1 5126 117 POST-TRANSLATIONAL PROTEIN MODIFICATION BY O-LINKED N-ACETYL-GLUCOSAMINE: ITS ROLE IN MEDIATING THE ADVERSE EFFECTS OF DIABETES ON THE HEART. THE POST-TRANSLATION ATTACHMENT OF O-LINKED N-ACETYLGLUCOSAMINE, OR O-GLCNAC, TO SERINE AND THREONINE RESIDUES OF NUCLEAR AND CYTOPLASMIC PROTEINS IS INCREASINGLY RECOGNIZED AS A KEY REGULATOR OF DIVERSE CELLULAR PROCESSES. O-GLCNAC SYNTHESIS IS ESSENTIAL FOR CELL SURVIVAL AND IT HAS BEEN SHOWN THAT ACUTE ACTIVATION OF PATHWAYS, WHICH INCREASE CELLULAR O-GLCNAC LEVELS IS CYTOPROTECTIVE; HOWEVER, PROLONGED INCREASES IN O-GLCNACYLATION HAVE BEEN IMPLICATED IN A NUMBER OF CHRONIC DISEASES. GLUCOSE METABOLISM VIA THE HEXOSAMINE BIOSYNTHESIS PATHWAY PLAYS A CENTRAL ROLE IN REGULATING O-GLCNAC SYNTHESIS; CONSEQUENTLY, SUSTAINED INCREASES IN O-GLCNAC LEVELS HAVE BEEN IMPLICATED IN GLUCOSE TOXICITY AND INSULIN RESISTANCE. STUDIES ON THE ROLE OF O-GLCNAC IN REGULATING CARDIOMYOCYTE FUNCTION HAVE GROWN RAPIDLY OVER THE PAST DECADE AND THERE IS GROWING EVIDENCE THAT INCREASED O-GLCNAC LEVELS CONTRIBUTE TO THE ADVERSE EFFECTS OF DIABETES ON THE HEART, INCLUDING IMPAIRED CONTRACTILITY, CALCIUM HANDLING, AND ABNORMAL STRESS RESPONSES. RECENT EVIDENCE ALSO SUGGESTS THAT O-GLCNAC PLAYS A ROLE IN EPIGENETIC CONTROL OF GENE TRANSCRIPTION. THE GOAL OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF OUR CURRENT KNOWLEDGE ABOUT THE REGULATION OF PROTEIN O-GLCNACYLATION AND TO EXPLORE IN MORE DETAIL O-GLCNAC-MEDIATED RESPONSES IN THE DIABETIC HEART. 2013 2 3840 37 IRON DEFICIENCY REPROGRAMS PHOSPHORYLATION SIGNALING AND REDUCES O-GLCNAC PATHWAYS IN NEURONAL CELLS. MICRONUTRIENT SENSING IS CRITICAL FOR CELLULAR GROWTH AND DIFFERENTIATION. DEFICIENCIES IN ESSENTIAL NUTRIENTS SUCH AS IRON STRONGLY AFFECT NEURONAL CELL DEVELOPMENT AND MAY LEAD TO DEFECTS IN NEURONAL FUNCTION THAT CANNOT BE REMEDIED BY SUBSEQUENT IRON SUPPLEMENTATION. TO UNDERSTAND THE ADAPTIVE INTRACELLULAR RESPONSES TO IRON DEFICIENCY IN NEURONAL CELLS, WE DEVELOPED AND UTILIZED A STABLE ISOTOPIC LABELING OF AMINO ACIDS IN CELL CULTURE (SILAC)-BASED QUANTITATIVE PHOSPHOPROTEOMICS WORKFLOW. OUR INTEGRATED APPROACH WAS DESIGNED TO COMPREHENSIVELY ELUCIDATE THE CHANGES IN PHOSPHORYLATION SIGNALING UNDER BOTH ACUTE AND CHRONIC IRON-DEFICIENT CELL MODELS. IN ADDITION, WE ANALYZED THE DIFFERENTIAL CELLULAR RESPONSES BETWEEN IRON DEFICIENCY AND HYPOXIA (OXYGEN-DEPRIVED) IN NEURONAL CELLS. OUR ANALYSIS IDENTIFIED NEARLY 16,000 PHOSPHORYLATION SITES IN HT-22 CELLS, A HIPPOCAMPAL-DERIVED NEURONAL CELL LINE, MORE THAN TEN PERCENT OF WHICH SHOWED AT LEAST 2-FOLD CHANGES IN RESPONSE TO EITHER HYPOXIA OR ACUTE/CHRONIC IRON DEFICIENCY. BIOINFORMATIC ANALYSIS REVEALED THAT IRON DEFICIENCY ALTERED KEY METABOLIC AND EPIGENETIC PATHWAYS INCLUDING THE PHOSPHORYLATION OF PROTEINS INVOLVED IN IRON SEQUESTRATION, GLUTAMATE METABOLISM, AND HISTONE METHYLATION. IN PARTICULAR, IRON DEFICIENCY INCREASED GLUTAMINE-FRUCTOSE-6-PHOSPHATE TRANSAMINASE (GFPT1) PHOSPHORYLATION, WHICH IS A KEY ENZYME IN THE GLUCOSAMINE BIOSYNTHESIS PATHWAY AND A TARGET OF 5' AMP-ACTIVATED PROTEIN KINASE (AMPK), LEADING TO REDUCED GFPT1 ENZYMATIC ACTIVITY AND CONSEQUENTLY LOWER GLOBAL O-GLCNAC MODIFICATION IN NEURONAL CELLS. TAKEN TOGETHER, OUR ANALYSIS OF THE PHOSPHOPROTEOME DYNAMICS IN RESPONSE TO IRON AND OXYGEN DEPRIVATION DEMONSTRATED AN ADAPTIVE CELLULAR RESPONSE BY MOUNTING POST-TRANSLATIONAL MODIFICATIONS THAT ARE CRITICAL FOR INTRACELLULAR SIGNALING AND EPIGENETIC PROGRAMMING IN NEURONAL CELLS. 2021 3 2319 29 EPIGENETIC REGULATION OF GABAERGIC NEUROTRANSMISSION AND NEUROSTEROID BIOSYNTHESIS IN ALCOHOL USE DISORDER. BACKGROUND: ALCOHOL USE DISORDER (AUD) IS A CHRONIC RELAPSING BRAIN DISORDER. GABAA RECEPTOR (GABAAR) SUBUNITS ARE A TARGET FOR THE PHARMACOLOGICAL EFFECTS OF ALCOHOL. NEUROSTEROIDS PLAY AN IMPORTANT ROLE IN THE FINE-TUNING OF GABAAR FUNCTION IN THE BRAIN. RECENTLY, WE HAVE SHOWN THAT AUD IS ASSOCIATED WITH CHANGES IN DNA METHYLATION MECHANISMS. HOWEVER, THE ROLE OF DNA METHYLATION IN THE REGULATION OF NEUROSTEROID BIOSYNTHESIS AND GABAERGIC NEUROTRANSMISSION IN AUD PATIENTS REMAINS UNDER-INVESTIGATED. METHODS: IN A COHORT OF POSTMORTEM BRAINS FROM 20 MALE CONTROLS AND AUD PATIENTS, WE INVESTIGATED THE EXPRESSION OF GABAAR SUBUNITS AND NEUROSTEROID BIOSYNTHETIC ENZYMES AND THEIR REGULATION BY DNA METHYLATION MECHANISMS. NEUROSTEROID LEVELS WERE QUANTIFIED BY GAS CHROMATOGRAPHY-MASS SPECTROMETRY. RESULTS: THE ALPHA 2 SUBUNIT EXPRESSION WAS REDUCED DUE TO INCREASED DNA METHYLATION AT THE GENE PROMOTER REGION IN THE CEREBELLUM OF AUD PATIENTS, A BRAIN AREA PARTICULARLY SENSITIVE TO THE EFFECTS OF ALCOHOL. ALCOHOL-INDUCED ALTERATION IN GABAAR SUBUNITS WAS ALSO OBSERVED IN THE PREFRONTAL CORTEX. NEUROSTEROID BIOSYNTHESIS WAS ALSO AFFECTED WITH REDUCED CEREBELLAR EXPRESSION OF THE 18KDA TRANSLOCATOR PROTEIN AND 3ALPHA-HYDROXYSTEROID DEHYDROGENASE MRNAS. NOTABLY, INCREASED DNA METHYLATION LEVELS WERE OBSERVED AT THE PROMOTER REGION OF 3ALPHA-HYDROXYSTEROID DEHYDROGENASE. THESE CHANGES WERE ASSOCIATED WITH MARKEDLY REDUCED LEVELS OF ALLOPREGNANOLONE AND PREGNANOLONE IN THE CEREBELLUM. CONCLUSION: GIVEN THE KEY ROLE OF NEUROSTEROIDS IN MODULATING THE STRENGTH OF GABAAR-MEDIATED INHIBITION, OUR DATA SUGGEST THAT ALCOHOL-INDUCED IMPAIRMENTS IN GABAERGIC NEUROTRANSMISSION MIGHT BE PROFOUNDLY IMPACTED BY REDUCED NEUROSTEROID BIOSYNTHESIS MOST LIKELY VIA DNA HYPERMETHYLATION. 2021 4 3155 31 GLUTAMINE METABOLISM IN ADIPOCYTES: A BONA FIDE EPIGENETIC MODULATOR OF INFLAMMATION. A CHRONIC LOW-GRADE INFLAMMATION OF WHITE ADIPOSE TISSUE (WAT) IS ONE OF THE HALLMARKS OF OBESITY AND IS PROPOSED TO CONTRIBUTE TO INSULIN RESISTANCE AND TYPE 2 DIABETES. DESPITE THIS, THE CAUSAL MECHANISMS UNDERLYING WAT INFLAMMATION REMAIN UNCLEAR. BASED ON METABOLOMIC ANALYSES OF HUMAN WAT, PETRUS ET AL. SHOWED THAT THE AMINO ACID GLUTAMINE WAS THE MOST MARKEDLY REDUCED POLAR METABOLITE IN THE OBESE STATE. REDUCED GLUTAMINE LEVELS IN ADIPOCYTES INDUCE AN INCREASE OF URIDINE DIPHOSPHATE N-ACETYLGLUCOSAMINE (UDP-GLCNAC) LEVELS VIA INDUCTION OF GLYCOLYSIS AND THE HEXOSAMINE BIOSYNTHETIC PATHWAYS. THIS PROMOTES NUCLEAR O-GLCNACYLATION, A POSTTRANSLATIONAL MODIFICATION THAT ACTIVATES THE TRANSCRIPTION OF PRO-INFLAMMATORY GENES. CONVERSELY, GLUTAMINE SUPPLEMENTATION IN VITRO AND IN VIVO, REVERSED THESE EFFECTS. ALTOGETHER, DYSREGULATION OF INTRACELLULAR GLUTAMINE METABOLISM IN WAT ESTABLISHES AN EPIGENETIC LINK BETWEEN ADIPOCYTES AND INFLAMMATION. THIS COMMENTARY DISCUSSES THESE FINDINGS AND THEIR POSSIBLY THERAPEUTIC RELEVANCE IN RELATION TO INSULIN RESISTANCE AND TYPE 2 DIABETES. 2020 5 4175 33 MELATONIN PROTECTS CHOLANGIOCYTES FROM OXIDATIVE STRESS-INDUCED PROAPOPTOTIC AND PROINFLAMMATORY STIMULI VIA MIR-132 AND MIR-34. BIOSYNTHESIS OF MELATONIN BY CHOLANGIOCYTES IS ESSENTIAL FOR MAINTAINING THE FUNCTION OF BILIARY EPITHELIUM. HOWEVER, THIS CYTOPROTECTIVE MECHANISM APPEARS TO BE IMPAIRED IN PRIMARY BILIARY CHOLANGITIS (PBC). MIR-132 HAS EMERGED AS A MEDIATOR OF INFLAMMATION IN CHRONIC LIVER DISEASES. THE EFFECT OF MELATONIN ON OXIDATIVE STRESS AND BILE ACID-INDUCED APOPTOSIS WAS ALSO EXAMINED IN CHOLANGIOCYES OVEREXPRESSING MIR506, AS A PBC-LIKE CELLULAR MODEL. IN PBC PATIENTS THE SERUM LEVELS OF MELATONIN WERE FOUND INCREASED IN COMPARISON TO HEALTHY CONTROLS. WHEREAS, IN CHOLANGIOCYTES WITHIN CIRRHOTIC PBC LIVERS THE MELATONIN BIOSYNTHETIC PATHWAY WAS SUBSTANTIALLY SUPPRESSED EVEN THOUGH THE EXPRESSIONS OF MELATONIN RATE-LIMITING ENZYME ARALKYLAMINE N-ACETYLTRANSFERASE (AANAT), AND CK-19 (MARKER OF CHOLANGIOCYTES) WERE ENHANCED. IN CHOLANGIOCYTES EXPOSED TO MITOCHONDRIAL OXIDATIVE STRESS MELATONIN DECREASED THE EXPRESSION OF PROAPOPTOTIC STIMULI (PTEN, BAX, MIR-34), WHICH WAS ACCOMPANIED BY THE INHIBITION OF A PIVOTAL MEDIATOR OF INFLAMMATORY RESPONSE NF-KAPPAB-P65 AND THE ACTIVATION OF ANTIAPOPTOTIC SIGNALING (MIR-132, BCL2). SIMILARLY, MELATONIN REDUCED BILE ACID-INDUCED PROAPOPTOTIC CASPASE 3 AND BIM LEVELS. IN SUMMARY, THE INSUFFICIENT HEPATIC EXPRESSION OF MELATONIN IN PBC PATIENTS MAY PREDISPOSE CHOLANGIOCYTES TO OXIDATIVE STRESS-RELATED DAMAGE. MELATONIN, VIA EPIGENETIC MODULATION, WAS ABLE TO SUPPRESS NF-KAPPAB SIGNALING ACTIVATION AND PROTECT AGAINST BILIARY CELLS APOPTOTIC SIGNALING. 2020 6 6166 42 THE GLUTATHIONE SYSTEM: A NEW DRUG TARGET IN NEUROIMMUNE DISORDERS. GLUTATHIONE (GSH) HAS A CRUCIAL ROLE IN CELLULAR SIGNALING AND ANTIOXIDANT DEFENSES EITHER BY REACTING DIRECTLY WITH REACTIVE OXYGEN OR NITROGEN SPECIES OR BY ACTING AS AN ESSENTIAL COFACTOR FOR GSH S-TRANSFERASES AND GLUTATHIONE PEROXIDASES. GSH ACTING IN CONCERT WITH ITS DEPENDENT ENZYMES, KNOWN AS THE GLUTATHIONE SYSTEM, IS RESPONSIBLE FOR THE DETOXIFICATION OF REACTIVE OXYGEN AND NITROGEN SPECIES (ROS/RNS) AND ELECTROPHILES PRODUCED BY XENOBIOTICS. ADEQUATE LEVELS OF GSH ARE ESSENTIAL FOR THE OPTIMAL FUNCTIONING OF THE IMMUNE SYSTEM IN GENERAL AND T CELL ACTIVATION AND DIFFERENTIATION IN PARTICULAR. GSH IS A UBIQUITOUS REGULATOR OF THE CELL CYCLE PER SE. GSH ALSO HAS CRUCIAL FUNCTIONS IN THE BRAIN AS AN ANTIOXIDANT, NEUROMODULATOR, NEUROTRANSMITTER, AND ENABLER OF NEURON SURVIVAL. DEPLETION OF GSH LEADS TO EXACERBATION OF DAMAGE BY OXIDATIVE AND NITROSATIVE STRESS; HYPERNITROSYLATION; INCREASED LEVELS OF PROINFLAMMATORY MEDIATORS AND INFLAMMATORY POTENTIAL; DYSFUNCTIONS OF INTRACELLULAR SIGNALING NETWORKS, E.G., P53, NUCLEAR FACTOR-KAPPAB, AND JANUS KINASES; DECREASED CELL PROLIFERATION AND DNA SYNTHESIS; INACTIVATION OF COMPLEX I OF THE ELECTRON TRANSPORT CHAIN; ACTIVATION OF CYTOCHROME C AND THE APOPTOTIC MACHINERY; BLOCKADE OF THE METHIONINE CYCLE; AND COMPROMISED EPIGENETIC REGULATION OF GENE EXPRESSION. AS SUCH, GSH DEPLETION HAS MARKED CONSEQUENCES FOR THE HOMEOSTATIC CONTROL OF THE IMMUNE SYSTEM, OXIDATIVE AND NITROSATIVE STRESS (O&NS) PATHWAYS, REGULATION OF ENERGY PRODUCTION, AND MITOCHONDRIAL SURVIVAL AS WELL. GSH DEPLETION AND CONCOMITANT INCREASE IN O&NS AND MITOCHONDRIAL DYSFUNCTIONS PLAY A ROLE IN THE PATHOPHYSIOLOGY OF DIVERSE NEUROIMMUNE DISORDERS, INCLUDING DEPRESSION, MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME AND PARKINSON'S DISEASE, SUGGESTING THAT DEPLETED GSH IS AN INTEGRAL PART OF THESE DISEASES. THERAPEUTICAL INTERVENTIONS THAT AIM TO INCREASE GSH CONCENTRATIONS IN VIVO INCLUDE N-ACETYL CYSTEINE; NRF-2 ACTIVATION VIA HYPERBARIC OXYGEN THERAPY; DIMETHYL FUMARATE; PHYTOCHEMICALS, INCLUDING CURCUMIN, RESVERATROL, AND CINNAMON; AND FOLATE SUPPLEMENTATION. 2014 7 2002 27 EPIGENETIC AND POST-TRANSCRIPTIONAL REPRESSION SUPPORT METABOLIC SUPPRESSION IN CHRONICALLY HYPOXIC GOLDFISH. GOLDFISH ENTER A HYPOMETABOLIC STATE TO SURVIVE CHRONIC HYPOXIA. WE RECENTLY DESCRIBED TISSUE-SPECIFIC CONTRIBUTIONS OF MEMBRANE LIPID COMPOSITION REMODELING AND MITOCHONDRIAL FUNCTION TO METABOLIC SUPPRESSION ACROSS DIFFERENT GOLDFISH TISSUES. HOWEVER, THE MOLECULAR AND ESPECIALLY EPIGENETIC FOUNDATIONS OF HYPOXIA TOLERANCE IN GOLDFISH UNDER METABOLIC SUPPRESSION ARE NOT WELL UNDERSTOOD. HERE WE SHOW THAT COMPONENTS OF THE MOLECULAR OXYGEN-SENSING MACHINERY ARE ROBUSTLY ACTIVATED ACROSS TISSUES IRRESPECTIVE OF HYPOXIA DURATION. INDUCTION OF GENE EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION TURNOVER AND MICRORNA BIOGENESIS SUGGEST A ROLE FOR EPIGENETIC TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL SUPPRESSION OF GENE EXPRESSION IN THE HYPOXIA-ACCLIMATED BRAIN. CONVERSELY, MECHANISTIC TARGET OF RAPAMYCIN-DEPENDENT TRANSLATIONAL MACHINERY ACTIVITY IS NOT REDUCED IN LIVER AND WHITE MUSCLE, SUGGESTING THIS PATHWAY DOES NOT CONTRIBUTE TO LOWERING CELLULAR ENERGY EXPENDITURE. FINALLY, MOLECULAR EVIDENCE SUPPORTS PREVIOUSLY REPORTED CHRONIC HYPOXIA-DEPENDENT CHANGES IN MEMBRANE CHOLESTEROL, LIPID METABOLISM AND MITOCHONDRIAL FUNCTION VIA CHANGES IN TRANSCRIPTS INVOLVED IN CHOLESTEROL BIOSYNTHESIS, BETA-OXIDATION, AND MITOCHONDRIAL FUSION IN MULTIPLE TISSUES. OVERALL, THIS STUDY SHOWS THAT CHRONIC HYPOXIA ROBUSTLY INDUCES EXPRESSION OF OXYGEN-SENSING MACHINERY ACROSS TISSUES, INDUCES REPRESSIVE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL EPIGENETIC MARKS ESPECIALLY IN THE CHRONIC HYPOXIA-ACCLIMATED BRAIN AND SUPPORTS A ROLE FOR MEMBRANE REMODELING AND MITOCHONDRIAL FUNCTION AND DYNAMICS IN PROMOTING METABOLIC SUPPRESSION. 2022 8 3432 32 HYDROGEN SULFIDE BIOSYNTHESIS IS IMPAIRED IN THE OSTEOARTHRITIC JOINT. OSTEOARTHRITIS (OA) IS THE MOST COMMON FORM OF ARTHRITIS AND IT IS A LEADING CAUSE OF DISABILITY IN THE ELDERLY. ITS COMPLETE ETIOLOGY IS NOT KNOWN ALTHOUGH THERE ARE SEVERAL METABOLIC, GENETIC, EPIGENETIC, AND LOCAL CONTRIBUTING FACTORS INVOLVED. AT THE MOMENT, THERE IS NO CURE FOR THIS PATHOLOGY AND TREATMENT ALTERNATIVES TO RETARD OR STOP ITS PROGRESSION ARE INTENSIVELY BEING SOUGHT. HYDROGEN SULFIDE (H(2)S) IS A SMALL GASEOUS MOLECULE AND IS PRESENT IN SULFUROUS MINERAL WATERS AS ITS ACTIVE COMPONENT. DATA FROM RECENT CLINICAL TRIALS SHOWS THAT BALNEOTHERAPY (IMMERSION IN MINERAL AND/OR THERMAL WATERS FROM NATURAL SPRINGS) IN SULFUROUS WATERS CAN IMPROVE OA SYMPTOMS, IN PARTICULAR, PAIN AND FUNCTION. YET, THE UNDERLYING MECHANISMS ARE POORLY KNOWN. HYDROGEN SULFIDE IS ALSO CONSIDERED, WITH NO AND CO, AN ENDOGENOUS SIGNALING GASOTRANSMITTER. IT IS SYNTHESIZED ENDOGENOUSLY WITH THE HELP OF THREE ENZYMES, CYSTATHIONINE GAMMA-LYASE (CTH), CYSTATHIONINE BETA-SYNTHASE (CBS), AND 3-MERCAPTOPYRUVATE SULFURTRANSFERASE (3-MPST). HERE, THE EXPRESSION OF THESE THREE ENZYMES WAS DEMONSTRATED BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR) AND THEIR PROTEIN ABUNDANCE [BY IMMUNOHISTOCHEMISTRY AND WESTERN BLOT (WB)] IN HUMAN ARTICULAR CARTILAGE. NO SIGNIFICANT DIFFERENCES WERE FOUND IN CBS OR CTH EXPRESSION OR ABUNDANCE, BUT MRNA AND PROTEIN LEVELS OF 3-MPST WERE SIGNIFICANTLY REDUCED IN CARTILAGE FORM OA DONORS. ALSO, THE BIOSYNTHESIS OF H(2)S FROM OA CARTILAGE, MEASURED WITH A SPECIFIC MICROELECTRODE, WAS SIGNIFICANTLY LOWER THAN IN OA-FREE TISSUE. YET, NO DIFFERENCES WERE FOUND IN H(2)S CONCENTRATION IN SERUM FROM OA PATIENTS AND OA-FREE DONORS. THE CURRENT RESULTS SUGGEST THAT REDUCED LEVELS OF THE MITOCHONDRIAL ENZYME 3-MPST IN OA CARTILAGE MIGHT BE, AT LEAST IN PART, RESPONSIBLE FOR A REDUCTION IN H(2)S BIOSYNTHESIS IN THIS TISSUE AND THAT IMPAIRED H(2)S BIOSYNTHESIS IN THE JOINT MIGHT BE A CONTRIBUTING FACTOR TO OA. THIS COULD CONTRIBUTE TO EXPLAIN WHY EXOGENOUS SUPPLEMENTATION OF H(2)S, FOR INSTANCE WITH SULFUROUS THERMAL WATER, HAS POSITIVE EFFECTS IN OA PATIENTS. 2020 9 1875 35 EMERGING ROLE OF ONE-CARBON METABOLISM AND DNA METHYLATION ENRICHMENT ON DELTA-CONTAINING GABAA RECEPTOR EXPRESSION IN THE CEREBELLUM OF SUBJECTS WITH ALCOHOL USE DISORDERS (AUD). BACKGROUND: CEREBELLUM IS AN AREA OF THE BRAIN PARTICULARLY SENSITIVE TO THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL CONSUMPTION. ALCOHOL EXPOSURE DECREASES CEREBELLAR PURKINJE CELL OUTPUT BY INCREASING GABA RELEASE FROM GOLGI CELLS ONTO EXTRASYNAPTIC ALPHA6/DELTA-CONTAINING GABAA RECEPTORS LOCATED ON GLUTAMATERGIC GRANULE CELLS. HERE, WE STUDIED WHETHER CHRONIC ALCOHOL CONSUMPTION INDUCES CHANGES IN GABAA RECEPTOR SUBUNIT EXPRESSION AND WHETHER THESE CHANGES ARE ASSOCIATED WITH ALTERATIONS IN EPIGENETIC MECHANISMS VIA DNA METHYLATION. METHODS: WE USED A COHORT OF POSTMORTEM CEREBELLUM FROM CONTROL AND CHRONIC ALCOHOLICS, HERE DEFINED AS ALCOHOL USE DISORDERS SUBJECTS (N=25/GROUP). S-ADENOSYL-METHIONINE/S-ADENOSYL-HOMOCYSTEINE WERE MEASURED BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY. MRNA LEVELS OF VARIOUS GENES WERE ASSESSED BY REVERSE TRANSCRIPTASE-QUANTITATIVE POLYMERASE CHAIN REACTION. PROMOTER METHYLATION ENRICHMENT WAS ASSESSED USING METHYLATED DNA IMMUNOPRECIPITATION AND HYDROXY-METHYLATED DNA IMMUNOPRECIPITATION ASSAYS. RESULTS: MRNAS ENCODING KEY ENZYMES OF 1-CARBON METABOLISM THAT DETERMINE THE S-ADENOSYL-METHIONINE/S-ADENOSYL-HOMOCYSTEINE RATIO WERE INCREASED, INDICATING HIGHER "METHYLATION INDEX" IN ALCOHOL USE DISORDER SUBJECTS. WE FOUND THAT INCREASED METHYLATION OF THE PROMOTER OF THE DELTA SUBUNIT GABAA RECEPTOR WAS ASSOCIATED WITH REDUCED MRNA AND PROTEIN LEVELS IN THE CEREBELLUM OF ALCOHOL USE DISORDER SUBJECTS. NO CHANGES WERE OBSERVED IN ALPHA1- OR ALPHA6-CONTAINING GABAA RECEPTOR SUBUNITS. THE EXPRESSION OF DNA-METHYLTRANSFERASES (1, 3A, AND 3B) WAS UNALTERED, WHEREAS THE MRNA LEVEL OF TET1, WHICH PARTICIPATES IN THE DNA DEMETHYLATION PATHWAY, WAS DECREASED. HENCE, INCREASED METHYLATION OF THE DELTA SUBUNIT GABAA RECEPTOR PROMOTER MAY RESULT FROM ALCOHOL-INDUCED REDUCTION OF DNA DEMETHYLATION. CONCLUSION: TOGETHER, THESE RESULTS SUPPORT THE HYPOTHESIS THAT ABERRANT DNA METHYLATION PATHWAYS MAY BE INVOLVED IN CEREBELLAR PATHOPHYSIOLOGY OF ALCOHOLISM. FURTHERMORE, THIS WORK PROVIDES NOVEL EVIDENCE FOR A CENTRAL ROLE OF DNA METHYLATION MECHANISMS IN THE ALCOHOL-INDUCED NEUROADAPTIVE CHANGES OF HUMAN CEREBELLAR GABAA RECEPTOR FUNCTION. 2017 10 936 28 CHRONIC LOW-LEVEL PERFLUOROOCTANE SULFONATE (PFOS) EXPOSURE PROMOTES TESTICULAR STEROIDOGENESIS THROUGH ENHANCED HISTONE ACETYLATION. PERFLUOROOCTANE SULFONATE (PFOS), AN ARTIFICIAL PERFLUORINATED COMPOUND, HAS BEEN ASSOCIATED WITH MALE REPRODUCTIVE DISORDERS. HISTONE MODIFICATIONS ARE IMPORTANT EPIGENETIC MEDIATORS; HOWEVER, THE IMPACT OF PFOS EXPOSURE ON TESTICULAR STEROIDOGENESIS THROUGH HISTONE MODIFICATION REGULATIONS REMAINS TO BE ELUCIDATED. IN THIS STUDY, WE EXAMINED THE ROLES OF HISTONE MODIFICATIONS IN REGULATING STEROID HORMONE PRODUCTION IN MALE RATS CHRONICALLY EXPOSED TO LOW-LEVEL PFOS. THE RESULTS INDICATE THAT PFOS EXPOSURE SIGNIFICANTLY UP-REGULATED THE EXPRESSIONS OF STAR, CYP11A1 AND 3BETA-HSD, WHILE CYP17A1 AND 17BETA-HSD WERE DOWN-REGULATED, THUS CONTRIBUTING TO THE ELEVATED PROGESTERONE AND TESTOSTERONE LEVELS. FURTHERMORE, PFOS SIGNIFICANTLY INCREASED THE HISTONES H3K9ME2, H3K9AC AND H3K18AC WHILE REDUCED H3K9ME3 IN RAT TESTIS. IT IS KNOWN THAT HISTONE MODIFICATIONS ARE CLOSELY INVOLVED IN GENE TRANSCRIPTION. THEREFORE, TO INVESTIGATE THE ASSOCIATION BETWEEN HISTONE MODIFICATIONS AND STEROIDOGENIC GENE REGULATION, THE LEVELS OF THESE HISTONE MARKS WERE FURTHER MEASURED IN STEROIDOGENIC GENE PROMOTER REGIONS BY CHIP. IT WAS FOUND THAT H3K18AC WAS AUGMENTED IN CYP11A1 PROMOTER, AND H3K9AC WAS INCREASED IN HSD3B AFTER PFOS EXPOSURE, WHICH IS PROPOSED TO RESULT IN THE ACTIVATION OF CYP11A1 AND 3BETA-HSD, RESPECTIVELY. TO SUM UP, CHRONIC LOW-LEVEL PFOS EXPOSURE ACTIVATED KEY STEROIDOGENIC GENE EXPRESSION THROUGH ENHANCING HISTONE ACETYLATION (H3K9AC AND H3K18AC), ULTIMATELY STIMULATING STEROID HORMONE BIOSYNTHESIS IN RAT TESTIS. 2021 11 1231 39 CROSSTALK BETWEEN GLUCOSE METABOLISM, LACTATE PRODUCTION AND IMMUNE RESPONSE MODULATION. METABOLITES OF GLYCOLYTIC METABOLISM HAVE BEEN IDENTIFIED AS SIGNALING MOLECULES AND REGULATORS OF GENE EXPRESSION, IN ADDITION TO THEIR BASIC FUNCTION AS MAJOR ENERGY AND BIOSYNTHETIC SOURCE. IMMUNE CELLS REPROGRAM METABOLIC PATHWAYS TO CATER TO ENERGY AND BIOSYNTHESIS DEMANDS UPON ACTIVATION. MOST LYMPHOCYTES, INCLUDING INFLAMMATORY M1 MACROPHAGES, MAINLY SHIFT FROM OXIDATIVE PHOSPHORYLATION TO GLYCOLYSIS, WHEREAS REGULATORY T CELLS AND M2 MACROPHAGES PREFERENTIALLY USE THE TRICARBOXYLIC ACID (TCA) CYCLE AND HAVE REDUCED GLYCOLYSIS. RECENT STUDIES HAVE REVEALED THE "NON-METABOLIC" SIGNALING FUNCTIONS OF INTERMEDIATES OF THE MITOCHONDRIAL PATHWAY AND GLYCOLYSIS. THE ROLES OF CITRATE, SUCCINATE AND ITACONATE IN IMMUNE RESPONSE, INCLUDING POST-TRANSLATIONAL MODIFICATIONS OF PROTEINS AND MACROPHAGES ACTIVATION, HAVE BEEN HIGHLIGHTED. AS AN END PRODUCT OF GLYCOLYSIS, LACTATE HAS RECEIVED CONSIDERABLE INTEREST FROM RESEARCHERS. IN THIS REVIEW, WE SPECIFICALLY FOCUSED ON STUDIES EXPLORING THE INTEGRATION OF LACTATE INTO IMMUNE CELL BIOLOGY AND ASSOCIATED PATHOLOGIES. LACTATE CAN ACT AS A DOUBLE-EDGED SWORD. ON ONE HAND, ACTIVATED IMMUNE CELLS PREFER TO USE LACTATE TO SUPPORT THEIR FUNCTION. ON THE OTHER HAND, ACCUMULATED LACTATE IN THE TISSUE MICROENVIRONMENT ACTS AS A SIGNALING MOLECULE THAT RESTRICTS IMMUNE CELL FUNCTION. RECENTLY, A NOVEL EPIGENETIC CHANGE MEDIATED BY HISTONE LYSINE LACTYLATION HAS BEEN PROPOSED. THE BURGEONING RESEARCHES SUPPORT THE IDEA THAT HISTONE LACTYLATION PARTICIPATES IN DIVERSE CELLULAR EVENTS. THIS REVIEW DESCRIBES GLYCOLYTIC METABOLISM, INCLUDING THE IMMUNOREGULATION OF METABOLITES OF THE TCA CYCLE AND LACTATE. THESE LATEST FINDINGS STRENGTHEN OUR UNDERSTANDING ON TUMOR AND CHRONIC INFLAMMATORY DISEASES AND OFFER POTENTIAL THERAPEUTIC OPTIONS. 2022 12 6425 28 THE TRANSCRIPTION FACTOR REST UP-REGULATES TYROSINE HYDROXYLASE AND ANTIAPOPTOTIC GENES AND PROTECTS DOPAMINERGIC NEURONS AGAINST MANGANESE TOXICITY. DOPAMINERGIC FUNCTIONS ARE IMPORTANT FOR VARIOUS BIOLOGICAL ACTIVITIES, AND THEIR IMPAIRMENT LEADS TO NEURODEGENERATION, A HALLMARK OF PARKINSON'S DISEASE (PD). CHRONIC MANGANESE (MN) EXPOSURE CAUSES THE NEUROLOGICAL DISORDER MANGANISM, PRESENTING SYMPTOMS SIMILAR TO THOSE OF PD. EMERGING EVIDENCE HAS LINKED THE TRANSCRIPTION FACTOR RE1-SILENCING TRANSCRIPTION FACTOR (REST) TO PD AND ALSO ALZHEIMER'S DISEASE. BUT REST'S ROLE IN DOPAMINERGIC NEURONS IS UNCLEAR. HERE, WE INVESTIGATED WHETHER REST PROTECTS DOPAMINERGIC NEURONS AGAINST MN-INDUCED TOXICITY AND ENHANCES EXPRESSION OF THE DOPAMINE-SYNTHESIZING ENZYME TYROSINE HYDROXYLASE (TH). WE REPORT THAT REST BINDS TO RE1 CONSENSUS SITES IN THE TH GENE PROMOTER, STIMULATES TH TRANSCRIPTION, AND INCREASES TH MRNA AND PROTEIN LEVELS IN DOPAMINERGIC CELLS. REST BINDING TO THE TH PROMOTER RECRUITED THE EPIGENETIC MODIFIER CAMP-RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN/P300 AND THEREBY UP-REGULATED TH EXPRESSION. REST RELIEVED MN-INDUCED REPRESSION OF TH PROMOTER ACTIVITY, MRNA, AND PROTEIN LEVELS AND ALSO REDUCED MN-INDUCED OXIDATIVE STRESS, INFLAMMATION, AND APOPTOSIS IN DOPAMINERGIC NEURONS. REST REDUCED MN-INDUCED PROINFLAMMATORY CYTOKINES, INCLUDING TUMOR NECROSIS FACTOR ALPHA, INTERLEUKIN 1BETA (IL-1BETA), IL-6, AND INTERFERON GAMMA. MOREOVER, REST INHIBITED THE MN-INDUCED PROAPOPTOTIC PROTEINS BCL-2-ASSOCIATED X PROTEIN (BAX) AND DEATH-ASSOCIATED PROTEIN 6 (DAXX) AND ATTENUATED AN MN-INDUCED DECREASE IN THE ANTIAPOPTOTIC PROTEINS BCL-2 AND BCL-XL. REST ALSO ENHANCED THE EXPRESSION OF ANTIOXIDANT PROTEINS, INCLUDING CATALASE, NF-E2-RELATED FACTOR 2 (NRF2), AND HEME OXYGENASE 1 (HO-1). OUR FINDINGS INDICATE THAT REST ACTIVATES TH EXPRESSION AND THEREBY PROTECTS NEURONS AGAINST MN-INDUCED TOXICITY AND NEUROLOGICAL DISORDERS ASSOCIATED WITH DOPAMINERGIC NEURODEGENERATION. 2020 13 5396 19 REDUCED HISTONE BIOSYNTHESIS AND CHROMATIN CHANGES ARISING FROM A DAMAGE SIGNAL AT TELOMERES. DURING REPLICATIVE AGING OF PRIMARY CELLS MORPHOLOGICAL TRANSFORMATIONS OCCUR, THE EXPRESSION PATTERN IS ALTERED AND CHROMATIN CHANGES GLOBALLY. HERE WE SHOW THAT CHRONIC DAMAGE SIGNALS, PROBABLY CAUSED BY TELOMERE PROCESSING, AFFECT EXPRESSION OF HISTONES AND LEAD TO THEIR DEPLETION. WE INVESTIGATED THE ABUNDANCE AND CELL CYCLE EXPRESSION OF HISTONES AND HISTONE CHAPERONES AND FOUND DEFECTS IN HISTONE BIOSYNTHESIS DURING REPLICATIVE AGING. SIMULTANEOUSLY, EPIGENETIC MARKS WERE REDISTRIBUTED ACROSS THE PHASES OF THE CELL CYCLE AND THE DNA DAMAGE RESPONSE (DDR) MACHINERY WAS ACTIVATED. THE AGE-DEPENDENT REPROGRAMMING AFFECTED TELOMERIC CHROMATIN ITSELF, WHICH WAS PROGRESSIVELY DESTABILIZED, LEADING TO A BOOST OF THE TELOMERE-ASSOCIATED DDR WITH EACH SUCCESSIVE CELL CYCLE. WE PROPOSE A MECHANISM IN WHICH CHANGES IN THE STRUCTURAL AND EPIGENETIC INTEGRITY OF TELOMERES AFFECT CORE HISTONES AND THEIR CHAPERONES, ENFORCING A SELF-PERPETUATING PATHWAY OF GLOBAL EPIGENETIC CHANGES THAT ULTIMATELY LEADS TO SENESCENCE. 2010 14 3318 32 HISTONE ACETYLATION AND EXPRESSION OF MONO-AMINERGIC TRANSMITTERS SYNTHETASES INVOLVED IN CUS-INDUCED DEPRESSIVE RATS. HISTONE ACETYLATION HAS BEEN LINKED TO DEPRESSION, THE ETIOLOGY OF WHICH INVOLVES MANY FACTORS SUCH AS GENETICS, ENVIRONMENTS, AND EPIGENETICS. THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE WHETHER IT WAS ASSOCIATED WITH EPIGENETIC HISTONE MODIFICATION AND GENE EXPRESSION OF ENZYMES RESPONSIBLE FOR THE BIOSYNTHESIS OF NOREPINEPHRINE AND SEROTONIN IN RAT DEPRESSION MODEL INDUCED BY CHRONIC UNPREDICTABLE STRESS (CUS). EIGHT-WEEK-OLD MALE SPRAGUE-DAWLEY RATS WERE EXPOSED TO CUS OVER 28 DAYS. IT WAS SHOWN THAT THE CUS-INDUCED RATS DISPLAYED REMARKED ANXIETY- AND DEPRESSION-LIKE BEHAVIOR WITH WEAKENED LOCOMOTOR ACTIVITY IN OPEN FIELD TEST AND PROLONGED IMMOBILITY IN FORCED SWIMMING TEST. WESTERN BLOT REVEALED THAT CUS LED TO SIGNIFICANT DECREASE IN ACETYLATION OF H3 AT LYSINE 9 (K9) AND H4 AT LYSINE 12 (K12) WITH OBVIOUSLY INCREASING HISTONE DEACETYLASES 5 (HDAC5) EXPRESSION IN HIPPOCAMPUS OF CUS-INDUCED RATS. MEANWHILE, THERE WAS AN OBVIOUSLY DECREASED EXPRESSION OF TYROSINE HYDROXYLASE (TH) AND TRYPTOPHAN HYDROXYLASE (TPH) BOTH AT PROTEIN AND MRNA LEVELS. ADMINISTRATION OF SODIUM VALPROATE (VPA), A HISTONE DEACETYLASE 5 (HDAC5) INHIBITOR, NOT ONLY SIGNIFICANTLY RELIEVED THE ANXIETY- AND DEPRESSION-LIKE BEHAVIORS OF CUS-INDUCED RATS BUT ALSO CLEARLY BLUNTED DECREASE OF H3(K9) AND H4(K12) ACETYLATION AND EXPRESSION OF TH AND TPH, AND PREVENTED INCREASE OF HDAC5 EXPRESSION. THE RESULTS INDICATE THAT THERE EXISTS POSSIBLE INTERRELATION BETWEEN TH AND TPH GENE EXPRESSION AND EPIGENETIC HISTONE ACETYLATION IN CUS-INDUCED DEPRESSIVE RATS, WHICH AT LEAST PARTLY CONTRIBUTES TO THE ETIOLOGY OF DEPRESSION. 2014 15 4118 29 MECHANISMS OF BRAIN GLUCOCORTICOID RESISTANCE IN STRESS-INDUCED PSYCHOPATHOLOGIES. EXPOSURE TO STRESS ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND LEADS TO INCREASED LEVELS OF GLUCOCORTICOID (GC) HORMONES. PROLONGED ELEVATION OF GC LEVELS CAUSES NEURONAL DYSFUNCTION, DECREASES THE DENSITY OF SYNAPSES, AND IMPAIRS NEURONAL PLASTICITY. DECREASED SENSITIVITY TO GLUCOCORTICOIDS (GLUCOCORTICOID RESISTANCE) THAT DEVELOPS AS A RESULT OF CHRONIC STRESS IS ONE OF THE CHARACTERISTIC FEATURES OF STRESS-INDUCED PSYCHOPATHOLOGIES. IN THIS ARTICLE, WE REVIEWED THE PUBLISHED DATA ON PROPOSED MOLECULAR MECHANISMS THAT CONTRIBUTE TO THE DEVELOPMENT OF GLUCOCORTICOID RESISTANCE IN BRAIN, INCLUDING CHANGES IN THE EXPRESSION OF THE GLUCOCORTICOID RECEPTOR (GR) GENE, BIOSYNTHESIS OF GR ISOFORMS, AND GR POSTTRANSLATIONAL MODIFICATIONS. WE ALSO PRESENT DATA ON ALTERATIONS IN THE EXPRESSION OF THE FKBP5 GENE ENCODING THE MAIN COMPONENT OF CELL ULTRA-SHORT NEGATIVE FEEDBACK LOOP OF GC SIGNALING REGULATION. RECENT DISCOVERIES ON STRESS- AND GR-INDUCED CHANGES IN EPIGENETIC MODIFICATION PATTERNS AS WELL AS NORMALIZING ACTION OF ANTIDEPRESSANTS ARE DISCUSSED. GR AND FKBP5 GENE POLYMORPHISMS ASSOCIATED WITH STRESS-INDUCED PSYCHOPATHOLOGIES ARE DESCRIBED, AND THEIR ROLE IN GLUCOCORTICOID RESISTANCE IS DISCUSSED. 2017 16 3341 32 HISTONE DEACETYLASE-2 IS INVOLVED IN STRESS-INDUCED COGNITIVE IMPAIRMENT VIA HISTONE DEACETYLATION AND PI3K/AKT SIGNALING PATHWAY MODIFICATION. EXPOSURE TO CHRONIC STRESS UPREGULATES BLOOD GLUCOCORTICOID LEVELS AND IMPAIRS COGNITION VIA DIVERSE EPIGENETIC MECHANISMS, SUCH AS HISTONE DEACETYLATION. HISTONE DEACETYLATION CAN LEAD TO TRANSCRIPTIONAL SILENCING OF MANY PROTEINS INVOLVED IN COGNITION AND MAY ALSO CAUSE LEARNING AND MEMORY DYSFUNCTION. HISTONE DEACETYLASE?2 (HDAC2) HAS BEEN DEMONSTRATED TO EPIGENETICALLY BLOCK COGNITION VIA A REDUCTION IN THE HISTONE ACETYLATION LEVEL; HOWEVER, IT IS UNKNOWN WHETHER HDAC2 IS INVOLVED IN THE COGNITIVE DECLINE INDUCED BY CHRONIC STRESS. TO THE BEST OF AUTHORS' KNOWLEDGE, THIS IS THE FIRST STUDY TO DEMONSTRATE THAT THE STRESS HORMONE CORTICOSTEROID UPREGULATE HDAC2 PROTEIN LEVELS IN NEURO?2A CELLS AND CAUSE CELL INJURIES. HDAC2 KNOCKDOWN RESULTED IN A SIGNIFICANT AMELIORATION OF THE PATHOLOGICAL CHANGES IN N2A CELLS VIA THE UPREGULATION OF HISTONE ACETYLATION AND MODIFICATIONS IN THE PHOSPHOINOSITIDE 3?KINASE/PROTEIN KINASE B SIGNALING PATHWAY. IN ADDITION, THE HDAC2 PROTEIN LEVELS WERE UPREGULATED IN 12?MONTH?OLD FEMALE C57BL/6J MICE UNDER CHRONIC STRESS IN VIVO. TAKEN TOGETHER, THESE FINDINGS SUGGESTED THAT HDAC2 MAY BE AN IMPORTANT NEGATIVE REGULATOR INVOLVED IN CHRONIC STRESS?INDUCED COGNITIVE IMPAIRMENT. 2017 17 4173 29 MELATONIN INDUCES HISTONE HYPERACETYLATION IN THE RAT BRAIN. WE HAVE REPORTED THAT MELATONIN INDUCES HISTONE HYPERACETYLATION IN MOUSE NEURAL STEM CELLS, SUGGESTING AN EPIGENETIC ROLE FOR THIS PLEIOTROPIC HORMONE. TO SUPPORT SUCH A ROLE, IT IS NECESSARY TO DEMONSTRATE THAT MELATONIN PRODUCES SIMILAR EFFECTS IN VIVO. HISTONE ACETYLATION, FOLLOWING CHRONIC TREATMENT WITH MELATONIN (4MUG/ML IN DRINKING WATER FOR 17 DAYS), WAS EXAMINED BY WESTERN BLOTTING IN SELECTED RAT BRAIN REGIONS. MELATONIN INDUCED SIGNIFICANT INCREASES IN HISTONE H3 AND HISTONE H4 ACETYLATION IN THE HIPPOCAMPUS. HISTONE H4 WAS ALSO HYPERACETYLATED IN THE STRIATUM, BUT THERE WERE NO SIGNIFICANT CHANGES IN HISTONE H3 ACETYLATION IN THIS BRAIN REGION. NO SIGNIFICANT CHANGES IN THE ACETYLATION OF EITHER HISTONE H3 OR H4 WERE OBSERVED IN THE MIDBRAIN AND CEREBELLUM. AN EXAMINATION OF KINASE ACTIVATION, WHICH MAY BE RELATED TO THESE CHANGES, REVEALED THAT MELATONIN TREATMENT INCREASED THE LEVELS OF PHOSPHO-ERK (EXTRACELLULAR SIGNAL-REGULATED KINASE) IN THE HIPPOCAMPUS AND STRIATUM, BUT PHOSPHO-AKT (PROTEIN KINASE B) LEVELS WERE UNCHANGED. THESE FINDINGS SUGGEST THAT CHROMATIN REMODELING AND ASSOCIATED CHANGES IN THE EPIGENETIC REGULATION OF GENE EXPRESSION UNDERLIE THE MULTIPLE PHYSIOLOGICAL EFFECTS OF MELATONIN. 2013 18 6389 34 THE ROLE OF THE ENDOCANNABINOID SYSTEM IN THE BRAIN-GUT AXIS. THE ACTIONS OF CANNABIS ARE MEDIATED BY RECEPTORS THAT ARE PART OF AN ENDOGENOUS CANNABINOID SYSTEM. THE ENDOCANNABINOID SYSTEM (ECS) CONSISTS OF THE NATURALLY OCCURRING LIGANDS N-ARACHIDONOYLETHANOLAMINE (ANANDAMIDE) AND 2-ARACHIDONOYLGLYCEROL (2-AG), THEIR BIOSYNTHETIC AND DEGRADATIVE ENZYMES, AND THE CANNABINOID (CB) RECEPTORS CB1 AND CB2. THE ECS IS A WIDELY DISTRIBUTED TRANSMITTER SYSTEM THAT CONTROLS GUT FUNCTIONS PERIPHERALLY AND CENTRALLY. IT IS AN IMPORTANT PHYSIOLOGIC REGULATOR OF GASTROINTESTINAL MOTILITY. POLYMORPHISMS IN THE GENE ENCODING CB1 (CNR1) HAVE BEEN ASSOCIATED WITH SOME FORMS OF IRRITABLE BOWEL SYNDROME. THE ECS IS INVOLVED IN THE CONTROL OF NAUSEA AND VOMITING AND VISCERAL SENSATION. THE HOMEOSTATIC ROLE OF THE ECS ALSO EXTENDS TO THE CONTROL OF INTESTINAL INFLAMMATION. WE REVIEW THE MECHANISMS BY WHICH THE ECS LINKS STRESS AND VISCERAL PAIN. CB1 IN SENSORY GANGLIA CONTROLS VISCERAL SENSATION, AND TRANSCRIPTION OF CNR1 IS MODIFIED THROUGH EPIGENETIC PROCESSES UNDER CONDITIONS OF CHRONIC STRESS. THESE PROCESSES MIGHT LINK STRESS WITH ABDOMINAL PAIN. THE ECS IS ALSO INVOLVED CENTRALLY IN THE MANIFESTATION OF STRESS, AND ENDOCANNABINOID SIGNALING REDUCES THE ACTIVITY OF HYPOTHALAMIC-PITUITARY-ADRENAL PATHWAYS VIA ACTIONS IN SPECIFIC BRAIN REGIONS, NOTABLY THE PREFRONTAL CORTEX, AMYGDALA, AND HYPOTHALAMUS. AGENTS THAT MODULATE THE ECS ARE IN EARLY STAGES OF DEVELOPMENT FOR TREATMENT OF GASTROINTESTINAL DISEASES. INCREASING OUR UNDERSTANDING OF THE ECS WILL GREATLY ADVANCE OUR KNOWLEDGE OF INTERACTIONS BETWEEN THE BRAIN AND GUT AND COULD LEAD TO NEW TREATMENTS FOR GASTROINTESTINAL DISORDERS. 2016 19 995 30 CHRONIC STRESS LEADS TO EPIGENETIC DYSREGULATION IN THE NEUROPEPTIDE-Y AND CANNABINOID CB1 RECEPTOR GENES IN THE MOUSE CINGULATE CORTEX. PERSISTENT STRESS TRIGGERS A VARIETY OF MECHANISMS, WHICH MAY ULTIMATELY LEAD TO THE OCCURRENCE OF ANXIETY- AND DEPRESSION-RELATED DISORDERS. EPIGENETIC MODIFICATIONS REPRESENT A MECHANISM BY WHICH CHRONIC STRESS MEDIATES LONG-TERM EFFECTS. HERE, WE ANALYZED BRAIN TISSUE FROM MICE EXPOSED TO CHRONIC UNPREDICTABLE STRESS (CUS), WHICH INDUCED IMPAIRED EMOTIONAL AND NOCICEPTIVE BEHAVIORS. AS ENDOCANNABINOID (ECB) AND NEUROPEPTIDE-Y (NPY) SYSTEMS MODULATE EMOTIONAL PROCESSES, WE HYPOTHESIZED THAT CUS MAY AFFECT THESE SYSTEMS THROUGH EPIGENETIC MECHANISMS. WE FOUND REDUCED NPY EXPRESSION AND NPY TYPE 1 RECEPTOR (NPY1R) SIGNALING, AND DECREASED EXPRESSION OF THE CANNABINOID TYPE 1 RECEPTOR (CB1) IN THE CINGULATE CORTEX OF CUS MICE SPECIFICALLY IN LOW CB1-EXPRESSING NEURONS. EPIGENETIC INVESTIGATIONS REVEALED REDUCED LEVELS OF HISTONE H3K9 ACETYLATION (H3K9AC) ASSOCIATED TO NPY AND CB1 GENES, WHICH MAY REPRESENT A FACTOR DETERMINING THE DYSREGULATION OCCURRING AT EXPRESSION AND SIGNALING LEVEL. CUS MICE ALSO SHOWED INCREASED NUCLEAR PROTEIN LEVELS AND ACTIVITY OF THE HISTONE DEACETYLASE TYPE 2 (HDAC2) IN THE CINGULATE CORTEX AS COMPARED TO CONTROLS. CHRONIC ADMINISTRATION OF URB597, AN INHIBITOR OF ANANDAMIDE DEGRADATION, WHICH IS KNOWN TO INDUCE ANXIOLYSIS IN CUS MICE, REVERSED THE EPIGENETIC CHANGES FOUND IN THE NPY GENE, BUT WAS INEFFECTIVE IN ALLEVIATING THE DYSREGULATION OF NPY AT TRANSCRIPTIONAL AND SIGNALING LEVEL. OUR FINDINGS SUGGEST THAT EPIGENETIC ALTERATIONS IN THE NPY AND CB1 GENES REPRESENT ONE OF THE POTENTIAL MECHANISMS CONTRIBUTING TO THE EMOTIONAL IMBALANCE INDUCED BY CUS IN MICE, AND THAT THE NPY AND ECB SYSTEMS MAY REPRESENT THERAPEUTIC TARGETS FOR THE TREATMENT OF PSYCHOPATHOLOGIES ASSOCIATED WITH OR TRIGGERED BY CHRONIC STRESS STATES. 2017 20 4704 26 NITRATION OF DISTINCT TYROSINE RESIDUES CAUSES INACTIVATION OF HISTONE DEACETYLASE 2. HISTONE DEACETYLASES (HDACS) ARE KEY MOLECULES INVOLVED IN EPIGENETIC REGULATION OF GENE EXPRESSION. WE HAVE PREVIOUSLY DEMONSTRATED THAT OXIDATIVE STRESS CAUSED A REDUCTION IN HDAC2, RESULTING IN AMPLIFIED INFLAMMATION AND REDUCED CORTICOSTEROID RESPONSIVENESS. HERE WE SHOWED NITRATIVE/OXIDATIVE STRESS REDUCED HDAC2 EXPRESSION VIA NITRATION OF DISTINCT TYROSINE RESIDUES. PEROXYNITRITE, HYDROGEN PEROXIDE AND CIGARETTE SMOKE-CONDITIONED MEDIUM REDUCED HDAC2 EXPRESSION IN A549 EPITHELIAL CELLS IN VITRO. THIS REDUCTION WAS DUE TO INCREASED PROTEASOMAL DEGRADATION FOLLOWING UBIQUITINATION RATHER THAN REDUCTION OF MRNA EXPRESSION OR STABILITY. HDAC2 WAS NITRATED UNDER NITRATIVE/OXIDATIVE STRESS AND IN THE PERIPHERAL LUNG TISSUES OF SMOKERS AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. MUTAGENESIS STUDIES REPLACING TYROSINE (Y) RESIDUES WITH ALANINE REVEALED THAT Y253 IS AT LEAST PARTLY RESPONSIBLE FOR THE PROTEASOMAL DEGRADATION OF HDAC2 UNDER NITRATIVE STRESS. THUS, NITRATION OF DISTINCT TYROSINE RESIDUES MODIFIES BOTH THE EXPRESSION AND ACTIVITY OF HDAC2, HAVING AN IMPACT ON EPIGENETIC REGULATION. 2009