1 2969 513 GENETIC AND EPIGENETIC REGULATION OF THE INNATE IMMUNE RESPONSE TO GOUT. GOUT IS A DISEASE CAUSED BY URIC ACID (UA) ACCUMULATION IN THE JOINTS, CAUSING INFLAMMATION. TWO UA FORMS - MONOSODIUM URATE (MSU) AND SOLUBLE URIC ACID (SUA) HAVE BEEN SHOWN TO INTERACT PHYSICALLY WITH INFLAMMASOMES, ESPECIALLY WITH THE NOD-LIKE RECEPTOR (NLR) FAMILY PYRIN DOMAIN CONTAINING 3 (NLRP3), ALBEIT THE ROLE OF THE IMMUNE RESPONSE TO UA IS POORLY UNDERSTOOD, GIVEN THAT ASYMPTOMATIC HYPERURICEMIA DOES ALSO EXIST. MACROPHAGE PHAGOCYTOSIS OF UA ACTIVATE NLRP3, LEAD TO CYTOKINES RELEASE, AND ULTIMATELY, LEAD TO CHEMOATTRACT NEUTROPHILS AND LYMPHOCYTES TO THE GOUT FLARE JOINT SPOT. GENETIC VARIANTS OF INFLAMMASOME GENES AND OF GENES ENCODING THEIR MOLECULAR PARTNERS MAY INFLUENCE HYPERURICEMIA AND GOUT SUSCEPTIBILITY, WHILE ALSO INFLUENCING OTHER COMORBIDITIES SUCH AS METABOLIC SYNDROME AND CARDIOVASCULAR DISEASES. IN THIS REVIEW, WE SUMMARIZE THE INFLAMMATORY RESPONSES IN ACUTE AND CHRONIC GOUT, SPECIFICALLY FOCUSING ON INNATE IMMUNE CELL MECHANISMS AND GENETIC AND EPIGENETIC CHARACTERISTICS OF PARTICIPATING MOLECULES. UNPRECEDENTLY, A NOVEL UA BINDING PROTEIN - THE NEURONAL APOPTOSIS INHIBITOR PROTEIN (NAIP) - IS SUGGESTED AS RESPONSIBLE FOR THE ASYMPTOMATIC HYPERURICEMIA PARADOX.ABBREVIATION: BETA2-INTEGRINS: LEUKOCYTE-SPECIFIC ADHESION MOLECULES; ABCG2: ATP-BINDING CASSETE FAMILY/BREAST CANCER-RESISTANT PROTEIN; ACR: AMERICAN COLLEGE OF RHEUMATOLOGY; AIM2: ABSENT IN MELANOMA 2, TYPE OF PATTERN RECOGNITION RECEPTOR; ALPK1: ALPHA-PROTEIN KINASE 1; ANGPTL2: ANGIOPOIETIN-LIKE PROTEIN 2; ASC: APOPTOSIS-ASSOCIATED SPECK-LIKE PROTEIN; BIR: BACULOVIRUS INHIBITOR OF APOPTOSIS PROTEIN REPEAT; BIRC1: BACULOVIRUS IAP REPEAT-CONTAINING PROTEIN 1; BIRC2: BACULOVIRAL IAP REPEAT-CONTAINING PROTEIN 2; C5A: COMPLEMENT ANAPHYLATOXIN; CAMP: CYCLIC ADENOSINE MONOPHOSPHATE; CARD: CASPASE ACTIVATION AND RECRUITMENT DOMAINS; CARD8: CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 8; CASP1: CASPASE 1; CCL3: CHEMOKINE (C-C MOTIF) LIGAND 3; CD14: CLUSTER OF DIFFERENTIATION 14; CD44: CLUSTER OF DIFFERENTIATION 44; CG05102552: DNA-METHYLATION SITE, USUALLY CYTOSINE FOLLOWED BY GUANINE NUCLEOTIDES; CONTAINS ARBITRARY IDENTIFICATION CODE; CIDEC: CELL DEATH-INDUCING DNA FRAGMENTATION FACTOR-LIKE EFFECTOR FAMILY; CKD: CHRONIC KIDNEY DISEASE; CNV: COPY NUMBER VARIATION; CPT1A: CARNITINE PALMITOYL TRANSFERASE - TYPE 1A; CXCL1: CHEMOKINE (CXC MOTIF) LIGAND 1; DAMPS: DAMAGE ASSOCIATED MOLECULAR PATTERNS; DC: DENDRITIC CELLS; DNMT(1): MAINTENANCE DNA METHYLTRANSFERASE; EQTL: EXPRESSION QUANTITATIVE TRAIT LOCI; ERK1: EXTRACELLULAR SIGNAL-REGULATED KINASE 1; ERK2: EXTRACELLULAR SIGNAL-REGULATED KINASE 2; EULAR: EUROPEAN LEAGUE AGAINST RHEUMATISM; GMCSF: GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR; GWAS: GLOBAL WIDE ASSOCIATION STUDIES; H3K27ME3: TRI-METHYLATION AT THE 27TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; H3K4ME1: MONO-METHYLATION AT THE 4TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; H3K4ME3: TRI-METHYLATION AT THE 4TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; HOTAIR: HUMAN GENE LOCATED BETWEEN HOXC11 AND HOXC12 ON CHROMOSOME 12; IKAPPABALPHA: CYTOPLASMATIC PROTEIN/NF-KAPPAB TRANSCRIPTION INHIBITOR; IAP: INHIBITORY APOPTOSIS PROTEIN; IFNGAMMA: INTERFERON GAMMA; IL-1BETA: INTERLEUKIN 1 BETA; IL-12: INTERLEUKIN 12; IL-17: INTERLEUKIN 17; IL18: INTERLEUKIN 18; IL1R1: INTERLEUKIN-1 RECEPTOR; IL-1RA: INTERLEUKIN-1 RECEPTOR ANTAGONIST; IL-22: INTERLEUKIN 22; IL-23: INTERLEUKIN 23; IL23R: INTERLEUKIN 23 RECEPTOR; IL-33: INTERLEUKIN 33; IL-6: INTERLEUKIN 6; IMP: INOSINE MONOPHOSPHATE; INSIG1: INSULIN-INDUCED GENE 1; JNK1: C-JUN N-TERMINAL KINASE 1; LNCRNA: LONG NON-CODING RIBONUCLEIC ACID; LRR: LEUCINE-RICH REPEATS; MIR: MATURE NON-CODING MICRORNAS MEASURING FROM 20 TO 24 NUCLEOTIDES, ANIMAL ORIGIN; MIR-1: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-145: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-146A: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE, "A" STANDS FOR MIR FAMILY; "A" FAMILY PRESENTS SIMILAR MIR SEQUENCE TO "B" FAMILY, BUT DIFFERENT PRECURSORS; MIR-20B: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "B" STANDS FOR MIR FAMILY; "B" FAMILY PRESENTS SIMILAR MIR SEQUENCE TO "A" FAMILY, BUT DIFFERENT PRECURSORS; MIR-221: MIR - FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-221-5P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "5P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 5' ARM OF THE PRE-MIRNA HAIRPIN; MIR-223: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-223-3P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "3P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 3' ARM OF THE PRE-MIRNA HAIRPIN; MIR-22-3P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE, "3P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 3' ARM OF THE PRE-MIRNA HAIRPIN; MLKL: MIXED LINEAGE KINASE DOMAIN-LIKE PSEUDO KINASE; MM2P: INDUCTOR OF M2-MACROPHAGE POLARIZATION; MSU: MONOSODIUM URATE; MTOR: MAMMALIAN TARGET OF RAPAMYCIN; MYD88: MYELOID DIFFERENTIATION PRIMARY RESPONSE 88; N-3-PUFAS: N-3-POLYUNSATURATED FATTY-ACIDS; NACHT: ACRONYM FOR NAIP (NEURONAL APOPTOSIS INHIBITOR PROTEIN), C2TA (MHC CLASS 2 TRANSCRIPTION ACTIVATOR), HET-E (INCOMPATIBILITY LOCUS PROTEIN FROM PODOSPORA ANSERINA) AND TP1 (TELOMERASE-ASSOCIATED PROTEIN); NAIP: NEURONAL APOPTOSIS INHIBITORY PROTEIN (HUMAN); NAIP1: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 1 (MURINE); NAIP5: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 5 (MURINE); NAIP6: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 6 (MURINE); NBD: NUCLEOTIDE-BINDING DOMAIN; NEK7: SMALLEST NIMA-RELATED KINASE; NET: NEUTROPHIL EXTRACELLULAR TRAPS; NF-KAPPAB: NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS; NFIL3: NUCLEAR-FACTOR, INTERLEUKIN 3 REGULATED PROTEIN; NIIMA: NETWORK OF IMMUNITY IN INFECTION, MALIGNANCY, AND AUTOIMMUNITY; NLR: NOD-LIKE RECEPTOR; NLRA: NOD-LIKE RECEPTOR NLRA CONTAINING ACIDIC DOMAIN; NLRB: NOD-LIKE RECEPTOR NLRA CONTAINING BIR DOMAIN; NLRC: NOD-LIKE RECEPTOR NLRA CONTAINING CARD DOMAIN; NLRC4: NOD-LIKE RECEPTOR FAMILY CARD DOMAIN CONTAINING 4; NLRP: NOD-LIKE RECEPTOR NLRA CONTAINING PYD DOMAIN; NLRP1: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN, LEUCINE-RICH REPEAT, AND PYRIN DOMAIN CONTAINING 1; NLRP12: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN, LEUCINE-RICH REPEAT, AND PYRIN DOMAIN CONTAINING 12; NLRP3: NOD-LIKE RECEPTOR FAMILY PYRIN DOMAIN CONTAINING 3; NOD2: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN; NRBP1: NUCLEAR RECEPTOR-BINDING PROTEIN; NRF2: NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2; OR: ODDS RATIO; P2X: GROUP OF MEMBRANE ION CHANNELS ACTIVATED BY THE BINDING OF EXTRACELLULAR; P2X7: P2X PURINOCEPTOR 7 GENE; P38: MEMBER OF THE MITOGEN-ACTIVATED PROTEIN KINASE FAMILY; PAMPS: PATHOGEN ASSOCIATED MOLECULAR PATTERS; PBMC: PERIPHERAL BLOOD MONONUCLEAR CELLS; PGGT1B: GERANYLGERANYL TRANSFERASE TYPE-1 SUBUNIT BETA; PHGDH: PHOSPHOGLYCERATE DEHYDROGENASE; PI3-K: PHOSPHO-INOSITOL; PPARGAMMA: PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA; PPARGC1B: PEROXISOME PROLIFERATIVE ACTIVATED RECEPTOR, GAMMA, COACTIVATOR 1 BETA; PR3: PROTEINASE 3 ANTIGEN; PRO-CASP1: INACTIVE PRECURSOR OF CASPASE 1; PRO-IL1BETA: INACTIVE PRECURSOR OF INTERLEUKIN 1 BETA; PRR: PATTERN RECOGNITION RECEPTORS; PYD: PYRIN DOMAIN; RAPTOR: REGULATORY ASSOCIATED PROTEIN OF MTOR COMPLEX 1; RAS: RENIN-ANGIOTENSIN SYSTEM; REDD1: REGULATED IN DNA DAMAGE AND DEVELOPMENT 1; ROS: REACTIVE OXYGEN SPECIES; RS000*G: SINGLE NUCLEAR POLYMORPHISM, "*G" IS RELATED TO SNP WHERE REPLACED NUCLEOTIDE IS GUANINE, USUALLY PRECEDED BY AN ID NUMBER; SLC2A9: SOLUTE CARRIER FAMILY 2, MEMBER 9; SLC7A11: SOLUTE CARRIER FAMILY 7, MEMBER 11; SMA: SMOOTH MUSCULAR ATROPHY; SMAC: SECOND MITOCHONDRIAL-DERIVED ACTIVATOR OF CASPASES; SNP: SINGLE NUCLEAR POLYMORPHISM; SP3: SPECIFICITY PROTEIN 3; ST2: SERUM STIMULATION-2; STK11: SERINE/THREONINE KINASE 11; SUA: SOLUBLE URIC ACID; SYK: SPLEEN TYROSINE KINASE; TAK1: TRANSFORMING GROWTH FACTOR BETA ACTIVATED KINASE; TH1: TYPE 1 HELPER T CELLS; TH17: TYPE 17 HELPER T CELLS; TH2: TYPE 2 HELPER T CELLS; TH22: TYPE 22 HELPER T CELLS; TLR: TOOL-LIKE RECEPTOR; TLR2: TOLL-LIKE RECEPTOR 2; TLR4: TOLL-LIKE RECEPTOR 4; TNFALPHA: TUMOR NECROSIS FACTOR ALPHA; TNFR1: TUMOR NECROSIS FACTOR RECEPTOR 1; TNFR2: TUMOR NECROSIS FACTOR RECEPTOR 2; UA: URIC ACID; UBAP1: UBIQUITIN ASSOCIATED PROTEIN; ULT: URATE-LOWERING THERAPY; URAT1: URATE TRANSPORTER 1; VDAC1: VOLTAGE-DEPENDENT ANION-SELECTIVE CHANNEL 1. 2023 2 6669 46 URIC ACID IN METABOLIC SYNDROME: DOES URIC ACID HAVE A DEFINITIVE ROLE? INCREASED SERUM URIC ACID (SUA) LEVELS ARE COMMONLY SEEN IN PATIENTS WITH METABOLIC SYNDROME AND ARE WIDELY ACCEPTED AS RISK FACTORS FOR HYPERTENSION, GOUT, NON-ALCOHOLIC FATTY LIVER DISEASE, CHRONIC KIDNEY DISEASE (CKD), AND CARDIOVASCULAR DISEASES. ALTHOUGH SOME AMBIGUITY FOR THE EXACT ROLE OF URIC ACID (UA) IN THESE DISEASES IS STILL PRESENT, SEVERAL PATHOPHYSIOLOGICAL MECHANISMS HAVE BEEN IDENTIFIED SUCH AS INCREASED OXIDATIVE STRESS, INFLAMMATION, AND APOPTOSIS. ACCUMULATING EVIDENCE IN GENOMICS ENLIGHTENS GENETIC VARIABILITIES AND SOME EPIGENETIC CHANGES THAT CAN CONTRIBUTE TO HYPERURICEMIA. HERE WE DISCUSS THE ROLE OF UA WITHIN METABOLISM AND THE CONSEQUENCES OF ASYMPTOMATIC HYPERURICEMIA WHILE PROVIDING NEWFOUND EVIDENCE FOR THE ASSOCIATIONS BETWEEN UA AND GUT MICROBIOTA AND VITAMIN D. INCREASED SUA LEVELS AND BENEFICIAL EFFECTS OF LOWERING SUA LEVELS NEED TO BE ELUCIDATED MORE TO UNDERSTAND ITS COMPLICATED FUNCTION WITHIN DIFFERENT METABOLIC PATHWAYS AND SET OPTIMAL TARGET LEVELS FOR SUA FOR REDUCING RISKS FOR METABOLIC AND CARDIOVASCULAR DISEASES. 2022 3 5760 58 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION. 2016 4 614 41 BINGE ALCOHOL-INDUCED MICROVESICULAR LIVER STEATOSIS AND INJURY ARE ASSOCIATED WITH DOWN-REGULATION OF HEPATIC HDAC 1, 7, 9, 10, 11 AND UP-REGULATION OF HDAC 3. BACKGROUND: BINGE, AS WELL AS CHRONIC, ALCOHOL CONSUMPTION AFFECTS GLOBAL HISTONE ACETYLATION LEADING TO CHANGES IN GENE EXPRESSION. IT IS BECOMING INCREASINGLY EVIDENT THAT THESE HISTONE-ASSOCIATED EPIGENETIC MODIFICATIONS PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF ALCOHOL-MEDIATED HEPATIC INJURY. METHODS: C57BL/6 MICE WERE GAVAGED 3 TIMES (12-HOUR INTERVALS) WITH ETHANOL (ETOH; 4.5 G/KG). HEPATIC HISTONE DEACETYLASE (HDAC) MRNAS WERE ASSESSED BY QRT-PCR. TOTAL HDAC ACTIVITY WAS ESTIMATED BY A COLORIMETRIC HDAC ACTIVITY/INHIBITION ASSAY. HISTONE ACETYLATION LEVELS WERE EVALUATED BY WESTERN BLOT. LIVER STEATOSIS AND INJURY WERE EVALUATED BY HISTOPATHOLOGY, PLASMA AMINOTRANSFERASE (ALT) ACTIVITY, AND LIVER TRIGLYCERIDE ACCUMULATION. EXPRESSION OF FATTY ACID SYNTHASE (FAS) AND CARNITINE PALMITOYL TRANSFERASE 1A (CPT1A) WAS ALSO EXAMINED. HDAC 9 ASSOCIATION WITH FAS PROMOTER WAS ANALYZED. RESULTS: BINGE ALCOHOL EXPOSURE RESULTED IN ALTERATIONS OF HEPATIC HDAC MRNA LEVELS. DOWN-REGULATION OF HDAC CLASS I (HDAC 1), CLASS II (HDAC 7, 9, 10), AND CLASS IV (HDAC 11) AND UP-REGULATION OF HDAC CLASS I (HDAC 3) GENE EXPRESSION WERE OBSERVED. CORRESPONDENT TO THE DECREASE IN HDAC ACTIVITY, AN INCREASE IN HEPATIC HISTONE ACETYLATION WAS OBSERVED. THESE MOLECULAR EVENTS WERE ASSOCIATED WITH MICROVESICULAR HEPATIC STEATOSIS AND INJURY CHARACTERIZED BY INCREASED HEPATIC TRIGLYCERIDES (48.02 +/- 3.83 VS. 19.90 +/- 3.48 MG/G LIVER, P < 0.05) AND ELEVATED PLASMA ALT ACTIVITY (51.98 +/- 6.91 VS. 20.8 +/- 0.62 U/L, P < 0.05). HEPATIC STEATOSIS WAS ASSOCIATED WITH AN INCREASE IN FAS AND A DECREASE IN CPT1A MRNA AND PROTEIN EXPRESSION. FAS PROMOTER ANALYSIS REVEALED THAT BINGE ETOH TREATMENT DECREASED HDAC 9 OCCUPANCY AT THE FAS PROMOTER RESULTING IN ITS TRANSCRIPTIONAL ACTIVATION. CONCLUSIONS: DEREGULATION OF HEPATIC HDAC EXPRESSION LIKELY PLAYS A MAJOR ROLE IN THE BINGE ALCOHOL-INDUCED HEPATIC STEATOSIS AND LIVER INJURY BY AFFECTING LIPOGENESIS AND FATTY ACID BETA-OXIDATION. 2012 5 3241 41 HEPATIC MICRORNA MODULATION MIGHT BE AN EARLY EVENT TO NON-ALCOHOLIC FATTY LIVER DISEASE DEVELOPMENT DRIVEN BY HIGH-FAT DIET IN MALE MICE. INTRODUCTION: METABOLIC ALTERATIONS CAUSED BY AN IMBALANCE OF MACRONUTRIENT CONSUMPTION ARE OFTEN RELATED TO THE MODULATION OF MICRORNAS (MIRNAS), WHICH COULD ALTER MRNAS EXPRESSION PROFILE AND ACCELERATE THE DEVELOPMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD). AIMS: THIS STUDY AIMED TO INVESTIGATE THE CONTRIBUTION OF MIRNAS IN MODULATING EARLY STAGES OF NAFLD IN MICE SUBMITTED TO A HIGH-FAT DIET (HFD). METHODS AND RESULTS: MALE SWISS MICE, FED EITHER A CONTROL DIET OR AN HFD FOR 1, 3, 7, 15, 30, 56 DAYS, WERE ASSESSED FOR METABOLIC ALTERATIONS, GENE EXPRESSION AND NAFLD MARKERS. A HEPATOCYTE CELL LINE WAS USED TO INVESTIGATE THE EFFECTS OF MIR-370 MODULATION ON ENZYMES INVOLVED IN BETA-OXIDATION. BODY WEIGHT AND ADIPOSITY WERE HIGHER AFTER 7 DAYS OF HFD. FASTING GLUCOSE AND INSULIN INCREASED AFTER 3 AND 7 DAYS OF HFD, RESPECTIVELY. WHILE HEPATIC LIPID CONTENT INCREASED FROM THE FIRST DAY ON, HEPATIC GLYCOGEN HAD A DECREASE AFTER 3 DAYS OF HFD CONSUMPTION. MIR-370 AND LET-7 EXPRESSION INCREASED WITH ACUTE AND CHRONIC EXPOSURE TO HFD, ACCOMPANIED BY CARNITINE PALMITOYLTRANSFERASE 1A (CPT1A), ACYL-COA DEHYDROGENASE VERY LONG CHAIN (ACADVL) AND PROTEIN KINASE AMP-ACTIVATED CATALYTIC SUBUNIT 2 (PRKAA2) DOWNREGULATION, WHILE DECREASED MIR-122 EXPRESSION WAS ACCOMPANIED BY 1-ACYLGLYCEROL-3-PHOSPHATE-O-ACYLTRANSFERASE (AGPAT) UPREGULATION AFTER 56 DAYS OF HFD CONSUMPTION, SOME OF THEM CONFIRMED BY IN VITRO EXPERIMENTS. DESPITE FLUCTUATIONS IN TNFA AND IL6 MRNA LEVELS, MOLECULAR MODULATION WAS CONSISTENT WITH HEPATIC TG AND NAFLD DEVELOPMENT. CONCLUSION: HEPATIC MIR-370-122-LET7 MIRNA MODULATION COULD BE THE FIRST INSULT TO NAFLD DEVELOPMENT, PRECEDING CHANGES IN GLYCEMIC HOMEOSTASIS AND ADIPOSITY. 2022 6 2118 51 EPIGENETIC HISTONE METHYLATION OF PPARGAMMA AND CPT1A SIGNALING CONTRIBUTES TO BETAHISTINE PREVENTING OLANZAPINE-INDUCED DYSLIPIDEMIA. AS A PARTIAL HISTAMINE H1 RECEPTOR AGONIST AND H3 ANTAGONIST, BETAHISTINE HAS BEEN REPORTED TO PARTIALLY PREVENT OLANZAPINE-INDUCED DYSLIPIDEMIA AND OBESITY THROUGH A COMBINATION THERAPY, ALTHOUGH THE UNDERLYING EPIGENETIC MECHANISMS ARE STILL NOT KNOWN. RECENT STUDIES HAVE REVEALED THAT HISTONE REGULATION OF KEY GENES FOR LIPOGENESIS AND ADIPOGENESIS IN THE LIVER IS ONE OF THE CRUCIAL MECHANISMS FOR OLANZAPINE-INDUCED METABOLIC DISORDERS. THIS STUDY INVESTIGATED THE ROLE OF EPIGENETIC HISTONE REGULATION IN BETAHISTINE CO-TREATMENT PREVENTING DYSLIPIDEMIA AND FATTY LIVER CAUSED BY CHRONIC OLANZAPINE TREATMENT IN A RAT MODEL. IN ADDITION TO ABNORMAL LIPID METABOLISM, THE UPREGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPARGAMMA) AND CCAAT/ENHANCER BINDING PROTEIN (C/EBPALPHA), AS WELL AS THE DOWNREGULATION OF CARNITINE PALMITOYLTRANSFERASE 1A (CPT1A) IN THE LIVER INDUCED BY OLANZAPINE, WERE SIGNIFICANTLY ATTENUATED BY BETAHISTINE CO-TREATMENT. IN ADDITION, BETAHISTINE CO-TREATMENT SIGNIFICANTLY ENHANCED THE GLOBAL EXPRESSION OF H3K4ME AND THE ENRICHMENT OF H3K4ME BINDING ON THE PROMOTER OF CPT1A GENE AS REVEALED BY CHIP-QPCR, BUT INHIBITED THE EXPRESSION OF ONE OF ITS SITE-SPECIFIC DEMETHYLASES, LYSINE (K)-SPECIFIC DEMETHYLASE 1A (KDM1A). BETAHISTINE CO-TREATMENT ALSO SIGNIFICANTLY ENHANCED THE GLOBAL EXPRESSION OF H3K9ME AND THE ENRICHMENT OF H3K9ME BINDING ON THE PROMOTER OF THE PPARG GENE, BUT INHIBITED THE EXPRESSION OF TWO OF ITS SITE-SPECIFIC DEMETHYLASES, LYSINE DEMETHYLASE 4B (KDM4B) AND PHD FINGER PROTEIN 2 (PHF2). THESE RESULTS SUGGEST THAT BETAHISTINE ATTENUATES ABNORMAL ADIPOGENESIS AND LIPOGENESIS TRIGGERED BY OLANZAPINE THROUGH MODULATING HEPATIC HISTONE METHYLATION, AND THUS INHIBITING THE PPARGAMMA PATHWAY-MEDIATED LIPID STORAGE, WHILE AT THE SAME TIME PROMOTING CP1A-MEDIATED FATTY ACID OXIDATION. 2023 7 3701 55 INFLAMMATORY RESPONSE TO REGULATED CELL DEATH IN GOUT AND ITS FUNCTIONAL IMPLICATIONS. GOUT, A CHRONIC INFLAMMATORY ARTHRITIS DISEASE, IS CHARACTERIZED BY HYPERURICEMIA AND CAUSED BY INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND METABOLIC FACTORS. ACUTE GOUT SYMPTOMS ARE TRIGGERED BY THE INFLAMMATORY RESPONSE TO MONOSODIUM URATE CRYSTALS, WHICH IS MEDIATED BY THE INNATE IMMUNE SYSTEM AND IMMUNE CELLS (E.G., MACROPHAGES AND NEUTROPHILS), THE NACHT, LRR, AND PYD DOMAINS-CONTAINING PROTEIN 3 (NLRP3) INFLAMMASOME ACTIVATION, AND PRO-INFLAMMATORY CYTOKINE (E.G., IL-1BETA) RELEASE. RECENT STUDIES HAVE INDICATED THAT THE MULTIPLE PROGRAMMED CELL DEATH PATHWAYS INVOLVED IN THE INFLAMMATORY RESPONSE INCLUDE PYROPTOSIS, NETOSIS, NECROPTOSIS, AND APOPTOSIS, WHICH INITIATE INFLAMMATORY REACTIONS. IN THIS REVIEW, WE EXPLORE THE CORRELATION AND INTERACTIONS AMONG THESE FACTORS AND THEIR ROLES IN THE PATHOGENESIS OF GOUT TO PROVIDE FUTURE RESEARCH DIRECTIONS AND POSSIBILITIES FOR IDENTIFYING POTENTIAL NOVEL THERAPEUTIC TARGETS AND ENHANCING OUR UNDERSTANDING OF GOUT PATHOGENESIS. 2022 8 5480 33 RESVERATROL REVERSES MORPHINE-INDUCED NEUROINFLAMMATION IN MORPHINE-TOLERANT RATS BY REVERSAL HDAC1 EXPRESSION. BACKGROUND/PURPOSE: WE PREVIOUSLY SHOWED THAT SUBSEQUENT INTRATHECAL (I.T.) INJECTION OF RESVERATROL (30 MUG) SIGNIFICANTLY REVERSES MORPHINE-EVOKED NEUROINFLAMMATION IN MORPHINE-TOLERANT RATS. THE PRESENT STUDY EXAMINED THE UNDERLYING MECHANISM. METHODS: MALE WISTAR RATS WERE IMPLANTED WITH TWO I.T. CATHETERS, ONE OF WHICH WAS CONNECTED TO A MINIOSMOTIC PUMP AND USED FOR MORPHINE (15 MUG/H) OR SALINE INFUSION FOR 120 HOURS. TO EXAMINE THE EFFECTS ON SPINAL CORD EXPRESSION OF HISTONE DEACETYLASE 1 (HDAC1), THE INFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), AND TNF RECEPTOR (TNFR) 1 AND TNFR2 DURING TOLERANCE INDUCTION, A TAIL-FLICK TEST WAS PERFORMED PRIOR TO INFUSION AND AFTER 24 HOURS, 48 HOURS, 72 HOURS, 96 HOURS, AND 120 HOURS OF INFUSION. RESULTS: RESVERATROL TREATMENT PRIOR TO MORPHINE CHALLENGE RESTORED THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN MORPHINE-TOLERANT RATS AND REVERSED THE MORPHINE INFUSION-INDUCED INCREASE IN HDAC1, TNF-ALPHA, AND TNFR1 EXPRESSION. MOREOVER, CHRONIC MORPHINE INFUSION INCREASED TNFR1-SPECIFIC EXPRESSION IN NEURON IN MORPHINE-TOLERANT RAT SPINAL CORDS, AND THIS EFFECT WAS ALMOST COMPLETELY INHIBITED BY RESVERATROL TREATMENT PRIOR TO MORPHINE CHALLENGE. CONCLUSION: RESVERATROL RESTORES THE ANTINOCICEPTIVE EFFECT OF MORPHINE BY REVERSING MORPHINE INFUSION-INDUCED SPINAL CORD NEUROINFLAMMATION AND INCREASE IN TNFR1 EXPRESSION. THE REVERSAL OF THE MORPHINE-INDUCED INCREASE IN TNFR1 EXPRESSION BY RESVERATROL IS PARTIALLY DUE TO REVERSAL OF THE MORPHINE INFUSION-INDUCED INCREASE IN HDAC1 EXPRESSION. RESVERATROL PRETREATMENT CAN BE USED AS AN ADJUVANT IN CLINICAL PAIN MANAGEMENT FOR PATIENTS WHO NEED LONG-TERM MORPHINE TREATMENT OR WITH NEUROPATHIC PAIN. 2016 9 2326 40 EPIGENETIC REGULATION OF HOTAIR IN ADVANCED CHRONIC MYELOID LEUKEMIA. PURPOSE: CHRONIC MYELOID LEUKEMIA (CML) ACCOUNTS FOR ~10% OF LEUKEMIA CASES, AND ITS PROGRESSION INVOLVES EPIGENETIC GENE REGULATION. THIS STUDY INVESTIGATED EPIGENETIC REGULATION OF HOTAIR AND ITS TARGET MICRORNA, MIR-143, IN ADVANCED CML. PATIENTS AND METHODS: WE FIRST ISOLATED BONE MARROW MONONUCLEAR CELLS FROM 70 PATIENTS WITH DIFFERENT PHASES OF CML AND FROM HEALTHY DONORS AS NORMAL CONTROL; WE ALSO CULTURED K562 AND KCL22 CELLS, TREATED WITH DEMETHYLATION DRUG; MTT ASSAY, FLOW CYTOMETRY, QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR), METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), WESTERN BLOT, LUCIFERASE ASSAY, RNA PULL-DOWN ASSAY AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION (RIP) ASSAY WERE PERFORMED. RESULT: AS MEASURED BY QPCR, HOTAIR EXPRESSION IN K562 CELLS, KCL22 CELLS, AND SAMPLES FROM CASES OF ADVANCED-STAGE CML INCREASED WITH LEVELS OF SEVERAL DNA METHYLTRANSFERASES AND HISTONE DEACETYLATES, INCLUDING DNMT1, DNMT3A, HDAC1, EZH2, AND LSD1, AND MIR-143 LEVELS WERE DECREASED AND HOTAIR LEVELS WERE INCREASED. TREATMENT WITH 5-AZACYTIDINE, A DNA METHYLATION INHIBITOR, DECREASED DNMT1, DNMT3A, HDAC1, EZH2, LSD1 MRNA, PROTEIN LEVELS, AND HOTAIR MRNA LEVELS BUT INCREASED MIR-143 LEVELS. HOTAIR KNOCKDOWN AND MIR-143 OVEREXPRESSION BOTH INHIBITED PROLIFERATION AND PROMOTED APOPTOSIS IN KCL22 AND K562 CELLS THROUGH THE PI3K/AKT PATHWAY. RNA PULL-DOWN, MASS SPECTROMETRY, AND RIP ASSAYS SHOWED THAT HOTAIR INTERACTED WITH EZH2 AND LSD1. A DUAL-LUCIFERASE ASSAY DEMONSTRATED THAT HOTAIR INTERACTED WITH MIR-143. CONCLUSION: OUR FINDINGS DEMONSTRATE THE KEY EPIGENETIC INTERACTIONS OF HOTAIR RELATED TO CML PROGRESSION AND SUGGEST HOTAIR AS A POTENTIAL THERAPEUTIC TARGET FOR ADVANCED CML. FURTHERMORE, OUR RESULTS SUPPORT THE USE OF DEMETHYLATION DRUGS AS A CML TREATMENT STRATEGY. 2018 10 5594 48 ROLES OF AIM2 GENE AND AIM2 INFLAMMASOME IN THE PATHOGENESIS AND TREATMENT OF PSORIASIS. PSORIASIS IS AN IMMUNE-MEDIATED CHRONIC INFLAMMATORY SKIN DISEASE CAUSED BY A COMBINATION OF ENVIRONMENTAL INCENTIVES, POLYGENIC GENETIC CONTROL, AND IMMUNE REGULATION. THE INFLAMMATION-RELATED GENE ABSENT IN MELANOMA 2 (AIM2) WAS IDENTIFIED AS A SUSCEPTIBILITY GENE FOR PSORIASIS. AIM2 INFLAMMASOME FORMED FROM THE COMBINATION OF AIM2, PYD-LINKED APOPTOSIS-ASSOCIATED SPECK-LIKE PROTEIN (ASC) AND CASPASE-1 PROMOTES THE MATURATION AND RELEASE OF INFLAMMATORY CYTOKINES SUCH AS IL-1BETA AND IL-18, AND TRIGGERS AN INFLAMMATORY RESPONSE. STUDIES SHOWED THE GENETIC AND EPIGENETIC ASSOCIATIONS BETWEEN AIM2 GENE AND PSORIASIS. AIM2 GENE HAS AN ESSENTIAL ROLE IN THE OCCURRENCE AND DEVELOPMENT OF PSORIASIS, AND THE INHIBITORS OF AIM2 INFLAMMASOME WILL BE NEW THERAPEUTIC TARGETS FOR PSORIASIS. IN THIS REVIEW, WE SUMMARIZED THE ROLES OF THE AIM2 GENE AND AIM2 INFLAMMASOME IN PATHOGENESIS AND TREATMENT OF PSORIASIS, HOPEFULLY PROVIDING A BETTER UNDERSTANDING AND NEW INSIGHT INTO THE ROLES OF AIM2 GENE AND AIM2 INFLAMMASOME IN PSORIASIS. 2022 11 6456 43 THYMOSIN BETA4 PREVENTS OXIDATIVE STRESS, INFLAMMATION, AND FIBROSIS IN ETHANOL- AND LPS-INDUCED LIVER INJURY IN MICE. THYMOSIN BETA 4 (TBETA4), AN ACTIN-SEQUESTERING PROTEIN, IS INVOLVED IN TISSUE DEVELOPMENT AND REGENERATION. IT PREVENTS INFLAMMATION AND FIBROSIS IN SEVERAL TISSUES. WE INVESTIGATED THE ROLE OF TBETA4 IN CHRONIC ETHANOL- AND ACUTE LIPOPOLYSACCHARIDE- (LPS-) INDUCED MOUSE LIVER INJURY. C57BL/6 MICE WERE FED 5% ETHANOL IN LIQUID DIET FOR 4 WEEKS PLUS BINGE ETHANOL (5 G/KG, GAVAGE) WITH OR WITHOUT LPS (2 MG/KG, INTRAPERITONEAL) FOR 6 HOURS. TBETA4 (1 MG/KG, INTRAPERITONEAL) WAS ADMINISTERED FOR 1 WEEK. WE DEMONSTRATED THAT TBETA4 PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN LIVER INJURY MARKERS AS WELL AS CHANGES IN LIVER PATHOLOGY. IT ALSO PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN OXIDATIVE STRESS BY DECREASING ROS AND LIPID PEROXIDATION AND INCREASING THE ANTIOXIDANTS, REDUCED GLUTATHIONE AND MANGANESE-DEPENDENT SUPEROXIDE DISMUTASE. IT ALSO PREVENTED THE ACTIVATION OF NUCLEAR FACTOR KAPPA B BY BLOCKING THE PHOSPHORYLATION OF THE INHIBITORY PROTEIN, IKAPPAB, THEREBY PREVENTED PROINFLAMMATORY CYTOKINE PRODUCTION. MOREOVER, TBETA4 PREVENTED FIBROGENESIS BY SUPPRESSING THE EPIGENETIC REPRESSOR, METHYL-CPG-BINDING PROTEIN 2, THAT COORDINATELY REVERSED THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND DOWNREGULATED FIBROGENIC GENES, PLATELET-DERIVED GROWTH FACTOR-BETA RECEPTOR, ALPHA-SMOOTH MUSCLE ACTIN, COLLAGEN 1, AND FIBRONECTIN, RESULTING IN REDUCED FIBROSIS. OUR DATA SUGGEST THAT TBETA4 HAS ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTIFIBROTIC POTENTIAL DURING ALCOHOLIC LIVER INJURY. 2018 12 537 38 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT. 2020 13 5657 35 SEX-DEPENDENT PRONOCICEPTIVE ROLE OF SPINAL ALPHA(5) -GABA(A) RECEPTOR AND ITS EPIGENETIC REGULATION IN NEUROPATHIC RODENTS. EXTRASYNAPTIC ALPHA(5) -SUBUNIT CONTAINING GABA(A) (ALPHA(5) -GABA(A) ) RECEPTORS PARTICIPATE IN CHRONIC PAIN. PREVIOUSLY, WE REPORTED A SEX DIFFERENCE IN THE ACTION OF ALPHA(5) -GABA(A) RECEPTORS IN DYSFUNCTIONAL PAIN. HOWEVER, THE UNDERLYING MECHANISMS REMAIN UNKNOWN. THE AIM OF THIS STUDY WAS TO EXAMINE THIS SEXUAL DIMORPHISM IN NEUROPATHIC RODENTS AND THE MECHANISMS INVOLVED. FEMALE AND MALE WISTAR RATS OR ICR MICE WERE SUBJECTED TO NERVE INJURY FOLLOWED BY ALPHA(5) -GABA(A) RECEPTOR INVERSE AGONIST INTRATHECAL ADMINISTRATION, L-655,708. THE DRUG PRODUCED AN ANTIALLODYNIC EFFECT IN NERVE-INJURED FEMALE RATS AND MICE, AND A LOWER EFFECT IN MALES. WE HYPOTHESIZED THAT CHANGES IN ALPHA(5) -GABA(A) RECEPTOR, PROBABLY INFLUENCED BY HORMONAL AND EPIGENETIC STATUS, MIGHT UNDERLIE THIS SEX DIFFERENCE. THUS, WE PERFORMED QPCR AND WESTERN BLOT. NERVE INJURY INCREASED ALPHA(5) -GABA(A) MRNA AND PROTEIN IN FEMALE DORSAL ROOT GANGLIA (DRG) AND DECREASED THEM IN DRG AND SPINAL CORD OF MALES. TO INVESTIGATE THE HORMONAL INFLUENCE OVER ALPHA(5) -GABA(A) RECEPTOR ACTIONS, WE PERFORMED NERVE INJURY TO OVARIECTOMIZED RATS AND RECONSTITUTED THEM WITH 17BETA-ESTRADIOL (E2). OVARIECTOMY ABROGATED L-655,708 ANTIALLODYNIC EFFECT AND E2 RESTORED IT. OVARIECTOMY DECREASED ALPHA(5) -GABA(A) RECEPTOR AND ESTROGEN RECEPTOR ALPHA PROTEIN IN DRG OF NEUROPATHIC FEMALE RATS, WHILE E2 ENHANCED THEM. SINCE DNA METHYLATION MIGHT CONTRIBUTE TO ALPHA(5) -GABA(A) RECEPTOR DOWN-REGULATION IN MALES, WE EXAMINED CPG ISLAND DNA METHYLATION OF ALPHA(5) -GABA(A) RECEPTOR CODING GENE THROUGH PYROSEQUENCING. NERVE INJURY INCREASED METHYLATION IN MALE, BUT NOT FEMALE RATS. PHARMACOLOGICAL INHIBITION OF DNA METHYLTRANSFERASES INCREASED ALPHA(5) -GABA(A) RECEPTOR AND ENABLED L-655,708 ANTINOCICEPTIVE EFFECT IN MALE RATS. THESE RESULTS SUGGEST THAT ALPHA(5) -GABA(A) RECEPTOR IS A SUITABLE TARGET TO TREAT CHRONIC PAIN IN FEMALES. 2021 14 191 33 ACETYL-L-CARNITINE: FROM A BIOLOGICAL CURIOSITY TO A DRUG FOR THE PERIPHERAL NERVOUS SYSTEM AND BEYOND. ACETYL-L-CARNITINE (ALC) IS A MOLECULE DERIVED FROM ACETYLATION OF CARNITINE IN THE MITOCHONDRIA. CARNITINE ACETYLATION ENABLES THE FUNCTION OF COA AND FACILITATES ELIMINATION OF OXIDATIVE PRODUCTS. BEYOND THIS METABOLIC ACTIVITY, ALC PROVIDES ACETYL GROUPS FOR ACETYLCHOLINE SYNTHESIS, EXERTS A CHOLINERGIC EFFECT AND OPTIMIZES THE BALANCE OF ENERGY PROCESSES. ACETYLCARNITINE SUPPLEMENTATION INDUCES NEUROPROTECTIVE, NEUROTROPHIC AND ANALGESIC EFFECTS IN THE PERIPHERAL NERVOUS SYSTEM. IN THE RECENT STUDIES, ALC, BY ACTING AS A DONOR OF ACETYL GROUPS TO NF-KB P65/RELA, ENHANCED THE TRANSCRIPTION OF THE GRM2 GENE ENCODING THE MGLU2 RECEPTORS, INDUCING LONG-TERM UPREGULATION OF THE MGLUR2, EVIDENCING THEREFORE THAT ITS LONG-TERM ANALGESIC EFFECTS ARE DEPENDENT ON EPIGENETIC MODIFICATIONS. SEVERAL STUDIES, INCLUDING DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP STUDIES AND FEW OPEN STUDIES SHOWED THE EFFECT OF ALC IN DISEASES CHARACTERIZED BY NEUROPATHIES AND NEUROPATHIC PAIN: THE STUDIES INCLUDED DIABETIC NEUROPATHY, HIV AND ANTIRETROVIRAL THERAPY-INDUCED NEUROPATHIES, NEUROPATHIES DUE TO COMPRESSION AND CHEMOTHERAPEUTIC AGENTS. DOUBLE-BLINDED STUDIES INVOLVED 1773 PATIENTS. STATISTICAL EVALUATIONS EVIDENCED REDUCTION OF PAIN, IMPROVEMENTS OF NERVE FUNCTION AND TROPHISM. IN CONCLUSION, ALC REPRESENTS A CONSISTENT THERAPEUTIC OPTION FOR PERIPHERAL NEUROPATHIES, AND ITS COMPLEX EFFECTS, NEUROTROPHIC AND ANALGESIC, BASED ON EPIGENETIC MECHANISM, OPEN NEW PATHWAYS IN THE STUDY OF PERIPHERAL NERVE DISEASE MANAGEMENT. 2013 15 3242 45 HEPATIC NCOR1 DELETION EXACERBATES ALCOHOL-INDUCED LIVER INJURY IN MICE BY PROMOTING CCL2-MEDIATED MONOCYTE-DERIVED MACROPHAGE INFILTRATION. NUCLEAR RECEPTOR COREPRESSOR 1 (NCOR1) IS A COREPRESSOR OF THE EPIGENETIC REGULATION OF GENE TRANSCRIPTION THAT HAS IMPORTANT FUNCTIONS IN METABOLISM AND INFLAMMATION, BUT LITTLE IS KNOWN ABOUT ITS ROLE IN ALCOHOL-ASSOCIATED LIVER DISEASE (ALD). IN THIS STUDY, WE DEVELOPED MICE WITH HEPATOCYTE-SPECIFIC NCOR1 KNOCKOUT (NCOR1(HEP-/-)) USING THE ALBUMIN-CRE/LOXP SYSTEM AND INVESTIGATED THE ROLE OF NCOR1 IN THE PATHOGENESIS OF ALD AND THE UNDERLYING MECHANISMS. THE TRADITIONAL ALCOHOL FEEDING MODEL AND NIAAA MODEL OF ALD WERE BOTH ESTABLISHED IN WILD-TYPE AND NCOR1(HEP-/-) MICE. WE SHOWED THAT AFTER ALD WAS ESTABLISHED, NCOR1(HEP-/-) MICE HAD WORSE LIVER INJURY BUT LESS STEATOSIS THAN WILD-TYPE MICE. WE DEMONSTRATED THAT HEPATOCYTE-SPECIFIC LOSS OF NCOR1 ATTENUATED LIVER STEATOSIS BY PROMOTING FATTY ACID OXIDATION BY UPREGULATING BMAL1 (A CIRCADIAN CLOCK COMPONENT THAT HAS BEEN REPORTED TO PROMOTE PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA (PPARALPHA)-MEDIATED FATTY BETA-OXIDATION BY UPREGULATING DE NOVO LIPID SYNTHESIS). ON THE OTHER HAND, HEPATOCYTE-SPECIFIC LOSS OF NCOR1 EXACERBATED ALCOHOL-INDUCED LIVER INFLAMMATION AND OXIDATIVE STRESS BY RECRUITING MONOCYTE-DERIVED MACROPHAGES VIA C-C MOTIF CHEMOKINE LIGAND 2 (CCL2). IN THE MOUSE HEPATOCYTE LINE AML12, NCOR1 KNOCKDOWN SIGNIFICANTLY INCREASED ETHANOL-INDUCED CCL2 RELEASE. THESE RESULTS SUGGEST THAT HEPATOCYTE NCOR1 PLAYS DISTINCT ROLES IN CONTROLLING LIVER INFLAMMATION AND STEATOSIS, WHICH PROVIDES NEW INSIGHTS INTO THE DEVELOPMENT OF TREATMENTS FOR STEATOHEPATITIS INDUCED BY CHRONIC ALCOHOL CONSUMPTION. 2022 16 3164 45 GREEN TEA PREVENTS NAFLD BY MODULATION OF MIR-34A AND MIR-194 EXPRESSION IN A HIGH-FAT DIET MOUSE MODEL. BACKGROUND/AIMS: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS CONSIDERED THE HEPATIC MANIFESTATION OF METABOLIC SYNDROME. IT IS CURRENTLY THE MOST COMMON CHRONIC LIVER DISEASE WITH COMPLEX PATHOGENESIS AND CHALLENGING TREATMENT. HERE, WE INVESTIGATED THE HEPATOPROTECTIVE ROLE OF GREEN TEA (GT) AND DETERMINED THE INVOLVEMENT OF MIRNAS AND ITS MECHANISM OF ACTION. METHODS: MALE C57BL/6 MICE WERE FED WITH A HIGH-FAT DIET FOR 4 WEEKS. AFTER THIS PERIOD, THE ANIMALS RECEIVED GAVAGE WITH GT (500 MG/KG BODY WEIGHT) OVER 12 WEEKS (5 DAYS/WEEK). HEPG2 CELL LINES WERE TRANSFECTED WITH MIR-34A OR MIR-194 MIMETICS AND INHIBITORS TO VALIDATE THE IN VIVO RESULTS OR WERE TREATED WITH TNF-ALPHA TO EVALUATE MIRNA REGULATION. RESULTS: GT SUPPLEMENTATION PROTECTS AGAINST NAFLD DEVELOPMENT BY ALTERING LIPID METABOLISM, INCREASING GENE EXPRESSION INVOLVED IN TRIGLYCERIDES AND FATTY ACID CATABOLISM, AND DECREASING UPTAKE AND LIPID ACCUMULATION. THIS PHENOTYPE WAS ACCOMPANIED BY MIR-34A DOWNREGULATION AND AN INCREASE IN THEIR MRNA TARGETS SIRT1, PPARALPHA, AND INSIG2. GT UPREGULATED HEPATIC MIR-194 BY INHIBITING TNF-ALPHA ACTION LEADING TO A DECREASE IN MIR-194 TARGET GENES HMGCS/APOA5. CONCLUSION: OUR STUDY IDENTIFIED FOR THE FIRST TIME THAT THE BENEFICIAL EFFECTS OF GT IN THE LIVER CAN BE DUE TO THE MODULATION OF MIRNAS, OPENING NEW PERSPECTIVES FOR THE TREATMENT OF NAFLD FOCUSING ON EPIGENETIC REGULATION OF MIR-34A AND MIR-194 AS GREEN TEA TARGETS. 2019 17 3331 36 HISTONE DEACETYLASE INHIBITOR SUBERANILOHYDROXAMIC ACID TREATMENT REVERSES HYPOSENSITIVITY TO GAMMA-AMINOBUTYRIC ACID IN THE VENTRAL TEGMENTAL AREA DURING ETHANOL WITHDRAWAL. BACKGROUND: THE VENTRAL TEGMENTAL AREA (VTA) IS IMPORTANT FOR ALCOHOL-RELATED REWARD AND REINFORCEMENT. MOUSE VTA NEURONS ARE HYPOSENSITIVE TO GAMMA-AMINOBUTYRIC ACID (GABA) DURING ETHANOL (ETOH) WITHDRAWAL, AND GABA RESPONSIVENESS IS NORMALIZED BY IN VITRO TREATMENT WITH HISTONE DEACETYLASE INHIBITORS (HDACI). THE PRESENT STUDY EXAMINED THE EFFECT OF A SYSTEMICALLY ADMINISTERED HDACI, SUBERANILOHYDROXAMIC ACID (SAHA) ON GABA SENSITIVITY, AND RELATED MOLECULAR CHANGES IN VTA NEURONS DURING WITHDRAWAL AFTER CHRONIC ETOH INTAKE IN RATS. METHODS: SPRAGUE DAWLEY MALE ADULT RATS WERE FED WITH LIEBER-DECARLI DIET (9% ETOH OR CONTROL DIET) FOR 16 DAYS. EXPERIMENTAL GROUPS INCLUDED CONTROL DIET-FED AND ETOH DIET-FED (0- OR 24-HOUR WITHDRAWAL) RATS TREATED WITH EITHER SAHA OR VEHICLE INJECTION. SINGLE-UNIT RECORDINGS WERE USED TO MEASURE THE RESPONSE OF VTA NEURONS TO GABA. IMMUNOHISTOCHEMISTRY WAS PERFORMED TO EXAMINE LEVELS OF HDAC2, ACETYLATED HISTONE H3 LYSINE 9 (ACH3K9), AND GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS IN THE VTA; QUANTITATIVE POLYMERASE CHAIN REACTION WAS PERFORMED TO EXAMINE THE MRNA LEVELS OF HDAC2 AND GABA(A) RECEPTOR SUBUNITS. RESULTS: VTA NEURONS FROM THE WITHDRAWAL GROUP EXHIBITED GABA HYPOSENSITIVITY. IN VIVO SAHA TREATMENT 2 HOURS BEFORE SACRIFICE NORMALIZED THE SENSITIVITY OF VTA NEURONS TO GABA. ETOH WITHDRAWAL WAS ASSOCIATED WITH INCREASED HDAC2 AND DECREASED ACH3K9 PROTEIN LEVELS; SAHA TREATMENT NORMALIZED ACH3K9 LEVELS. INTERESTINGLY, NO SIGNIFICANT CHANGE WAS OBSERVED IN THE MRNA LEVELS OF HDAC2. THE MRNA LEVELS, BUT NOT PROTEIN LEVELS, OF GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS WERE INCREASED DURING WITHDRAWAL. CONCLUSIONS: WITHDRAWAL FROM CHRONIC ETOH EXPOSURE RESULTS IN A DECREASE IN GABA-MEDIATED INHIBITION, AND THIS GABA HYPOSENSITIVITY IS NORMALIZED BY IN VIVO SAHA TREATMENT. DISRUPTION OF SIGNALING IN THE VTA PRODUCED BY ALTERATION OF GABA NEUROTRANSMISSION COULD BE 1 NEUROADAPTIVE PHYSIOLOGICAL PROCESS LEADING TO CRAVING AND RELAPSE. THESE RESULTS SUGGEST THAT HDACI PHARMACOTHERAPY WITH AGENTS LIKE SAHA MIGHT BE AN EFFECTIVE TREATMENT FOR ALCOHOLISM. 2018 18 3841 29 IRON SUPPLEMENTATION REVERSES THE REDUCTION OF HYDROXYMETHYLCYTOSINE IN HEPATIC DNA ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION IN RATS. BACKGROUND: ALCOHOL IS KNOWN TO AFFECT TWO EPIGENETIC PHENOMENA, DNA METHYLATION AND DNA HYDROXYMETHYLATION, AND IRON IS A COFACTOR OF TEN-ELEVEN TRANSLOCATION (TET) ENZYMES THAT CATALYZE THE CONVERSION FROM METHYLCYTOSINE TO HYDROXYMETHYLCYTOSINE. IN THE PRESENT STUDY WE AIMED TO DETERMINE THE EFFECTS OF ALCOHOL ON DNA HYDROXYMETHYLATION AND FURTHER EFFECTS OF IRON ON ALCOHOL ASSOCIATED EPIGENETIC CHANGES. METHODS: TWENTY-FOUR MALE SPRAGUE-DAWLEY RATS WERE FED EITHER LIEBER-DECARLI ALCOHOL DIET (36% CALORIES FROM ETHANOL) OR LIEBER-DECARLI CONTROL DIET ALONG WITH OR WITHOUT IRON SUPPLEMENTATION (0.6% CARBONYL IRON) FOR 8 WEEKS. HEPATIC NON-HEME IRON CONCENTRATIONS WERE MEASURED BY COLORIMETRIC ASSAYS. PROTEIN LEVELS OF HEPATIC FERRITIN AND TRANSFERRIN RECEPTOR WERE DETERMINED BY WESTERN BLOTTING. METHYLCYTOSINE, HYDROXYMETHYLCYTOSINE AND UNMODIFIED CYTOSINE IN DNA WERE SIMULTANEOUSLY MEASURED BY LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY METHOD. RESULTS: IRON SUPPLEMENTATION SIGNIFICANTLY INCREASED HEPATIC NON-HEME IRON CONTENTS (P < 0.05) BUT ALCOHOL ALONE DID NOT. HOWEVER, BOTH ALCOHOL AND IRON SIGNIFICANTLY INCREASED HEPATIC FERRITIN LEVELS AND DECREASED HEPATIC TRANSFERRIN RECEPTOR LEVELS (P < 0.05). ALCOHOL REDUCED HEPATIC DNA HYDROXYMETHYLATION (0.21% +/- 0.04% VS. 0.33% +/- 0.04%, P = 0.01) COMPARED TO CONTROL, WHILE IRON SUPPLEMENTATION TO ALCOHOL DIET DID NOT CHANGE DNA HYDROXYMETHYLATION. THERE WAS NO SIGNIFICANT DIFFERENCE IN METHYLCYTOSINE LEVELS, WHILE UNMODIFIED CYTOSINE LEVELS WERE SIGNIFICANTLY INCREASED IN ALCOHOL-FED GROUPS COMPARED TO CONTROL (95.61% +/- 0.08% VS. 95.26% +/- 0.12%, P = 0.03), SUGGESTING THAT ALCOHOL FURTHER INCREASES THE CONVERSION FROM HYDROXYMETHYLCYTOSINE TO UNMODIFIED CYTOSINE. CONCLUSIONS: CHRONIC ALCOHOL CONSUMPTION ALTERS GLOBAL DNA HYDROXYMETHYLATION IN THE LIVER BUT IRON SUPPLEMENTATION REVERSES THE EPIGENETIC EFFECT OF ALCOHOL. 2016 19 3940 48 LNCRNA DLEU2 REGULATES SIRTUINS AND MITOCHONDRIAL RESPIRATORY CHAIN COMPLEX IV: A NOVEL PATHWAY IN OBESITY AND OFFSPRING'S HEALTH. BACKGROUND: LONG NON-CODING RNAS (LNCRNAS) HAVE EMERGED AS A RAPIDLY EXPANDING AREA OF INTEREST IN CHRONIC DISEASES. THEY ARE MOSTLY UNKNOWN FOR ROLES IN METABOLIC REGULATION. SIRTUINS, AN EPIGENETIC MODULATOR CLASS, REGULATE METABOLIC PATHWAYS. HOWEVER, HOW SIRTUINS ARE REGULATED VIA LNCRNA IS UNKNOWN. WE HYPOTHESIZED THAT A HIGH-FAT HIGH-FRUCTOSE DIET (HFD-HF) DURING PREGNANCY WOULD INCREASE THE RISK FOR OBESITY VIA LNCRNA-SIRTUIN PATHWAYS. METHODS: FEMALE C57BL/6 MICE (F0) WERE FED EITHER CHOW DIET (CD) OR HFD-HF FOR 6 WEEKS TILL BIRTH. THE PUPS (F1) WERE FED EITHER CD OR HFD-HF FOR 20 WEEKS. EXPRESSION OF DLEU2, SIRTUINS, MITOCHONDRIAL RESPIRATORY COMPLEXES, AND OXIDATIVE STRESS WERE INVESTIGATED IN THE F1 LIVERS. FASTING BLOOD GLUCOSE, INSULIN SENSITIVITY, GLUCOSE TOLERANCE, BODY AND TISSUES WEIGHT WERE MEASURED. A MECHANISTIC INTERACTION WAS THEN CARRIED OUT USING A DLEU2 KNOCKDOWN EXPERIMENT IN THE HEPG2 CELL. RESULTS: DLEU2 AND SIRTUINS WERE BOTH SIGNIFICANTLY DECREASED IN THE LIVERS OF HFD-HF FED MALE F1 WHOSE MOTHERS WERE EITHER FED CD OR HFD-HF DURING REPRODUCTIVE AND PREGNANCY WINDOWS. CONFIRMING THIS CONNECTION, UPON SILENCING DLEU2, TRANSCRIPTION LEVELS OF SIRT1 THROUGH 6 AND TRANSLATIONAL LEVELS OF SIRT1, 3, 5, AND 6 WERE SIGNIFICANTLY DOWNREGULATED. KNOCKDOWN OF DLEU2 SIGNIFICANTLY DECREASED THE PROTEIN LEVEL OF CYTOCHROME-C OXIDASE (COMPLEX IV, MTCO1) WITHOUT ALTERING OTHER MITOCHONDRIAL COMPLEXES, DECREASED MITOCHONDRIAL MEMBRANE POTENTIAL, DECREASED ATP, AND INCREASED REACTIVE OXYGEN SPECIES. INTERESTINGLY, IN F1 LIVERS, THE PROTEIN LEVEL OF MTCO1 WAS ALSO SIGNIFICANTLY DECREASED UNDER AN HFD-HF DIET OR EVEN UNDER CHOW DIET IF THE MOTHER WAS EXPOSED TO HFD-HF. CONCLUSION: OUR FINDINGS REVEAL FOR THE FIRST TIME THAT ONE LNCRNA CAN REGULATE SIRTUINS AND A SPECIFIC MITOCHONDRIAL COMPLEX. FURTHERMORE, DIET OR MATERNAL DIET CAN MODULATE DLEU2 AND ITS DOWNSTREAM REGULATORS IN OFFSPRING, SUGGESTING A POTENTIAL ROLE OF DLEU2 IN METABOLIC DISORDERS OVER ONE OR MORE GENERATIONS. 2022 20 1800 25 EFFECT OF HISTONE DEACETYLASE INHIBITOR ON ETHANOL WITHDRAWAL-INDUCED HYPERALGESIA IN RATS. BACKGROUND: INCREASED PAIN SENSITIVITY IS OBSERVED FOLLOWING ALCOHOL WITHDRAWAL, AND ATTEMPTS TO ALLEVIATE THIS HYPERALGESIA CAN CONTRIBUTE TO THE CYCLE OF ADDICTION. THE AIM OF THIS STUDY WAS TO DETERMINE IF ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA WAS OBSERVED IN A CHRONIC ETHANOL EXPOSURE MODEL AND IF THIS PAIN WAS AFFECTED BY HISTONE DEACETYLASE INHIBITORS, THUS REVEALING AN EPIGENETIC MECHANISM. METHODS: ADULT MALE SPRAGUE DAWLEY RATS RECEIVED LIEBER-DECARLI LIQUID CONTROL OR ETHANOL (9% V/V) DIET FOR 15 DAYS. MECHANICAL SENSITIVITY WAS MEASURED WITH VON FREY HAIR STIMULATION OF THE HINDPAW DURING ETHANOL ADMINISTRATION AND 24- AND 72-HOUR WITHDRAWAL. RESULTS: ETHANOL WITHDRAWAL PRODUCED SEVERE AND SUSTAINED MECHANICAL HYPERALGESIA, AN EFFECT NOT OBSERVED IN THE CONTROL OR ETHANOL-MAINTAINED GROUPS. FURTHERMORE, THIS HYPERALGESIA WAS ATTENUATED BY THE HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID TREATMENT. CONCLUSIONS: HEIGHTENED PAIN SENSITIVITY WAS OBSERVED FOLLOWING WITHDRAWAL FROM CHRONIC ETHANOL EXPOSURE, AND HISTONE DEACETYLASE INHIBITORS COULD BE NOVEL TREATMENTS FOR THIS ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA. 2019