THERE IS ENORMOUS INTEREST IN ASSESSING THE POTENTIAL FOR CHANGES IN FOLATE INTAKE TO MODULATE DNA METHYLATION BOTH AS A BIOMARKER FOR FOLATE STATUS AND AS A MECHANISTIC LINK TO DEVELOPMENTAL DISORDERS AND CHRONIC DISEASES INCLUDING CANCER. THIS REVIEW HIGHLIGHTS THE ROLE OF DNA METHYLATION IN NORMAL GENOME FUNCTION, HOW IT CAN BE ALTERED, AND THE EVIDENCE OF THE ROLE OF FOLATE/FOLIC ACID IN THESE PROCESSES. 2012 13 4788 39 NUTRITION, EPIGENETICS, AND METABOLIC SYNDROME. SIGNIFICANCE: EPIDEMIOLOGICAL AND ANIMAL STUDIES HAVE DEMONSTRATED A CLOSE LINK BETWEEN MATERNAL NUTRITION AND CHRONIC METABOLIC DISEASE IN CHILDREN AND ADULTS. COMPELLING EXPERIMENTAL RESULTS ALSO INDICATE THAT ADVERSE EFFECTS OF INTRAUTERINE GROWTH RESTRICTION ON OFFSPRING CAN BE CARRIED FORWARD TO SUBSEQUENT GENERATIONS THROUGH COVALENT MODIFICATIONS OF DNA AND CORE HISTONES. RECENT ADVANCES: DNA METHYLATION IS CATALYZED BY S-ADENOSYLMETHIONINE-DEPENDENT DNA METHYLTRANSFERASES. METHYLATION, DEMETHYLATION, ACETYLATION, AND DEACETYLATION OF HISTONE PROTEINS ARE PERFORMED BY HISTONE METHYLTRANSFERASE, HISTONE DEMETHYLASE, HISTONE ACETYLTRANSFERASE, AND HISTONE DEACETYLTRANSFERASE, RESPECTIVELY. HISTONE ACTIVITIES ARE ALSO INFLUENCED BY PHOSPHORYLATION, UBIQUITINATION, ADP-RIBOSYLATION, SUMOYLATION, AND GLYCOSYLATION. METABOLISM OF AMINO ACIDS (GLYCINE, HISTIDINE, METHIONINE, AND SERINE) AND VITAMINS (B6, B12, AND FOLATE) PLAYS A KEY ROLE IN PROVISION OF METHYL DONORS FOR DNA AND PROTEIN METHYLATION. CRITICAL ISSUES: DISRUPTION OF EPIGENETIC MECHANISMS CAN RESULT IN OXIDATIVE STRESS, OBESITY, INSULIN RESISTANCE, DIABETES, AND VASCULAR DYSFUNCTION IN ANIMALS AND HUMANS. DESPITE A RECOGNIZED ROLE FOR EPIGENETICS IN FETAL PROGRAMMING OF METABOLIC SYNDROME, RESEARCH ON THERAPIES IS STILL IN ITS INFANCY. POSSIBLE INTERVENTIONS INCLUDE: 1) INHIBITION OF DNA METHYLATION, HISTONE DEACETYLATION, AND MICRORNA EXPRESSION; 2) TARGETING EPIGENETICALLY DISTURBED METABOLIC PATHWAYS; AND 3) DIETARY SUPPLEMENTATION WITH FUNCTIONAL AMINO ACIDS, VITAMINS, AND PHYTOCHEMICALS. FUTURE DIRECTIONS: MUCH WORK IS NEEDED WITH ANIMAL MODELS TO UNDERSTAND THE BASIC MECHANISMS RESPONSIBLE FOR THE ROLES OF SPECIFIC NUTRIENTS IN FETAL AND NEONATAL PROGRAMMING. SUCH NEW KNOWLEDGE IS CRUCIAL TO DESIGN EFFECTIVE THERAPEUTIC STRATEGIES FOR PREVENTING AND TREATING METABOLIC ABNORMALITIES IN OFFSPRING BORN TO MOTHERS WITH A PREVIOUS EXPERIENCE OF MALNUTRITION. 2012 14 6220 26 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 15 2104 35 EPIGENETIC EVENTS IN LIVER CANCER RESULTING FROM ALCOHOLIC LIVER DISEASE. EPIGENETIC MECHANISMS PLAY AN EXTENSIVE ROLE IN THE DEVELOPMENT OF LIVER CANCER (I.E., HEPATOCELLULAR CARCINOMA [HCC]) ASSOCIATED WITH ALCOHOLIC LIVER DISEASE (ALD) AS WELL AS IN LIVER DISEASE ASSOCIATED WITH OTHER CONDITIONS. FOR EXAMPLE, EPIGENETIC MECHANISMS, SUCH AS CHANGES IN THE METHYLATION AND/OR ACETYLATION PATTERN OF CERTAIN DNA REGIONS OR OF THE HISTONE PROTEINS AROUND WHICH THE DNA IS WRAPPED, CONTRIBUTE TO THE REVERSION OF NORMAL LIVER CELLS INTO PROGENITOR AND STEM CELLS THAT CAN DEVELOP INTO HCC. CHRONIC EXPOSURE TO BEVERAGE ALCOHOL (I.E., ETHANOL) CAN INDUCE ALL OF THESE EPIGENETIC CHANGES. THUS, ETHANOL METABOLISM RESULTS IN THE FORMATION OF COMPOUNDS THAT CAN CAUSE CHANGES IN DNA METHYLATION AND INTERFERE WITH OTHER COMPONENTS OF THE NORMAL PROCESSES REGULATING DNA METHYLATION. ALCOHOL EXPOSURE ALSO CAN ALTER HISTONE ACETYLATION/DEACETYLATION AND METHYLATION PATTERNS THROUGH A VARIETY OF MECHANISMS AND SIGNALING PATHWAYS. ALCOHOL ALSO ACTS INDIRECTLY ON ANOTHER MOLECULE CALLED TOLL-LIKE RECEPTOR 4 (TLR4) THAT IS A KEY COMPONENT IN A CRUCIAL REGULATORY PATHWAY IN THE CELLS AND WHOSE DYSREGULATION IS INVOLVED IN THE DEVELOPMENT OF HCC. FINALLY, ALCOHOL USE REGULATES AN EPIGENETIC MECHANISM INVOLVING SMALL MOLECULES CALLED MIRNAS THAT CONTROL TRANSCRIPTIONAL EVENTS AND THE EXPRESSION OF GENES IMPORTANT TO ALD. 2013 16 474 26 ARSENIC BIOTRANSFORMATION AS A CANCER PROMOTING FACTOR BY INDUCING DNA DAMAGE AND DISRUPTION OF REPAIR MECHANISMS. CHRONIC EXPOSURE TO ARSENIC IN DRINKING WATER POSES A MAJOR GLOBAL HEALTH CONCERN. POPULATIONS EXPOSED TO HIGH CONCENTRATIONS OF ARSENIC-CONTAMINATED DRINKING WATER SUFFER SERIOUS HEALTH CONSEQUENCES, INCLUDING ALARMING CANCER INCIDENCE AND DEATH RATES. ARSENIC IS BIOTRANSFORMED THROUGH SEQUENTIAL ADDITION OF METHYL GROUPS, ACQUIRED FROM S-ADENOSYLMETHIONINE (SAM). METABOLISM OF ARSENIC GENERATES A VARIETY OF GENOTOXIC AND CYTOTOXIC SPECIES, DAMAGING DNA DIRECTLY AND INDIRECTLY, THROUGH THE GENERATION OF REACTIVE OXIDATIVE SPECIES AND INDUCTION OF DNA ADDUCTS, STRAND BREAKS AND CROSS LINKS, AND INHIBITION OF THE DNA REPAIR PROCESS ITSELF. SINCE SAM IS THE METHYL GROUP DONOR USED BY DNA METHYLTRANSFERASES TO MAINTAIN NORMAL EPIGENETIC PATTERNS IN ALL HUMAN CELLS, ARSENIC IS ALSO POSTULATED TO AFFECT MAINTENANCE OF NORMAL DNA METHYLATION PATTERNS, CHROMATIN STRUCTURE, AND GENOMIC STABILITY. THE BIOLOGICAL PROCESSES UNDERLYING THE CANCER PROMOTING FACTORS OF ARSENIC METABOLISM, RELATED TO DNA DAMAGE AND REPAIR, WILL BE DISCUSSED HERE. 2011 17 4214 39 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 18 4659 40 NEW APPROACHES FOR STUDYING ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) IS MAJOR CAUSE OF CHRONIC LIVER INJURY WHICH RESULTS IN LIVER FIBROSIS AND CIRRHOSIS. ACCORDING TO THE SURVEILLANCE REPORT PUBLISHED BY THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM, LIVER CIRRHOSIS IS THE 12TH LEADING CAUSE OF DEATH IN THE UNITED STATES WITH 48 % OF THESE DEATHS BEING ATTRIBUTED TO EXCESSIVE ALCOHOL CONSUMPTION. ALD INCLUDES A SPECTRUM OF DISORDERS FROM SIMPLE STEATOSIS TO STEATOHEPATITIS, FIBROSIS, AND HEPATOCELLULAR CARCINOMA. SEVERAL MECHANISMS PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF ALD. THESE INCLUDE ETHANOL-INDUCED OXIDATIVE STRESS AND DEPLETION OF GLUTATHIONE, PATHOLOGICAL METHIONINE METABOLISM, INCREASED GUT PERMEABILITY AND RELEASE OF ENDOTOXINS INTO THE PORTAL BLOOD, RECRUITMENT AND ACTIVATION OF INFLAMMATORY CELLS INCLUDING BONE MARROW-DERIVED AND LIVER RESIDENT MACROPHAGES (KUPFFER CELLS). CHRONIC ALCOHOL CONSUMPTION RESULTS IN LIVER DAMAGE AND ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) AND MYOFIBROBLASTS, LEADING TO LIVER FIBROSIS. HERE WE DISCUSS THE CURRENT VIEW ON FACTORS THAT ARE SPECIFIC FOR DIFFERENT STAGES OF ALD AND THOSE THAT REGULATE ITS PROGRESSION, INCLUDING CYTOKINES AND CHEMOKINES, ALCOHOL-RESPONSIVE INTRACELLULAR SIGNALING PATHWAYS, AND TRANSCRIPTIONAL FACTORS. WE ALSO REVIEW RECENT STUDIES DEMONSTRATING THAT ALCOHOL-MEDIATED CHANGES CAN BE REGULATED ON AN EPIGENETIC LEVEL, INCLUDING MICRORNAS. FINALLY, WE DISCUSS THE REVERSIBILITY OF LIVER FIBROSIS AND INACTIVATION OF HSCS AS A POTENTIAL STRATEGY FOR TREATING ALCOHOL-INDUCED LIVER DAMAGE. 2014 19 4768 29 NUCLEAR EFFECTS OF ETHANOL-INDUCED PROTEASOME INHIBITION IN LIVER CELLS. ALCOHOL INGESTION CAUSES ALTERATION IN SEVERAL CELLULAR MECHANISMS, AND LEADS TO INFLAMMATION, APOPTOSIS, IMMUNOLOGICAL RESPONSE DEFECTS, AND FIBROSIS. THESE PHENOMENA ARE ASSOCIATED WITH SIGNIFICANT CHANGES IN THE EPIGENETIC MECHANISMS, AND SUBSEQUENTLY, TO LIVER CELL MEMORY. THE UBIQUITIN-PROTEASOME PATHWAY IS ONE OF THE VITAL PATHWAYS IN THE CELL THAT BECOMES DYSFUNCTIONAL AS A RESULT OF CHRONIC ETHANOL CONSUMPTION. INHIBITION OF THE PROTEASOME ACTIVITY IN THE NUCLEUS CAUSES CHANGES IN THE TURNOVER OF TRANSCRIPTIONAL FACTORS, HISTONE MODIFYING ENZYMES, AND THEREFORE, AFFECTS EPIGENETIC MECHANISMS. ALCOHOL CONSUMPTION HAS BEEN ASSOCIATED WITH AN INCREASE IN HISTONE ACETYLATION AND A DECREASE IN HISTONE METHYLATION, WHICH LEADS TO GENE EXPRESSION CHANGES. DNA AND HISTONE MODIFICATIONS THAT RESULT FROM ETHANOL-INDUCED PROTEASOME INHIBITION ARE KEY PLAYERS IN REGULATING GENE EXPRESSION, ESPECIALLY GENES INVOLVED IN THE CELL CYCLE, IMMUNOLOGICAL RESPONSES, AND METABOLISM OF ETHANOL. THE PRESENT REVIEW HIGHLIGHTS THE CONSEQUENCES OF ETHANOL-INDUCED PROTEASOME INHIBITION IN THE NUCLEUS OF LIVER CELLS THAT ARE CHRONICALLY EXPOSED TO ETHANOL. 2009 20 6399 33 THE ROLES AND MECHANISMS OF ACTIONS OF VITAMIN C IN BONE: NEW DEVELOPMENTS. VITAMIN C IS AN IMPORTANT ANTIOXIDANT AND COFACTOR THAT IS INVOLVED IN THE REGULATION OF DEVELOPMENT, FUNCTION, AND MAINTENANCE OF SEVERAL CELL TYPES IN THE BODY. DEFICIENCIES IN VITAMIN C CAN LEAD TO CONDITIONS SUCH AS SCURVY, WHICH, AMONG OTHER AILMENTS, CAUSES GINGIVIA, BONE PAIN, AND IMPAIRED WOUND HEALING. THIS REVIEW EXAMINES THE FUNCTIONAL IMPORTANCE OF VITAMIN C AS IT RELATES TO THE DEVELOPMENT AND MAINTENANCE OF BONE TISSUES. ANALYSIS OF SEVERAL EPIDEMIOLOGICAL STUDIES AND GENETIC MOUSE MODELS REGARDING THE EFFECT OF VITAMIN C SHOWS A POSITIVE EFFECT ON BONE HEALTH. OVERALL, VITAMIN C EXERTS A POSITIVE EFFECT ON TRABECULAR BONE FORMATION BY INFLUENCING EXPRESSION OF BONE MATRIX GENES IN OSTEOBLASTS. RECENT STUDIES ON THE MOLECULAR PATHWAY FOR VITAMIN C ACTIONS THAT INCLUDE DIRECT EFFECTS OF VITAMIN C ON TRANSCRIPTIONAL REGULATION OF TARGET GENES BY INFLUENCING THE ACTIVITY OF TRANSCRIPTION FACTORS AND BY EPIGENETIC MODIFICATION OF KEY GENES INVOLVED IN SKELETAL DEVELOPMENT AND MAINTENANCE ARE DISCUSSED. WITH AN UNDERSTANDING OF MECHANISMS INVOLVED IN THE UPTAKE AND METABOLISM OF VITAMIN C AND KNOWLEDGE OF PRECISE MOLECULAR PATHWAYS FOR VITAMIN C ACTIONS IN BONE CELLS, IT IS POSSIBLE THAT NOVEL THERAPEUTIC STRATEGIES CAN BE DEVELOPED OR EXISTING THERAPIES CAN BE MODIFIED FOR THE TREATMENT OF OSTEOPOROTIC FRACTURES. 2015