1 870 102 CHRONIC ALCOHOL BINGING INJURES THE LIVER AND OTHER ORGANS BY REDUCING NAD(+) LEVELS REQUIRED FOR SIRTUIN'S DEACETYLASE ACTIVITY. NAD(+) LEVELS ARE MARKEDLY REDUCED WHEN BLOOD ALCOHOL LEVELS ARE HIGH DURING BINGE DRINKING. THIS CAUSES LIVER INJURY TO OCCUR BECAUSE THE ENZYMES THAT REQUIRE NAD(+) AS A COFACTOR SUCH AS THE SIRTUIN DE-ACETYLASES CANNOT DE-ACETYLATE ACETYLATED PROTEINS SUCH AS ACETYLATED HISTONES. THIS PREVENTS THE EPIGENETIC CHANGES THAT REGULATE METABOLIC PROCESSES AND WHICH PREVENT ORGAN INJURY SUCH AS FATTY LIVER IN RESPONSE TO ALCOHOL ABUSE. HYPER ACETYLATION OF NUMEROUS REGULATORY PROTEINS DEVELOPS. SYSTEMIC MULTI-ORGAN INJURY OCCURS WHEN NAD(+) IS REDUCED. FOR INSTANCE THE CIRCADIAN CLOCK IS ALTERED IF NAD(+) IS NOT AVAILABLE. CELL CYCLE ARREST OCCURS DUE TO UP REGULATION OF CELL CYCLE INHIBITORS LEADING TO DNA DAMAGE, MUTATIONS, APOPTOSIS AND TUMORIGENESIS. NAD(+) IS LINKED TO AGING IN THE REGULATION OF TELOMERE STABILITY. NAD(+) IS REQUIRED FOR MITOCHONDRIAL RENEWAL. ALCOHOL DEHYDROGENASE IS PRESENT IN EVERY VISCERAL ORGAN IN THE BODY SO THAT THERE IS A SYSTEMIC REDUCTION OF NAD(+) LEVELS IN ALL OF THESE ORGANS DURING BINGE DRINKING. 2016 2 313 33 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 3 4768 30 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 4 4897 32 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 5 6467 27 TISSUE-SPECIFIC EFFECTS OF EXERCISE AS NAD(+) -BOOSTING STRATEGY: CURRENT KNOWLEDGE AND FUTURE PERSPECTIVES. NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+) ) IS AN EVOLUTIONARILY HIGHLY CONSERVED COENZYME WITH MULTI-FACETED CELL FUNCTIONS, INCLUDING ENERGY METABOLISM, MOLECULAR SIGNALING PROCESSES, EPIGENETIC REGULATION, AND DNA REPAIR. SINCE THE DISCOVERY THAT LOWER NAD(+) LEVELS ARE A SHARED CHARACTERISTIC OF VARIOUS DISEASES AND AGING PER SE, SEVERAL NAD(+) -BOOSTING STRATEGIES HAVE EMERGED. OTHER THAN PHARMACOLOGICAL AND NUTRITIONAL APPROACHES, EXERCISE IS THOUGHT TO RESTORE NAD(+) HOMEOSTASIS THROUGH METABOLIC ADAPTION TO CHRONICALLY RECURRING STATES OF INCREASED ENERGY DEMAND. IN THIS REVIEW WE DISCUSS THE IMPACT OF ACUTE EXERCISE AND EXERCISE TRAINING ON TISSUE-SPECIFIC NAD(+) METABOLISM OF RODENTS AND HUMANS TO HIGHLIGHT THE POTENTIAL VALUE AS NAD(+) -BOOSTING STRATEGY. BY INTERCONNECTING RESULTS FROM DIFFERENT INVESTIGATIONS, WE AIM TO DRAW ATTENTION TO TISSUE-SPECIFIC ALTERATIONS IN NAD(+) METABOLISM AND THE ASSOCIATED IMPLICATIONS FOR WHOLE-BODY NAD(+) HOMEOSTASIS. ACUTE EXERCISE LED TO PROFOUND ALTERATIONS OF INTRACELLULAR NAD(+) METABOLISM IN VARIOUS INVESTIGATIONS, WITH THE MAGNITUDE AND DIRECTION OF CHANGES BEING STRONGLY DEPENDENT ON THE APPLIED EXERCISE MODALITY, CELL TYPE, AND INVESTIGATED ANIMAL MODEL OR HUMAN POPULATION. EXERCISE TRAINING ELEVATED NAD(+) LEVELS AND NAD(+) METABOLISM ENZYMES IN VARIOUS TISSUES. BASED ON THESE RESULTS, WE DISCUSS MOLECULAR MECHANISMS THAT MIGHT CONNECT ACUTE EXERCISE-INDUCED DISRUPTIONS OF NAD(+) /NADH HOMEOSTASIS TO CHRONIC EXERCISE ADAPTIONS IN NAD(+) METABOLISM. TAKING THIS HYPOTHESIS-DRIVEN APPROACH, WE HOPE TO INSPIRE FUTURE RESEARCH ON THE MOLECULAR MECHANISMS OF EXERCISE AS NAD(+) -MODIFYING LIFESTYLE INTERVENTION, THEREBY ELUCIDATING THE POTENTIAL THERAPEUTIC VALUE IN NAD(+) -RELATED PATHOLOGIES. 2023 6 315 26 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 7 3398 23 HOW ALCOHOL DRINKING AFFECTS OUR GENES: AN EPIGENETIC POINT OF VIEW. THIS WORK HIGHLIGHTS RECENT STUDIES IN EPIGENETIC MECHANISMS THAT PLAY A ROLE IN ALCOHOLISM, WHICH IS A COMPLEX MULTIFACTORIAL DISORDER. THERE IS A LARGE BODY OF EVIDENCE SHOWING THAT ALCOHOL CAN MODIFY GENE EXPRESSION THROUGH EPIGENETIC PROCESSES, NAMELY DNA METHYLATION AND NUCLEOSOMAL REMODELING VIA HISTONE MODIFICATIONS. IN THAT REGARD, CHRONIC EXPOSURE TO ETHANOL MODIFIES DNA AND HISTONE METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION. THE ALCOHOL-MEDIATED CHROMATIN REMODELING IN THE BRAIN PROMOTES THE TRANSITION FROM USE TO ABUSE AND ADDICTION. UNRAVELLING THE MULTIPLEX PATTERN OF MOLECULAR MODIFICATIONS INDUCED BY ETHANOL COULD SUPPORT THE DEVELOPMENT OF NEW THERAPIES FOR ALCOHOLISM AND DRUG ADDICTION TARGETING EPIGENETIC PROCESSES. 2019 8 2306 34 EPIGENETIC REGULATION OF CELL-FATE CHANGES THAT DETERMINE ADULT LIVER REGENERATION AFTER INJURY. THE ADULT LIVER HAS EXCELLENT REGENERATIVE POTENTIAL FOLLOWING INJURY. IN CONTRAST TO OTHER ORGANS OF THE BODY THAT HAVE HIGH CELLULAR TURNOVER DURING HOMEOSTASIS (E.G., INTESTINE, STOMACH, AND SKIN), THE ADULT LIVER IS A SLOWLY SELF-RENEWING ORGAN AND DOES NOT CONTAIN A DEFINED STEM-CELL COMPARTMENT THAT MAINTAINS HOMEOSTASIS. HOWEVER, TISSUE DAMAGE INDUCES SIGNIFICANT PROLIFERATION ACROSS THE LIVER AND CAN TRIGGER CELL-FATE CHANGES, SUCH AS TRANS-DIFFERENTIATION AND DE-DIFFERENTIATION INTO LIVER PROGENITORS, WHICH CONTRIBUTE TO EFFICIENT TISSUE REGENERATION AND RESTORATION OF LIVER FUNCTIONS. EPIGENETIC MECHANISMS HAVE BEEN SHOWN TO REGULATE CELL-FATE DECISIONS IN BOTH EMBRYONIC AND ADULT TISSUES IN RESPONSE TO ENVIRONMENTAL CUES. UNDERLYING THEIR RELEVANCE IN LIVER BIOLOGY, EXPRESSION LEVELS AND EPIGENETIC ACTIVITY OF CHROMATIN MODIFIERS ARE OFTEN ALTERED IN CHRONIC LIVER DISEASE AND LIVER CANCER. IN THIS REVIEW, I EXAMINE THE ROLE OF SEVERAL CHROMATIN MODIFIERS IN THE REGULATION OF CELL-FATE CHANGES THAT DETERMINE EFFICIENT ADULT LIVER EPITHELIAL REGENERATION IN RESPONSE TO TISSUE INJURY IN MOUSE MODELS. SPECIFICALLY, I FOCUS ON EPIGENETIC MECHANISMS SUCH AS CHROMATIN REMODELLING, DNA METHYLATION AND HYDROXYMETHYLATION, AND HISTONE METHYLATION AND DEACETYLATION. FINALLY, I ADDRESS HOW ALTERED EPIGENETIC MECHANISMS AND THE INTERPLAY BETWEEN EPIGENETICS AND METABOLISM MAY CONTRIBUTE TO THE INITIATION AND PROGRESSION OF LIVER DISEASE AND CANCER. 2021 9 5550 30 ROLE OF EPIGENETICS IN INFLAMMATION-ASSOCIATED DISEASES. THERE IS CONSIDERABLE EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS MAY MEDIATE DEVELOPMENT OF CHRONIC INFLAMMATION BY MODULATING THE EXPRESSION OF PRO-INFLAMMATORY CYTOKINE TNF-ALPHA, INTERLEUKINS, TUMOR SUPPRESSOR GENES, ONCOGENES AND AUTOCRINE AND PARACRINE ACTIVATION OF THE TRANSCRIPTION FACTOR NF-KAPPAB. THESE MOLECULES ARE CONSTITUTIVELY PRODUCED BY A VARIETY OF CELLS UNDER CHRONIC INFLAMMATORY CONDITIONS, WHICH IN TURN LEADS TO THE DEVELOPMENT OF MAJOR DISEASES SUCH AS AUTOIMMUNE DISORDERS, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEURODEGENERATIVE DISEASES AND CANCER. DISTINCT OR GLOBAL CHANGES IN THE EPIGENETIC LANDSCAPE ARE HALLMARKS OF CHRONIC INFLAMMATION DRIVEN DISEASES. EPIGENETICS INCLUDE CHANGES TO DISTINCT MARKERS ON THE GENOME AND ASSOCIATED CELLULAR TRANSCRIPTIONAL MACHINERY THAT ARE COPIED DURING CELL DIVISION (MITOSIS AND MEIOSIS). THESE CHANGES APPEAR FOR A SHORT SPAN OF TIME AND THEY NECESSARILY DO NOT MAKE PERMANENT CHANGES TO THE PRIMARY DNA SEQUENCE ITSELF. HOWEVER, THE MOST FREQUENTLY OBSERVED EPIGENETIC CHANGES INCLUDE ABERRANT DNA METHYLATION, AND HISTONE ACETYLATION AND DEACETYLATION. IN THIS CHAPTER, WE FOCUS ON PRO-INFLAMMATORY MOLECULES THAT ARE REGULATED BY ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS ARGININE AND LYSINE METHYL TRANSFERASES, DNA METHYLTRANSFERASE, HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASES AND THEIR ROLE IN INFLAMMATION DRIVEN DISEASES. AGENTS THAT MODULATE OR INHIBIT THESE EPIGENETIC MODIFICATIONS, SUCH AS HAT OR HDAC INHIBITORS HAVE SHOWN GREAT POTENTIAL IN INHIBITING THE PROGRESSION OF THESE DISEASES. GIVEN THE PLASTICITY OF THESE EPIGENETIC CHANGES AND THEIR READINESS TO RESPOND TO INTERVENTION BY SMALL MOLECULE INHIBITORS, THERE IS A TREMENDOUS POTENTIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS THAT WILL SERVE AS DIRECT OR ADJUVANT THERAPEUTIC COMPOUNDS IN THE TREATMENT OF THESE DISEASES. 2013 10 318 29 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 11 5117 24 POSSIBLE ADVERSE EFFECTS OF HIGH-DOSE NICOTINAMIDE: MECHANISMS AND SAFETY ASSESSMENT. NICOTINAMIDE (NAM) AT DOSES FAR ABOVE THOSE RECOMMENDED FOR VITAMINS IS SUGGESTED TO BE EFFECTIVE AGAINST A WIDE SPECTRUM OF DISEASES AND CONDITIONS, INCLUDING NEUROLOGICAL DYSFUNCTIONS, DEPRESSION AND OTHER PSYCHOLOGICAL DISORDERS, AND INFLAMMATORY DISEASES. RECENT INCREASES IN PUBLIC AWARENESS ON POSSIBLE PRO-LONGEVITY EFFECTS OF NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)) PRECURSORS HAVE CAUSED FURTHER GROWTH OF NAM CONSUMPTION NOT ONLY FOR CLINICAL TREATMENTS, BUT ALSO AS A DIETARY SUPPLEMENT, RAISING CONCERNS ON THE SAFETY OF ITS LONG-TERM USE. HOWEVER, POSSIBLE ADVERSE EFFECTS AND THEIR MECHANISMS ARE POORLY UNDERSTOOD. HIGH-LEVEL NAM ADMINISTRATION CAN EXERT NEGATIVE EFFECTS THROUGH MULTIPLE ROUTES. FOR EXAMPLE, NAM BY ITSELF INHIBITS POLY(ADP-RIBOSE) POLYMERASES (PARPS), WHICH PROTECT GENOME INTEGRITY. ELEVATION OF THE NAD(+) POOL ALTERS CELLULAR ENERGY METABOLISM. MEANWHILE, HIGH-LEVEL NAM ALTERS CELLULAR METHYL METABOLISM AND AFFECTS METHYLATION OF DNA AND PROTEINS, LEADING TO CHANGES IN CELLULAR TRANSCRIPTOME AND PROTEOME. ALSO, METHYL METABOLITES OF NAM, NAMELY METHYLNICOTINAMIDE, ARE PREDICTED TO PLAY ROLES IN CERTAIN DISEASES AND CONDITIONS. IN THIS REVIEW, A COLLECTIVE LITERATURE SEARCH WAS PERFORMED TO PROVIDE A COMPREHENSIVE LIST OF POSSIBLE ADVERSE EFFECTS OF NAM AND TO PROVIDE UNDERSTANDING OF THEIR UNDERLYING MECHANISMS AND ASSESSMENT OF THE RAISED SAFETY CONCERNS. OUR REVIEW ASSURES SAFETY IN CURRENT USAGE LEVEL OF NAM, BUT ALSO FINDS POTENTIAL RISKS FOR EPIGENETIC ALTERATIONS ASSOCIATED WITH CHRONIC USE OF NAM AT HIGH DOSES. IT ALSO SUGGESTS DIRECTIONS OF THE FUTURE STUDIES TO ENSURE SAFER APPLICATION OF NAM. 2020 12 2104 27 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 13 5410 29 REGULATION OF ADAPTIVE IMMUNE CELLS BY SIRTUINS. IT IS NOW WELL-ESTABLISHED THAT THE PATHWAYS THAT CONTROL LYMPHOCYTE METABOLISM AND FUNCTION ARE INTIMATELY LINKED, AND CHANGES IN LYMPHOCYTE METABOLISM CAN INFLUENCE AND DIRECT CELLULAR FUNCTION. INTERESTINGLY, A NUMBER OF RECENT ADVANCES INDICATE THAT LYMPHOCYTE IDENTITY AND METABOLISM IS PARTIALLY CONTROLLED VIA EPIGENETIC REGULATION. EPIGENETIC MECHANISMS, SUCH AS CHANGES IN DNA METHYLATION OR HISTONE ACETYLATION, HAVE BEEN FOUND TO ALTER IMMUNE FUNCTION AND PLAY A ROLE IN NUMEROUS CHRONIC DISEASE STATES. THERE ARE SEVERAL ENZYMES THAT CAN MEDIATE EPIGENETIC CHANGES; OF PARTICULAR INTEREST ARE SIRTUINS, PROTEIN DEACETYLASES THAT MEDIATE ADAPTIVE RESPONSES TO A VARIETY OF STRESSES (INCLUDING CALORIE RESTRICTION AND METABOLIC STRESS) AND ARE NOW UNDERSTOOD TO PLAY A SIGNIFICANT ROLE IN IMMUNITY. THIS REVIEW WILL FOCUS ON RECENT ADVANCES IN THE UNDERSTANDING OF HOW SIRTUINS AFFECT THE ADAPTIVE IMMUNE SYSTEM. THESE PATHWAYS ARE OF SIGNIFICANT INTEREST AS THERAPEUTIC TARGETS FOR THE TREATMENT OF AUTOIMMUNITY, CANCER, AND TRANSPLANT TOLERANCE. 2019 14 5711 27 SIRT1 IS A HIGHLY NETWORKED PROTEIN THAT MEDIATES THE ADAPTATION TO CHRONIC PHYSIOLOGICAL STRESS. SIRT1 IS A NAD(+)-DEPENDENT PROTEIN DEACETYLASE THAT HAS A VERY LARGE NUMBER OF ESTABLISHED PROTEIN SUBSTRATES AND AN EQUALLY IMPRESSIVE LIST OF BIOLOGICAL FUNCTIONS THOUGHT TO BE REGULATED BY ITS ACTIVITY. PERHAPS AS NOTABLE IS THE REMARKABLE NUMBER OF POINTS OF CONFLICT CONCERNING THE ROLE OF SIRT1 IN BIOLOGICAL PROCESSES. FOR EXAMPLE, EVIDENCE EXISTS SUGGESTING THAT SIRT1 IS A TUMOR SUPPRESSOR, IS AN ONCOGENE, OR HAS NO EFFECT ON ONCOGENESIS. SIMILARLY, SIRT1 IS VARIABLY REPORTED TO INDUCE, INHIBIT, OR HAVE NO EFFECT ON AUTOPHAGY. WE BELIEVE THAT THE RESOLUTION OF MANY CONFLICTING RESULTS IS POSSIBLE BY CONSIDERING RECENT REPORTS INDICATING THAT SIRT1 IS AN IMPORTANT HUB INTERACTING WITH A COMPLEX NETWORK OF PROTEINS THAT COLLECTIVELY REGULATE A WIDE VARIETY OF BIOLOGICAL PROCESSES INCLUDING CANCER AND AUTOPHAGY. A NUMBER OF THE INTERACTING PROTEINS ARE THEMSELVES HUBS THAT, LIKE SIRT1, UTILIZE INTRINSICALLY DISORDERED REGIONS FOR THEIR PROMISCUOUS INTERACTIONS. MANY STUDIES INVESTIGATING SIRT1 FUNCTION HAVE BEEN CARRIED OUT ON CELL LINES CARRYING UNDETERMINED NUMBERS OF ALTERATIONS TO THE PROTEINS COMPRISING THE SIRT1 NETWORK OR ON INBRED MOUSE STRAINS CARRYING FIXED MUTATIONS AFFECTING SOME OF THESE PROTEINS. THUS, THE EFFECTS OF MODULATING SIRT1 AMOUNT AND/OR ACTIVITY ARE IMPORTANTLY DETERMINED BY THE GENETIC BACKGROUND OF THE CELL (OR THE INBRED STRAIN OF MICE), AND THE EFFECTS ATTRIBUTED TO SIRT1 ARE SYNTHETIC WITH THE BACKGROUND OF MUTATIONS AND EPIGENETIC DIFFERENCES BETWEEN CELLS AND ORGANISMS. WORK ON MICE CARRYING ALTERATIONS TO THE SIRT1 GENE SUGGESTS THAT THE NETWORK IN WHICH SIRT1 FUNCTIONS PLAYS AN IMPORTANT ROLE IN MEDIATING PHYSIOLOGICAL ADAPTATION TO VARIOUS SOURCES OF CHRONIC STRESS SUCH AS CALORIE RESTRICTION AND CALORIE OVERLOAD. WHETHER THE CATALYTIC ACTIVITY OF SIRT1 AND THE NUCLEAR CONCENTRATION OF THE CO-FACTOR, NAD(+), ARE RESPONSIBLE FOR MODULATING THIS ACTIVITY REMAINS TO BE DETERMINED. HOWEVER, THE EFFECT OF MODULATING SIRT1 ACTIVITY MUST BE INTERPRETED IN THE CONTEXT OF THE CELL OR TISSUE UNDER INVESTIGATION. INDEED, FOR SIRT1, WE ARGUE THAT CONTEXT IS EVERYTHING. 2013 15 6257 26 THE MOLECULAR BASIS OF TOLERANCE. TOLERANCE IS DEFINED AS THE DIMINISHED RESPONSE TO ALCOHOL OR OTHER DRUGS OVER THE COURSE OF REPEATED OR PROLONGED EXPOSURE. THIS MECHANISM ALLOWS PHYSIOLOGICAL PROCESSES TO ACHIEVE STABILITY IN A CONSTANTLY CHANGING ENVIRONMENT. THE ONSET OF TOLERANCE MAY OCCUR WITHIN MINUTES, DURING A SINGLE EXPOSURE TO ALCOHOL (I.E., ACUTE TOLERANCE), OR OVER LONGER TIMEFRAMES AND WITH PROLONGED EXPOSURE TO ALCOHOL (I.E., RAPID OR CHRONIC TOLERANCE). CHANGES IN TOLERANCE INDUCED BY ALCOHOL MAY AFFECT SEVERAL PROCESSES AT THE MOLECULAR, CELLULAR, OR BEHAVIORAL LEVEL. THESE EFFECTS OFTEN ARE INTERRELATED AND MAY BE DIFFICULT TO SEPARATE. THIS ARTICLE DESCRIBES CHANGES AT THE MOLECULAR LEVEL THAT ARE RELATED TO THE ONSET OF ACUTE, RAPID, OR CHRONIC TOLERANCE. IT FOCUSES ON NEURONAL MEMBRANE-BOUND CHANNELS AND THE FACTORS THAT AFFECT THEIR FUNCTION AND PRODUCTION, SUCH AS MODIFICATION OF PROTEIN SYNTHESIS AND ACTIVITY, INTERACTION WITH THE MEMBRANE LIPID MICROENVIRONMENT, EPIGENETIC EFFECTS ON CYTOPLASMIC REGULATION, AND GENE TRANSCRIPTION. ALSO CONSIDERED IS THE GENETICS OF TOLERANCE. 2008 16 6527 24 TRANSCRIPTIONAL CONTROL OF MALADAPTIVE AND PROTECTIVE RESPONSES IN ALCOHOLICS: A ROLE OF THE NF-KAPPAB SYSTEM. ALCOHOL DEPENDENCE AND ASSOCIATED COGNITIVE IMPAIRMENT APPEAR TO RESULT FROM MALADAPTIVE NEUROPLASTICITY IN RESPONSE TO CHRONIC ALCOHOL CONSUMPTION, NEUROINFLAMMATION AND NEURODEGENERATION. THE INHERENT STABILITY OF BEHAVIORAL ALTERATIONS ASSOCIATED WITH THE ADDICTED STATE SUGGESTS THAT TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS ARE OPERATIVE. NF-KAPPAB TRANSCRIPTION FACTORS ARE REGULATORS OF SYNAPTIC PLASTICITY AND INFLAMMATION, AND RESPONSIVE TO A VARIETY OF STIMULI INCLUDING ALCOHOL. THESE FACTORS ARE ABUNDANT IN THE BRAIN WHERE THEY HAVE DIVERSE FUNCTIONS THAT DEPEND ON THE COMPOSITION OF THE NF-KAPPAB COMPLEX AND CELLULAR CONTEXT. IN NEURON CELL BODIES, NF-KAPPAB IS CONSTITUTIVELY ACTIVE, AND INVOLVED IN NEURONAL INJURY AND NEUROPROTECTION. HOWEVER, AT THE SYNAPSE, NF-KAPPAB IS PRESENT IN A LATENT FORM AND UPON ACTIVATION IS TRANSPORTED TO THE CELL NUCLEUS. IN GLIA, NF-KAPPAB IS INDUCIBLE AND REGULATES INFLAMMATORY PROCESSES THAT EXACERBATE ALCOHOL-INDUCED NEURODEGENERATION. ANIMAL STUDIES DEMONSTRATE THAT ACUTE ALCOHOL EXPOSURE TRANSIENTLY ACTIVATES NF-KAPPAB, WHICH INDUCES NEUROINFLAMMATORY RESPONSES AND NEURODEGENERATION. POSTMORTEM STUDIES OF BRAINS OF HUMAN ALCOHOLICS SUGGEST THAT REPEATED CYCLES OF ALCOHOL CONSUMPTION AND WITHDRAWAL CAUSE ADAPTIVE CHANGES IN THE NF-KAPPAB SYSTEM THAT MAY PERMIT THE SYSTEM TO BETTER TOLERATE EXCESSIVE STIMULATION. THIS TYPE OF TOLERANCE, ENSURING A LOW DEGREE OF RESPONSIVENESS TO APPLIED STIMULI, APPARENTLY DIFFERS FROM THAT IN THE IMMUNE SYSTEM, AND MAY REPRESENT A COMPENSATORY RESPONSE THAT PROTECTS BRAIN CELLS AGAINST ALCOHOL NEUROTOXICITY. THIS VIEW IS SUPPORTED BY FINDINGS SHOWING PREFERENTIAL DOWNREGULATION OF PRO-APOPTOTIC GENE EXPRESSION IN THE AFFECTED BRAIN AREAS IN HUMAN ALCOHOLICS. ALTHOUGH FURTHER VERIFICATION IS NEEDED, WE SPECULATE THAT NF-KAPPAB-DRIVEN NEUROINFLAMMATION AND DISRUPTION TO NEUROPLASTICITY PLAY A SIGNIFICANT ROLE IN REGULATING ALCOHOL DEPENDENCE AND COGNITIVE IMPAIRMENT. 2011 17 860 25 CHROMATIN MODIFICATIONS DURING REPAIR OF ENVIRONMENTAL EXPOSURE-INDUCED DNA DAMAGE: A POTENTIAL MECHANISM FOR STABLE EPIGENETIC ALTERATIONS. EXPOSURES TO ENVIRONMENTAL TOXICANTS AND TOXINS CAUSE EPIGENETIC CHANGES THAT LIKELY PLAY A ROLE IN THE DEVELOPMENT OF DISEASES ASSOCIATED WITH EXPOSURE. THE MECHANISM BEHIND THESE EXPOSURE-INDUCED EPIGENETIC CHANGES IS CURRENTLY UNKNOWN. ONE COMMONALITY BETWEEN MOST ENVIRONMENTAL EXPOSURES IS THAT THEY CAUSE DNA DAMAGE EITHER DIRECTLY OR THROUGH CAUSING AN INCREASE IN REACTIVE OXYGEN SPECIES, WHICH CAN DAMAGE DNA. LIKE TRANSCRIPTION, DNA DAMAGE REPAIR MUST OCCUR IN THE CONTEXT OF CHROMATIN REQUIRING BOTH HISTONE MODIFICATIONS AND ATP-DEPENDENT CHROMATIN REMODELING. THESE CHROMATIN CHANGES AID IN DNA DAMAGE ACCESSIBILITY AND SIGNALING. SEVERAL PROTEINS AND COMPLEXES INVOLVED IN EPIGENETIC SILENCING DURING BOTH DEVELOPMENT AND CANCER HAVE BEEN FOUND TO BE LOCALIZED TO SITES OF DNA DAMAGE. THE CHROMATIN-BASED RESPONSE TO DNA DAMAGE IS CONSIDERED A TRANSIENT EVENT, WITH CHROMATIN BEING RESTORED TO NORMAL AS DNA DAMAGE REPAIR IS COMPLETED. HOWEVER, IN INDIVIDUALS CHRONICALLY EXPOSED TO ENVIRONMENTAL TOXICANTS OR WITH CHRONIC INFLAMMATORY DISEASE, REPEATED DNA DAMAGE-INDUCED CHROMATIN REARRANGEMENT MAY ULTIMATELY LEAD TO PERMANENT EPIGENETIC ALTERATIONS. UNDERSTANDING THE MECHANISM BEHIND EXPOSURE-INDUCED EPIGENETIC CHANGES WILL ALLOW US TO DEVELOP STRATEGIES TO PREVENT OR REVERSE THESE CHANGES. THIS REVIEW FOCUSES ON EPIGENETIC CHANGES AND DNA DAMAGE INDUCED BY ENVIRONMENTAL EXPOSURES, THE CHROMATIN CHANGES THAT OCCUR AROUND SITES OF DNA DAMAGE, AND HOW THESE TRANSIENT CHROMATIN CHANGES MAY LEAD TO HERITABLE EPIGENETIC ALTERATIONS AT SITES OF CHRONIC EXPOSURE. 2014 18 2499 21 EPIGENETICS AND EXERCISE. EPIGENETICS CAN BE DEFINED AS 'THE STRUCTURAL ADAPTATION OF CHROMOSOMAL REGIONS SO AS TO REGISTER, SIGNAL, OR PERPETUATE ALTERED ACTIVITY STATES.' INCREASED TRANSCRIPTION OF KEY REGULATORY, METABOLIC, AND MYOGENIC GENES IS AN EARLY RESPONSE TO EXERCISE AND IS IMPORTANT IN MEDIATING SUBSEQUENT ADAPTATIONS IN SKELETAL MUSCLE. DNA HYPOMETHYLATION AND HISTONE HYPERACETYLATION ARE EMERGING AS IMPORTANT CRUCIAL EVENTS FOR INCREASED TRANSCRIPTION. THE COMPLEX INTERACTIONS BETWEEN MULTIPLE EPIGENETIC MODIFICATIONS AND THEIR REGULATION BY METABOLIC CHANGES AND SIGNALING EVENTS DURING EXERCISE, WITH IMPLICATIONS FOR ENHANCED UNDERSTANDING OF THE ACUTE AND CHRONIC ADAPTATIONS TO EXERCISE, ARE QUESTIONS FOR FURTHER INVESTIGATION. 2019 19 2360 20 EPIGENETIC REGULATION OF SKELETAL MUSCLE METABOLISM. NORMAL SKELETAL MUSCLE METABOLISM IS ESSENTIAL FOR WHOLE BODY METABOLIC HOMOEOSTASIS AND DISRUPTIONS IN MUSCLE METABOLISM ARE ASSOCIATED WITH A NUMBER OF CHRONIC DISEASES. TRANSCRIPTIONAL CONTROL OF METABOLIC ENZYME EXPRESSION IS A MAJOR REGULATORY MECHANISM FOR MUSCLE METABOLIC PROCESSES. SUBSTANTIAL EVIDENCE IS EMERGING THAT HIGHLIGHTS THE IMPORTANCE OF EPIGENETIC MECHANISMS IN THIS PROCESS. THIS REVIEW WILL EXAMINE THE IMPORTANCE OF EPIGENETICS IN THE REGULATION OF MUSCLE METABOLISM, WITH A PARTICULAR EMPHASIS ON DNA METHYLATION AND HISTONE ACETYLATION AS EPIGENETIC CONTROL POINTS. THE EMERGING CROSS-TALK BETWEEN METABOLISM AND EPIGENETICS IN THE CONTEXT OF HEALTH AND DISEASE WILL ALSO BE EXAMINED. THE CONCEPT OF INHERITANCE OF SKELETAL MUSCLE METABOLIC PHENOTYPES WILL BE DISCUSSED, IN ADDITION TO EMERGING EPIGENETIC THERAPIES THAT COULD BE USED TO ALTER MUSCLE METABOLISM IN CHRONIC DISEASE STATES. 2016 20 2493 35 EPIGENETICS AND CHROMATIN REMODELING PLAY A ROLE IN LUNG DISEASE. EPIGENETICS IS DEFINED AS HERITABLE CHANGES THAT AFFECT GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. EPIGENETIC REGULATION OF GENE EXPRESSION IS FACILITATED THROUGH DIFFERENT MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-ASSOCIATED SILENCING BY SMALL NON-CODING RNAS. ALL THESE MECHANISMS ARE CRUCIAL FOR NORMAL DEVELOPMENT, DIFFERENTIATION AND TISSUE-SPECIFIC GENE EXPRESSION. THESE THREE SYSTEMS INTERACT AND STABILIZE ONE ANOTHER AND CAN INITIATE AND SUSTAIN EPIGENETIC SILENCING, THUS DETERMINING HERITABLE CHANGES IN GENE EXPRESSION. HISTONE ACETYLATION REGULATES DIVERSE CELLULAR FUNCTIONS INCLUDING INFLAMMATORY GENE EXPRESSION, DNA REPAIR AND CELL PROLIFERATION. TRANSCRIPTIONAL COACTIVATORS POSSESS INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY AND THIS ACTIVITY DRIVES INFLAMMATORY GENE EXPRESSION. ELEVEN CLASSICAL HISTONE DEACETYLASES (HDACS) ACT TO REGULATE THE EXPRESSION OF DISTINCT SUBSETS OF INFLAMMATORY/IMMUNE GENES. THUS, LOSS OF HDAC ACTIVITY OR THE PRESENCE OF HDAC INHIBITORS CAN FURTHER ENHANCE INFLAMMATORY GENE EXPRESSION BY PRODUCING A GENE-SPECIFIC CHANGE IN HAT ACTIVITY. FOR EXAMPLE, HDAC2 EXPRESSION AND ACTIVITY ARE REDUCED IN LUNG MACROPHAGES, BIOPSY SPECIMENS, AND BLOOD CELLS FROM PATIENTS WITH SEVERE ASTHMA AND SMOKING ASTHMATICS, AS WELL AS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS MAY ACCOUNT, AT LEAST IN PART, FOR THE ENHANCED INFLAMMATION AND REDUCED STEROID RESPONSIVENESS SEEN IN THESE PATIENTS. OTHER PROTEINS, PARTICULARLY TRANSCRIPTION FACTORS, ARE ALSO ACETYLATED AND ARE TARGETS FOR DEACETYLATION BY HDACS AND SIRTUINS, A RELATED FAMILY OF 7 PREDOMINANTLY PROTEIN DEACETYLASES. THUS THE ACETYLATION/DEACETYLATION STATUS OF NF-KAPPAB AND THE GLUCOCORTICOID RECEPTOR CAN ALSO AFFECT THE OVERALL EXPRESSION PATTERN OF INFLAMMATORY GENES AND REGULATE THE INFLAMMATORY RESPONSE. UNDERSTANDING AND TARGETING SPECIFIC ENZYMES INVOLVED IN THIS PROCESS MIGHT LEAD TO NEW THERAPEUTIC AGENTS, PARTICULARLY IN SITUATIONS IN WHICH CURRENT ANTI-INFLAMMATORY THERAPIES ARE SUBOPTIMAL. 2011