1 702 155 BROWN RICE-SPECIFIC GAMMA-ORYZANOL AS A PROMISING PROPHYLACTIC AVENUE TO PROTECT AGAINST DIABETES MELLITUS AND OBESITY IN HUMANS. CHRONIC OVERCONSUMPTION OF ANIMAL FATS CAUSES A VARIETY OF HEALTH PROBLEMS, INCLUDING DIABETES MELLITUS AND OBESITY. UNDERLYING MOLECULAR MECHANISMS ENCOMPASS LEPTIN RESISTANCE, A DECREASE IN REWARDING EFFECTS OF PHYSICAL ACTIVITIES, XANTHINE OXIDASE-INDUCED OXIDATIVE STRESS IN VASCULATURE AND PERIPHERAL TISSUE, IMPAIRED ACTIVATION OF INCRETIN SIGNALING, DEVIATION IN FOOD PREFERENCE, AND DYSBIOSIS OF GUT MICROBIOTA. BASED ON OUR CLINICAL OBSERVATION THAT DAILY INTAKE OF BROWN RICE EFFECTIVELY AMELIORATES BODYWEIGHT GAIN, IMPAIRED GLUCOSE TOLERANCE/INSULIN RESISTANCE AND DEPENDENCE ON FATTY FOODS IN OBESE, PREDIABETES MEN, A LINE OF RESEARCH ON BROWN RICE (RICE BRAN)-DERIVED GAMMA-ORYZANOL IN MICE EXPERIMENTS, CULTURED CELLS AND HUMAN CLINICAL TRIALS IS UNDERWAY IN OUR LABORATORY. OUR WORKS IN MICE SHOWED THAT GAMMA-ORYZANOL, AN ESTER MIXTURE OF FERULIC ACID AND SEVERAL KINDS OF PHYTOSTEROLS, ACTS AS A MOLECULAR CHAPERONE, THEREBY ATTENUATING THE STRONG PREFERENCE FOR ANIMAL FATS THROUGH SUPPRESSION OF ENDOPLASMIC RETICULUM STRESS IN THE HYPOTHALAMUS. IN PANCREATIC ISLETS FROM BOTH HIGH-FAT DIET-INDUCED AND STREPTOZOTOCIN-INDUCED DIABETIC MICE, GAMMA-ORYZANOL AMELIORATES ENDOPLASMIC RETICULUM STRESS AND PROTECTS BETA-CELLS AGAINST APOPTOSIS. NOTICEABLY, GAMMA-ORYZANOL ALSO ACTS AS A POTENT INHIBITOR AGAINST DEOXYRIBONUCLEIC ACID METHYLTRANSFERASES IN THE BRAIN REWARD SYSTEM (STRIATUM) IN MICE, THEREBY ATTENUATING, AT LEAST PARTLY, THE PREFERENCE FOR A HIGH-FAT DIET THROUGH THE EPIGENETIC MODULATION OF STRIATAL DOPAMINE D2 RECEPTOR. BECAUSE DOPAMINE D2 RECEPTOR SIGNALING IN THE BRAIN REWARD SYSTEM IS CONSIDERABLY ATTENUATED IN OBESE HUMANS AND RODENTS, GAMMA-ORYZANOL MIGHT REPRESENT A UNIQUE PROPERTY TO AMELIORATE BOTH HEDONIC AND METABOLIC DYSREGULATION OF FEEDING BEHAVIOR, HIGHLIGHTING A PROMISING PROPHYLACTIC AVENUE TO PROTECT AGAINST METABOLIC DERANGEMENT. 2019 2 3152 29 GLUCOSE VARIABILITY: HOW DOES IT WORK? A GROWING BODY OF EVIDENCE POINTS TO THE ROLE OF GLUCOSE VARIABILITY (GV) IN THE DEVELOPMENT OF THE MICROVASCULAR AND MACROVASCULAR COMPLICATIONS OF DIABETES. IN THIS REVIEW, WE SUMMARIZE DATA ON GV-INDUCED BIOCHEMICAL, CELLULAR AND MOLECULAR EVENTS INVOLVED IN THE PATHOGENESIS OF DIABETIC COMPLICATIONS. CURRENT DATA INDICATE THAT THE DETERIORATING EFFECT OF GV ON TARGET ORGANS CAN BE REALIZED THROUGH OXIDATIVE STRESS, GLYCATION, CHRONIC LOW-GRADE INFLAMMATION, ENDOTHELIAL DYSFUNCTION, PLATELET ACTIVATION, IMPAIRED ANGIOGENESIS AND RENAL FIBROSIS. THE EFFECTS OF GV ON OXIDATIVE STRESS, INFLAMMATION, ENDOTHELIAL DYSFUNCTION AND HYPERCOAGULABILITY COULD BE AGGRAVATED BY HYPOGLYCEMIA, ASSOCIATED WITH HIGH GV. OSCILLATING HYPERGLYCEMIA CONTRIBUTES TO BETA CELL DYSFUNCTION, WHICH LEADS TO A FURTHER INCREASE IN GV AND COMPLETES THE VICIOUS CIRCLE. IN CELLS, THE GV-INDUCED CYTOTOXIC EFFECT INCLUDES MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS AND DISTURBANCES IN AUTOPHAGIC FLUX, WHICH ARE ACCOMPANIED BY REDUCED VIABILITY, ACTIVATION OF APOPTOSIS AND ABNORMALITIES IN CELL PROLIFERATION. THESE EFFECTS ARE REALIZED THROUGH THE UP- AND DOWN-REGULATION OF A LARGE NUMBER OF GENES AND THE ACTIVITY OF SIGNALING PATHWAYS SUCH AS PI3K/AKT, NF-KAPPAB, MAPK (ERK), JNK AND TGF-BETA/SMAD. EPIGENETIC MODIFICATIONS MEDIATE THE POSTPONED EFFECTS OF GLUCOSE FLUCTUATIONS. THE MULTIPLE DETERIORATIVE EFFECTS OF GV PROVIDE FURTHER SUPPORT FOR CONSIDERING IT AS A THERAPEUTIC TARGET IN DIABETES. 2021 3 2597 25 EPIGENETICS OF SUBCELLULAR STRUCTURE FUNCTIONING IN THE ORIGIN OF RISK OR RESILIENCE TO COMORBIDITY OF NEUROPSYCHIATRIC AND CARDIOMETABOLIC DISORDERS. MECHANISMS CONTROLLING MITOCHONDRIAL FUNCTION, PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM (ER) AND NUCLEAR PROCESSES SUCH AS TELOMERE LENGTH AND DNA REPAIR MAY BE SUBJECT TO EPIGENETIC CUES THAT RELATE THE GENOMIC EXPRESSION AND ENVIRONMENTAL EXPOSURES IN EARLY STAGES OF LIFE. THEY MAY ALSO BE INVOLVED IN THE COMORBID APPEARANCE OF CARDIOMETABOLIC (CMD) AND NEUROPSYCHIATRIC DISORDERS (NPD) DURING ADULTHOOD. MITOCHONDRIAL FUNCTION AND PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM ARE ASSOCIATED WITH OXIDATIVE STRESS AND ELEVATED INTRACELLULAR CALCIUM LEVELS AND MAY ALSO UNDERLIE THE VULNERABILITY FOR COMORBID CMD AND NPD. MITOCHONDRIA PROVIDE KEY METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+), ATP, ALPHA-KETOGLUTARATE AND ACETYL COENZYME A THAT ARE REQUIRED FOR MANY TRANSCRIPTIONAL AND EPIGENETIC PROCESSES. THEY ARE ALSO A SOURCE OF FREE RADICALS. ON THE OTHER HAND, EPIGENETIC MARKERS IN NUCLEAR DNA DETERMINE MITOCHONDRIAL BIOGENESIS. THE ER IS THE SUBCELLULAR ORGANELLE IN WHICH SECRETORY PROTEINS ARE FOLDED. MANY ENVIRONMENTAL FACTORS STOP THE ABILITY OF CELLS TO PROPERLY FOLD PROTEINS AND MODIFY POST-TRANSLATIONALLY SECRETORY AND TRANSMEMBRANE PROTEINS LEADING TO ENDOPLASMIC RETICULUM STRESS AND OXIDATIVE STRESS. ER FUNCTIONING MAY BE EPIGENETICALLY DETERMINED. CHRONIC ER STRESS IS EMERGING AS A KEY CONTRIBUTOR TO A GROWING LIST OF HUMAN DISEASES, INCLUDING CMD AND NPD. TELOMERE LOSS CAUSES CHROMOSOMAL FUSION, ACTIVATION OF THE CONTROL OF DNA DAMAGE-RESPONSES, UNSTABLE GENOME AND ALTERED STEM CELL FUNCTION, WHICH MAY UNDERLIE THE COMORBIDITY OF CMD AND NPD. THE LENGTH OF TELOMERES IS RELATED TO OXIDATIVE STRESS AND MAY BE EPIGENETICALLY PROGRAMMED. PATHWAYS INVOLVED IN DNA REPAIR MAY BE EPIGENETICALLY PROGRAMMED AND MAY CONTRIBUTE TO DISEASES. IN THIS PAPER, WE DESCRIBE SUBCELLULAR MECHANISMS THAT ARE DETERMINED BY EPIGENETIC MARKERS AND THEIR POSSIBLE RELATION TO THE DEVELOPMENT OF INCREASED SUSCEPTIBILITY TO DEVELOP CMD AND NPD. 2018 4 2616 19 EPIGENOME MODULATION INDUCED BY KETOGENIC DIETS. KETOGENIC DIETS (KD) ARE DIETARY STRATEGIES LOW IN CARBOHYDRATES, NORMAL IN PROTEIN, AND HIGH, NORMAL, OR REDUCED IN FAT WITH OR WITHOUT (VERY LOW-CALORIES KETOGENIC DIET, VLCKD) A REDUCED CALORIC INTAKE. KDS HAVE BEEN SHOWN TO BE USEFUL IN THE TREATMENT OF OBESITY, METABOLIC DISEASES AND RELATED DISORDERS, NEUROLOGICAL DISEASES, AND VARIOUS PATHOLOGICAL CONDITIONS SUCH AS CANCER, NONALCOHOLIC LIVER DISEASE, AND CHRONIC PAIN. SEVERAL STUDIES HAVE INVESTIGATED THE INTRACELLULAR METABOLIC PATHWAYS THAT CONTRIBUTE TO THE BENEFICIAL EFFECTS OF THESE DIETS. ALTHOUGH EPIGENETIC CHANGES ARE AMONG THE MOST IMPORTANT DETERMINANTS OF AN ORGANISM'S ABILITY TO ADAPT TO ENVIRONMENTAL CHANGES, DATA ON THE EPIGENETIC CHANGES ASSOCIATED WITH THESE DIETARY PATHWAYS ARE STILL LIMITED. THIS REVIEW PROVIDES AN OVERVIEW OF THE MAJOR EPIGENETIC CHANGES ASSOCIATED WITH KDS. 2022 5 4992 19 PEELING THE ONION: ANOTHER LAYER IN THE REGULATION OF INSULIN SECRETION. INSULIN SECRETION BY PANCREATIC BETA CELLS IS A DYNAMIC AND HIGHLY REGULATED PROCESS DUE TO THE CENTRAL IMPORTANCE OF INSULIN IN ENABLING EFFICIENT UTILIZATION AND STORAGE OF GLUCOSE. MULTIPLE REGULATORY LAYERS ENABLE BETA CELLS TO ADAPT TO ACUTE CHANGES IN NUTRIENT AVAILABILITY AS WELL AS CHRONIC CHANGES IN METABOLIC DEMAND. WHILE EPIGENETIC FACTORS HAVE BEEN WELL ESTABLISHED AS REGULATORS OF CHRONIC BETA CELL ADAPTATIONS TO INSULIN RESISTANCE, THEIR ROLE IN ACUTE ADAPTATIONS IN RESPONSE TO NUTRIENT STIMULATION HAS BEEN RELATIVELY UNEXPLORED. IN THIS ISSUE OF THE JCI, WORTHAM ET AL. REPORT THAT SHORT-TERM DYNAMIC CHANGES IN HISTONE MODIFICATIONS REGULATED INSULIN SECRETION AND ACUTE BETA CELL ADAPTATIONS IN RESPONSE TO FASTING AND FEEDING CYCLES. THESE FINDINGS HIGHLIGHT THE IMPORTANCE OF INVESTIGATING WHETHER OTHER EPIGENETIC MECHANISMS MAY CONTRIBUTE TO ACUTE PHYSIOLOGIC ADAPTATIONS IN BETA CELLS. 2023 6 3591 21 IMPAIRED ONE CARBON METABOLISM AND DNA METHYLATION IN ALCOHOL TOXICITY. EXCESSIVE ALCOHOL CONSUMPTION IS A PROMINENT PROBLEM AND ONE OF THE MAJOR CAUSES OF MORTALITY AND MORBIDITY AROUND THE WORLD. LONG-TERM, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH A NUMBER OF DELETERIOUS HEALTH CONSEQUENCES, SUCH AS CANCER, HEART AND LIVER DISEASE, A VARIETY OF NEUROLOGICAL, COGNITIVE, AND BEHAVIORAL DEFICITS. ALCOHOL CONSUMPTION IS ALSO ASSOCIATED WITH DEVELOPMENTAL DEFECTS. THE CAUSES OF ALCOHOL-INDUCED TOXICITY ARE PRESENTLY UNCLEAR. ONE OF THE MECHANISMS UNDERLYING ALCOHOL TOXICITY HAS TO DO WITH ITS INTERACTION WITH FOLIC ACID/HOMOCYSTEINE OR ONE-CARBON METABOLISM (OCM). OCM IS A MAJOR DONOR OF METHYL GROUPS FOR METHYLATION, PARTICULARLY DNA METHYLATION CRITICAL FOR EPIGENETIC REGULATION OF GENE EXPRESSION, AND ITS DISTURBANCE MAY COMPROMISE DNA METHYLATION, THEREBY AFFECTING GENE EXPRESSION. OCM DISTURBANCE MEDIATED BY NUTRIENT DEFICITS IS A WELL-KNOWN RISK FACTOR FOR VARIOUS DISORDERS AND DEVELOPMENTAL DEFECTS (E.G., NEURAL TUBE DEFECTS). IN THIS REVIEW, WE SUMMARIZE THE ROLE OF OCM DISTURBANCE AND ASSOCIATED EPIGENETIC ABERRATIONS IN CHRONIC ALCOHOL-INDUCED TOXICITY. IN THIS REVIEW, WE SUMMARIZE THE ROLE OF ONE-CARBON METABOLISM (OCM) ABERRATIONS IN CHRONIC ALCOHOL-INDUCED TOXICITY. OCM IS A MAJOR DONOR OF METHYL GROUPS FOR METHYLATION REACTIONS, PARTICULARLY DNA METHYLATION CRITICAL FOR EPIGENETIC REGULATION OF GENE EXPRESSION. ALCOHOL INTERFERENCE WITH OCM AND CONSEQUENT REDUCED AVAILABILITY OF METHYL GROUPS, IMPROPER DNA METHYLATION, AND ABERRANT GENE EXPRESSION CAN PLAY A CAUSATIVE ROLE IN ALCOHOL TOXICITY. 2014 7 2246 30 EPIGENETIC MODULATION OF INFLAMMATION AND SYNAPTIC PLASTICITY PROMOTES RESILIENCE AGAINST STRESS IN MICE. MAJOR DEPRESSIVE DISORDER IS ASSOCIATED WITH ABNORMALITIES IN THE BRAIN AND THE IMMUNE SYSTEM. CHRONIC STRESS IN ANIMALS SHOWED THAT EPIGENETIC AND INFLAMMATORY MECHANISMS PLAY IMPORTANT ROLES IN MEDIATING RESILIENCE AND SUSCEPTIBILITY TO DEPRESSION. HERE, THROUGH A HIGH-THROUGHPUT SCREENING, WE IDENTIFY TWO PHYTOCHEMICALS, DIHYDROCAFFEIC ACID (DHCA) AND MALVIDIN-3'-O-GLUCOSIDE (MAL-GLUC) THAT ARE EFFECTIVE IN PROMOTING RESILIENCE AGAINST STRESS BY MODULATING BRAIN SYNAPTIC PLASTICITY AND PERIPHERAL INFLAMMATION. DHCA/MAL-GLUC ALSO SIGNIFICANTLY REDUCES DEPRESSION-LIKE PHENOTYPES IN A MOUSE MODEL OF INCREASED SYSTEMIC INFLAMMATION INDUCED BY TRANSPLANTATION OF HEMATOPOIETIC PROGENITOR CELLS FROM STRESS-SUSCEPTIBLE MICE. DHCA REDUCES PRO-INFLAMMATORY INTERLEUKIN 6 (IL-6) GENERATIONS BY INHIBITING DNA METHYLATION AT THE CPG-RICH IL-6 SEQUENCES INTRONS 1 AND 3, WHILE MAL-GLUC MODULATES SYNAPTIC PLASTICITY BY INCREASING HISTONE ACETYLATION OF THE REGULATORY SEQUENCES OF THE RAC1 GENE. PERIPHERAL INFLAMMATION AND SYNAPTIC MALADAPTATION ARE IN LINE WITH NEWLY HYPOTHESIZED CLINICAL INTERVENTION TARGETS FOR DEPRESSION THAT ARE NOT ADDRESSED BY CURRENTLY AVAILABLE ANTIDEPRESSANTS. 2018 8 773 29 CELL AND MOLECULAR MECHANISMS BEHIND DIET-INDUCED HYPOTHALAMIC INFLAMMATION AND OBESITY. DIET-INDUCED OBESITY (DIO) IS ASSOCIATED WITH CHRONIC, LOW-GRADE INFLAMMATION IN THE HYPOTHALAMUS, A KEY REGULATOR OF ENERGY HOMEOSTASIS. CURRENT STUDIES HAVE REVEALED THE INVOLVEMENT OF DIFFERENT CELL TYPES, AS WELL AS CELL AND MOLECULAR MECHANISMS, THAT CONTRIBUTE TO DIET-INDUCED HYPOTHALAMIC INFLAMMATION (DIHI) AND DIO. SUBSEQUENT TO THE DISCOVERY THAT HIGH-FAT DIET AND SATURATED FATTY ACIDS INCREASE THE EXPRESSION OF HYPOTHALAMIC CYTOKINES PRIOR TO WEIGHT GAIN, RESEARCH HAS FOCUSED ON UNDERSTANDING THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING THESE CHANGES, IN ADDITION TO THE ROLE OF INFLAMMATION IN THE PATHOGENESIS OF OBESITY. RECENT STUDIES HAVE PROPOSED THAT THE INHIBITION OF PRO-INFLAMMATORY PATHWAYS IN MICROGLIA AND ASTROCYTES IS SUFFICIENT TO PROTECT AGAINST DIHI AND PREVENT OBESITY. IN ADDITION, IMPAIRMENT OF INTRACELLULAR AND EPIGENETIC MECHANISMS, SUCH AS HYPOTHALAMIC AUTOPHAGY AND CHANGES IN THE METHYLATION PATTERN OF CERTAIN GENES, HAVE BEEN IMPLICATED IN SUSCEPTIBILITY TO DIHI AND DIO. INTERESTINGLY, A SEXUAL DIMORPHISM HAS BEEN FOUND DURING DIO IN HYPOTHALAMIC INFLAMMATION, GLIAL ACTIVATION AND METABOLIC DISEASES, AND RECENT DATA SUPPORT AN IMPORTANT ROLE OF SEX STEROIDS IN DIHI. THESE NEW EXCITING FINDINGS UNCOVER NOVEL OBESITY PATHOGENIC MECHANISMS AND PROVIDE TARGETS TO DEVELOP THERAPEUTIC APPROACHES. 2018 9 4627 19 NEUROENDOCRINOLOGICAL AND EPIGENETIC MECHANISMS SUBSERVING AUTONOMIC IMBALANCE AND HPA DYSFUNCTION IN THE METABOLIC SYNDROME. IMPACT OF ENVIRONMENTAL STRESS UPON PATHOPHYSIOLOGY OF THE METABOLIC SYNDROME (METS) HAS BEEN SUBSTANTIATED BY EPIDEMIOLOGICAL, PSYCHOPHYSIOLOGICAL, AND ENDOCRINOLOGICAL STUDIES. THIS REVIEW DISCUSSES RECENT ADVANCES IN THE UNDERSTANDING OF CAUSATIVE ROLES OF NUTRITIONAL FACTORS, SYMPATHOMEDULLO-ADRENAL (SMA) AND HYPOTHALAMIC-PITUITARY ADRENOCORTICAL (HPA) AXES, AND ADIPOSE TISSUE CHRONIC LOW-GRADE INFLAMMATION PROCESSES IN METS. DISTURBANCES IN THE NEUROENDOCRINE SYSTEMS FOR LEPTIN, MELANOCORTIN, AND NEUROPEPTIDE Y (NPY)/AGOUTI-RELATED PROTEIN SYSTEMS HAVE BEEN FOUND RESULTING DIRECTLY IN METS-LIKE CONDITIONS. THE REVIEW IDENTIFIES CANDIDATE RISK GENES FROM FACTORS SHOWN CRITICAL FOR THE FUNCTIONING OF EACH OF THESE NEUROENDOCRINE SIGNALING CASCADES. IN ITS META-ANALYTIC PART, RECENT STUDIES IN EPIGENETIC MODIFICATION (HISTONE METHYLATION, ACETYLATION, PHOSPHORYLATION, UBIQUITINATION) AND POSTTRANSCRIPTIONAL GENE REGULATION BY MICRORNAS ARE EVALUATED. SEVERAL STUDIES SUGGEST MODIFICATION MECHANISMS OF EARLY LIFE STRESS (ELS) AND DIET-INDUCED OBESITY (DIO) PROGRAMMING IN THE HYPOTHALAMIC REGIONS WITH POPULATIONS OF POMC-EXPRESSING NEURONS. EPIGENETIC MODIFICATIONS WERE FOUND IN CORTISOL (HERE HSD11B1 EXPRESSION), MELANOCORTIN, LEPTIN, NPY, AND ADIPONECTIN GENES. WITH RESPECT TO ADIPOSITY GENES, EPIGENETIC MODIFICATIONS WERE DOCUMENTED FOR FAT MASS GENE CLUSTER APOA1/C3/A4/A5, AND THE LIPOLYSIS GENE LIPE. WITH REGARD TO INFLAMMATORY, IMMUNE AND SUBCELLULAR METABOLISM, PPARG, NKBF1, TNFA, TCF7C2, AND THOSE GENES EXPRESSING CYTOCHROME P450 FAMILY ENZYMES INVOLVED IN STEROIDOGENESIS AND IN HEPATIC LIPOPROTEINS WERE DOCUMENTED FOR EPIGENETIC MODIFICATIONS. 2016 10 1162 24 CONTRASTING EFFECTS OF ACUTE AND CHRONIC STRESS ON THE TRANSCRIPTOME, EPIGENOME, AND IMMUNE RESPONSE OF ATLANTIC SALMON. STRESS EXPERIENCED DURING EARLY LIFE MAY HAVE LASTING EFFECTS ON THE IMMUNE SYSTEM, WITH IMPACTS ON HEALTH AND DISEASE DEPENDENT ON THE NATURE AND DURATION OF THE STRESSOR. THE EPIGENOME IS ESPECIALLY SENSITIVE TO ENVIRONMENTAL STIMULI DURING EARLY LIFE AND REPRESENTS A POTENTIAL MECHANISM THROUGH WHICH STRESS MAY CAUSE LONG-LASTING HEALTH EFFECTS. HOWEVER, THE EXTENT TO WHICH THE EPIGENOME RESPONDS DIFFERENTLY TO CHRONIC VS ACUTE STRESSORS IS UNCLEAR, ESPECIALLY FOR NON-MAMMALIAN SPECIES. WE EXAMINED THE EFFECTS OF ACUTE STRESS (COLD-SHOCK DURING EMBRYOGENESIS) AND CHRONIC STRESS (ABSENCE OF TANK ENRICHMENT DURING LARVAL-STAGE) ON GLOBAL GENE EXPRESSION (USING RNA-SEQ) AND DNA METHYLATION (USING RRBS) IN THE GILLS OF ATLANTIC SALMON (SALMO SALAR) FOUR MONTHS AFTER HATCHING. CHRONIC STRESS INDUCED PRONOUNCED TRANSCRIPTIONAL DIFFERENCES, WHILE ACUTE STRESS CAUSED FEW LASTING TRANSCRIPTIONAL EFFECTS. HOWEVER, BOTH ACUTE AND CHRONIC STRESS CAUSED LASTING AND CONTRASTING CHANGES IN THE METHYLOME. CRUCIALLY, WE FOUND THAT ACUTE STRESS ENHANCED TRANSCRIPTIONAL IMMUNE RESPONSE TO A PATHOGENIC CHALLENGE (BACTERIAL LIPOPOLYSACCHARIDE, LPS), WHILE CHRONIC STRESS SUPPRESSED IT. WE IDENTIFIED STRESS-INDUCED CHANGES IN PROMOTER AND GENE-BODY METHYLATION THAT WERE ASSOCIATED WITH ALTERED EXPRESSION FOR A SMALL PROPORTION OF IMMUNE-RELATED GENES, AND EVIDENCE OF WIDER EPIGENETIC REGULATION WITHIN SIGNALLING PATHWAYS INVOLVED IN IMMUNE RESPONSE. OUR RESULTS SUGGEST THAT STRESS CAN AFFECT IMMUNO-COMPETENCE THROUGH EPIGENETIC MECHANISMS, AND HIGHLIGHT THE MARKEDLY DIFFERENT EFFECTS OF CHRONIC LARVAL AND ACUTE EMBRYONIC STRESS. THIS KNOWLEDGE COULD BE USED TO HARNESS THE STIMULATORY EFFECTS OF ACUTE STRESS ON IMMUNITY, PAVING THE WAY FOR IMPROVED STRESS AND DISEASE MANAGEMENT THROUGH EPIGENETIC CONDITIONING. 2018 11 6008 31 THE ANTI-INFLAMMATORY AGENT 5-ASA REDUCES THE LEVEL OF SPECIFIC TSRNAS IN SPERM CELLS OF HIGH-FAT FED C57BL/6J MOUSE SIRES AND IMPROVES GLUCOSE TOLERANCE IN FEMALE OFFSPRING. INTRODUCTION: THE PREVALENCE OF OBESITY AND ASSOCIATED COMORBIDITIES HAVE INCREASED TO EPIDEMIC PROPORTIONS GLOBALLY. PATERNAL OBESITY IS AN INDEPENDENT RISK FACTOR FOR DEVELOPING OBESITY AND TYPE 2 DIABETES IN THE FOLLOWING GENERATION, AND GROWING EVIDENCE SUGGESTS EPIGENETIC INHERITANCE AS A MECHANISM FOR THIS PREDISPOSITION. HOW AND WHY OBESITY INDUCES EPIGENETIC CHANGES IN SPERM CELLS REMAIN TO BE CLARIFIED IN DETAIL. YET, RECENT STUDIES SHOW THAT ALTERATIONS IN SPERM CONTENT OF TRANSFER RNA-DERIVED SMALL RNAS (TSRNAS) CAN TRANSMIT THE EFFECTS OF PATERNAL OBESITY TO OFFSPRING. OBESITY IS CLOSELY ASSOCIATED WITH LOW-GRADE CHRONIC INFLAMMATION. THUS, WE EVALUATED WHETHER THE ANTI-INFLAMMATORY AGENT 5-AMINOSALICYLIC ACID (5-ASA) COULD INTERVENE IN THE TRANSMISSION OF EPIGENETIC INHERITANCE OF PATERNAL OBESITY BY REDUCING THE INFLAMMATORY STATE IN OBESE FATHERS. METHODS: MALE C57BL/6JBOMTAC MICE WERE EITHER FED A HIGH-FAT DIET OR A HIGH-FAT DIET WITH 5-ASA FOR TEN WEEKS BEFORE MATING. THE OFFSPRING METABOLIC PHENOTYPE WAS EVALUATED, AND SPERMATOZOA FROM SIRES WERE ISOLATED FOR ASSESSMENT OF SPECIFIC TSRNAS LEVELS. RESULTS: 5-ASA INTERVENTION REDUCED THE LEVELS OF GLU-CTC TSRNAS IN SPERM CELLS AND IMPROVED GLUCOSE TOLERANCE IN FEMALE OFFSPRING FED A CHOW DIET. PATERNAL HIGH-FAT DIET-INDUCED OBESITY PER SE HAD ONLY A MODERATE IMPACT ON THE METABOLIC PHENOTYPE OF BOTH MALE AND FEMALE OFFSPRING IN OUR SETTING. CONCLUSION: THE RESULTS INDICATE THAT THE LOW-GRADE INFLAMMATORY RESPONSE ASSOCIATED WITH OBESITY MAY BE AN IMPORTANT FACTOR IN EPIGENETIC INHERITANCE OF PATERNAL OBESITY. 2023 12 4875 28 OVEREXPRESSION OF AKT1 ENHANCES ADIPOGENESIS AND LEADS TO LIPOMA FORMATION IN ZEBRAFISH. BACKGROUND: OBESITY IS A COMPLEX, MULTIFACTORIAL DISORDER INFLUENCED BY THE INTERACTION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. OBESITY INCREASES THE RISK OF CONTRACTING MANY CHRONIC DISEASES OR METABOLIC SYNDROME. RESEARCHERS HAVE ESTABLISHED SEVERAL MAMMALIAN MODELS OF OBESITY TO STUDY ITS UNDERLYING MECHANISM. HOWEVER, A LOWER VERTEBRATE MODEL FOR CONVENIENTLY PERFORMING DRUG SCREENING AGAINST OBESITY REMAINS ELUSIVE. THE SPECIFIC AIM OF THIS STUDY WAS TO CREATE A ZEBRAFISH OBESITY MODEL BY OVER EXPRESSING THE INSULIN SIGNALING HUB OF THE AKT1 GENE. METHODOLOGY/PRINCIPAL FINDINGS: SKIN ONCOGENIC TRANSFORMATION SCREENING SHOWS THAT A STABLE ZEBRAFISH TRANSGENIC OF TG(KRT4HSA.MYRAKT1)(CY18) DISPLAYS SEVERELY OBESE PHENOTYPES AT THE ADULT STAGE. IN TG(KRT4:HSA.MYRAKT1)(CY18), THE EXPRESSION OF EXOGENOUS HUMAN CONSTITUTIVELY ACTIVE AKT1 (MYRAKT1) CAN ACTIVATE ENDOGENOUS DOWNSTREAM TARGETS OF MTOR, GSK-3ALPHA/BETA, AND 70S6K. DURING THE EMBRYONIC TO LARVAL TRANSITORY PHASE, THE SPECIFIC OVER EXPRESSION OF MYRAKT1 IN SKIN CAN PROMOTE HYPERTROPHIC AND HYPERPLASTIC GROWTH. FROM 21 HOUR POST-FERTILIZATION (HPF) ONWARDS, MYRAKT1 TRANSGENE WAS ECTOPICALLY EXPRESSED IN SEVERAL MESENCHYMAL DERIVED TISSUES. THIS MAY BE THE RESULT OF THE INTEGRATION POSITION EFFECT. TG(KRT4:HSA.MYRAKT1)(CY18) CAUSED A RAPID INCREASE OF BODY WEIGHT, HYPERPLASTIC GROWTH OF ADIPOCYTES, ABNORMAL ACCUMULATION OF FAT TISSUES, AND BLOOD GLUCOSE INTOLERANCE AT THE ADULT STAGE. REAL-TIME RT-PCR ANALYSIS SHOWED THE MAJORITY OF KEY GENES ON REGULATING ADIPOGENESIS, ADIPOCYTOKINE, AND INFLAMMATION ARE HIGHLY UPREGULATED IN TG(KRT4:HSA.MYRAKT1)(CY18). IN CONTRAST, THE MYOGENESIS- AND SKELETOGENESIS-RELATED GENE TRANSCRIPTS ARE SIGNIFICANTLY DOWNREGULATED IN TG(KRT4:HSA.MYRAKT1)(CY18), SUGGESTING THAT EXCESS ADIPOCYTE DIFFERENTIATION OCCURS AT THE EXPENSE OF OTHER MESENCHYMAL DERIVED TISSUES. CONCLUSION/SIGNIFICANCE: COLLECTIVELY, THE FINDINGS OF THIS STUDY PROVIDE DIRECT EVIDENCE THAT AKT1 SIGNALING PLAYS AN IMPORTANT ROLE IN BALANCING NORMAL LEVELS OF FAT TISSUE IN VIVO. THE OBESE ZEBRAFISH EXAMINED IN THIS STUDY COULD BE A NEW POWERFUL MODEL TO SCREEN NOVEL DRUGS FOR THE TREATMENT OF HUMAN OBESITY. 2012 13 4999 27 PERINATAL PROGRAMMING OF CIRCADIAN CLOCK-STRESS CROSSTALK. AN INTACT COMMUNICATION BETWEEN CIRCADIAN CLOCKS AND THE STRESS SYSTEM IS IMPORTANT FOR MAINTAINING PHYSIOLOGICAL HOMEOSTASIS UNDER RESTING CONDITIONS AND IN RESPONSE TO EXTERNAL STIMULI. THERE IS ACCUMULATING EVIDENCE FOR A RECIPROCAL INTERACTION BETWEEN BOTH-FROM THE SYSTEMIC TO THE MOLECULAR LEVEL. DISRUPTION OF THIS INTERACTION BY EXTERNAL FACTORS SUCH AS SHIFTWORK, JETLAG, OR CHRONIC STRESS INCREASES THE RISK OF DEVELOPING METABOLIC, IMMUNE, OR MOOD DISORDERS. FROM EXPERIMENTS IN RODENTS, WE KNOW THAT BOTH SYSTEMS MATURATE DURING THE PERINATAL PERIOD. DURING THAT TIME, EXOGENOUS FACTORS SUCH AS STRESS OR ALTERATIONS IN THE EXTERNAL PHOTOPERIOD MAY CRITICALLY AFFECT-OR PROGRAM-PHYSIOLOGICAL FUNCTIONS LATER IN LIFE. THIS DEVELOPMENTAL PROGRAMMING PROCESS HAS BEEN ATTRIBUTED TO MATERNAL STRESS SIGNALS REACHING THE EMBRYO, WHICH LASTINGLY CHANGE GENE EXPRESSION THROUGH THE INDUCTION OF EPIGENETIC MECHANISMS. DESPITE THE WELL-KNOWN FUNCTION OF THE ADULT CIRCADIAN SYSTEM IN TEMPORAL COORDINATION OF PHYSIOLOGY AND BEHAVIOR, THE ROLE OF MATERNAL AND EMBRYONIC CIRCADIAN CLOCKS DURING PREGNANCY AND POSTNATAL DEVELOPMENT IS STILL POORLY DEFINED. A BETTER UNDERSTANDING OF THE CIRCADIAN-STRESS CROSSTALK AT DIFFERENT PERIODS OF DEVELOPMENT MAY HELP TO IMPROVE STRESS RESISTANCE AND DEVISE PREVENTIVE AND THERAPEUTIC STRATEGIES AGAINST CHRONIC STRESS-ASSOCIATED DISORDERS. 2018 14 1824 23 EFFECTS OF ENVIRONMENTAL CONDITIONS ON NEPHRON NUMBER: MODELING MATERNAL DISEASE AND EPIGENETIC REGULATION IN RENAL DEVELOPMENT. A GROWING BODY OF EVIDENCE SUGGESTS THAT LOW NEPHRON NUMBERS AT BIRTH CAN INCREASE THE RISK OF CHRONIC KIDNEY DISEASE OR HYPERTENSION LATER IN LIFE. ENVIRONMENTAL STRESSORS, SUCH AS MATERNAL MALNUTRITION, MEDICATION AND SMOKING, CAN INFLUENCE RENAL SIZE AT BIRTH. USING METANEPHRIC ORGAN CULTURES TO MODEL SINGLE-VARIABLE ENVIRONMENTAL CONDITIONS, MODELS OF MATERNAL DISEASE WERE EVALUATED FOR PATTERNS OF DEVELOPMENTAL IMPAIRMENT. WHILE HYPERTHERMIA HAD LIMITED EFFECTS ON RENAL DEVELOPMENT, FETAL IRON DEFICIENCY WAS ASSOCIATED WITH SEVERE IMPAIRMENT OF RENAL GROWTH AND NEPHROGENESIS WITH AN ALL-PROXIMAL PHENOTYPE. CULTURING KIDNEY EXPLANTS UNDER HIGH GLUCOSE CONDITIONS LED TO CELLULAR AND TRANSCRIPTOMIC CHANGES RESEMBLING HUMAN DIABETIC NEPHROPATHY. SHORT-TERM HIGH GLUCOSE CULTURE CONDITIONS WERE SUFFICIENT FOR LONG-TERM ALTERATIONS IN DNA METHYLATION-ASSOCIATED EPIGENETIC MEMORY. FINALLY, THE ROLE OF EPIGENETIC MODIFIERS IN RENAL DEVELOPMENT WAS TESTED USING A SMALL COMPOUND LIBRARY. AMONG THE SELECTED EPIGENETIC INHIBITORS, VARIOUS COMPOUNDS ELICITED AN EFFECT ON RENAL GROWTH, SUCH AS HDAC (ENTINOSTAT, TH39), HISTONE DEMETHYLASE (DEFERASIROX, DEFEROXAMINE) AND HISTONE METHYLTRANSFERASE (CYPROHEPTADINE) INHIBITORS. THUS, METANEPHRIC ORGAN CULTURES PROVIDE A VALUABLE SYSTEM FOR STUDYING METABOLIC CONDITIONS AND A TOOL FOR SCREENING FOR EPIGENETIC MODIFIERS IN RENAL DEVELOPMENT. 2021 15 3238 33 HEPATIC EPIGENETIC REPROGRAMMING AFTER LIVER RESECTION IN OFFSPRING ALLEVIATES THE EFFECTS OF MATERNAL OBESITY. OBESITY HAS BECOME A PUBLIC HEALTH PROBLEM IN RECENT DECADES, AND DURING PREGNANCY, IT CAN LEAD TO AN INCREASED RISK OF GESTATIONAL COMPLICATIONS AND PERMANENT CHANGES IN THE OFFSPRING RESULTING FROM A PROCESS KNOWN AS METABOLIC PROGRAMMING. THE OFFSPRING OF OBESE DAMS ARE AT INCREASED RISK OF DEVELOPING NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD), EVEN IN THE ABSENCE OF HIGH-FAT DIET CONSUMPTION. NAFLD IS A CHRONIC FATTY LIVER DISEASE THAT CAN PROGRESS TO EXTREMELY SEVERE CONDITIONS THAT REQUIRE SURGICAL INTERVENTION WITH THE REMOVAL OF THE INJURED TISSUE. LIVER REGENERATION IS NECESSARY TO PRESERVE ORGAN FUNCTION. A RANGE OF PATHWAYS IS ACTIVATED IN THE LIVER REGENERATION PROCESS, INCLUDING THE HIPPO, TGFBETA, AND AMPK SIGNALING PATHWAYS THAT ARE UNDER EPIGENETIC CONTROL. WE INVESTIGATED WHETHER MICRORNA MODULATION IN THE LIVER OF THE OFFSPRING OF OBESE DAMS WOULD IMPACT GENE EXPRESSION OF HIPPO, TGFBETA, AND AMPK PATHWAYS AND TISSUE REGENERATION AFTER PARTIAL HEPATECTOMY (PHX). FEMALE SWISS MICE FED A STANDARD CHOW OR A HIGH-FAT DIET (HFD) BEFORE AND DURING PREGNANCY AND LACTATION WERE MATED WITH MALE CONTROL MICE. THE OFFSPRING FROM CONTROL (CT-O) AND OBESE (HF-O) DAMS WEANED TO STANDARD CHOW DIET UNTIL DAY 56 WERE SUBMITTED TO PHX SURGERY. PRIOR TO THE SURGERY, HF-O PRESENTED ALTERATIONS IN MIR-122, MIR-370, AND LET-7A EXPRESSION IN THE LIVER COMPARED TO CT-O, AS PREVIOUSLY SHOWN, AS WELL AS IN ITS TARGET GENES INVOLVED IN LIVER REGENERATION. HOWEVER, AFTER THE PHX (4 H OR 48 H POST-SURGERY), DIFFERENCES IN GENE EXPRESSION BETWEEN CT-O AND HF-O WERE SUPPRESSED, AS WELL AS IN MICRORNA EXPRESSION IN THE LIVER. FURTHERMORE, BOTH CT-O AND HF-O PRESENTED A SIMILAR REGENERATIVE CAPACITY OF THE LIVER WITHIN 48 H AFTER PHX. OUR RESULTS SUGGEST THAT SURVIVAL AND REGENERATIVE MECHANISMS INDUCED BY THE PARTIAL HEPATECTOMY MAY OVERCOME THE EPIGENETIC CHANGES IN THE LIVER OF OFFSPRING PROGRAMMED BY MATERNAL OBESITY. 2022 16 4210 26 METFORMIN AND VITAMIN D MODULATE INFLAMMATION AND AUTOPHAGY DURING ADIPOSE-DERIVED STEM CELL DIFFERENTIATION. ADIPOSE-DERIVED STEM CELLS (ADSCS) CAME OUT FROM THE REGENERATIVE MEDICINE LANDSCAPE FOR THEIR ABILITY TO DIFFERENTIATE INTO SEVERAL PHENOTYPES, CONTRIBUTING TO TISSUE REGENERATION BOTH IN VITRO AND IN VIVO. DYSREGULATION IN STEM CELL RECRUITMENT AND DIFFERENTIATION DURING ADIPOGENESIS IS LINKED TO A CHRONIC LOW-GRADE INFLAMMATION AND MACROPHAGE INFILTRATION INSIDE THE ADIPOSE TISSUE, INSULIN RESISTANCE, CARDIOVASCULAR DISEASE AND OBESITY. IN THE PRESENT PAPER WE AIMED TO EVALUATE THE ROLE OF METFORMIN AND VITAMIN D, ALONE OR IN COMBINATION, IN MODULATING INFLAMMATION AND AUTOPHAGY IN ADSCS DURING ADIPOGENIC COMMITMENT. ADSCS WERE CULTURED FOR 21 DAYS IN THE PRESENCE OF A SPECIFIC ADIPOGENIC DIFFERENTIATION MEDIUM, TOGETHER WITH METFORMIN, OR VITAMIN D, OR BOTH. WE THEN ANALYZED THE EXPRESSION OF FOXO1 AND HEAT SHOCK PROTEINS (HSP) AND THE SECRETION OF PROINFLAMMATORY CYTOKINES IL-6 AND TNF-ALPHA BY ELISA. AUTOPHAGY WAS ALSO ASSESSED BY SPECIFIC WESTERN BLOT ANALYSIS OF ATG12, LC3B I, AND LC3B II EXPRESSION. OUR RESULTS SHOWED THE ABILITY OF THE CONDITIONED MEDIA TO MODULATE ADIPOGENIC DIFFERENTIATION, FINELY TUNING THE INFLAMMATORY RESPONSE AND AUTOPHAGY. WE OBSERVED A MODULATION IN HSP MRNA LEVELS, AND A SIGNIFICANT DOWNREGULATION IN CYTOKINE SECRETION. TAKEN TOGETHER, OUR FINDINGS SUGGEST THE POSSIBLE APPLICATION OF THESE MOLECULES IN CLINICAL PRACTICE TO COUNTERACT UNCONTROLLED LIPOGENESIS AND PREVENT OBESITY AND OBESITY-RELATED METABOLIC DISORDERS. 2021 17 2886 20 GABA-AALPHA5 MIGHT BE INVOLVED IN LEARNING-MEMORY DYSFUNCTION IN THE OFFSPRINGS OF CHRONIC ETHANOL-TREATED RATS VIA GABA-AALPHA5 HISTONE H3K9 ACETYLATION. RECENTLY, NUMEROUS STUDIES HAVE BEEN FOCUSED ON THE RELATIONSHIP BETWEEN GABA-A RECEPTORS AND ALCOHOL-INDUCED SPATIAL LEARNING AND MEMORY DEFICITS. GABA-AALPHA5, A SUBUNIT OF GABA-A RECEPTORS, IS CONSIDERED TO PLAY AN IMPORTANT ROLE IN ALCOHOL-INDUCED COGNITIVE IMPAIRMENT, HOWEVER, THE MECHANISM REMAINS OBSCURE. IN THIS STUDY, WE FOUND THAT THE EXPRESSION OF GABA-AALPHA5 INCREASED IN RATS TREATED WITH CHRONIC ETHANOL VIA HISTONE H3K9 ACETYLATION. FURTHERMORE, THIS EPIGENETIC MODIFICATION COULD BE INHERITED BY THE NEXT GENERATIONS, WHICH EVENTUALLY EXHIBIT SIMILAR SPATIAL LEARNING AND MEMORY DEFICITS IN THE OFFSPRINGS. IN SUMMARY, OUR RESULTS SUGGESTED THAT GABA-AALPHA5 MIGHT BE INVOLVED IN CHRONIC ETHANOL TREATMENT-INDUCED LEARNING-MEMORY DYSFUNCTION AND FOR THE FIRST TIME PROVED THAT LEARNING-MEMORY DYSFUNCTION COULD BE INHERITED BY THE OFFSPRINGS VIA HISTONE H3K9 ACETYLATION. HOPEFULLY, IN THE NEAR FUTURE, GABA-AALPHA5 INHIBITORS WOULD BE AN EFFECTIVE WAY TO TREAT ALCOHOL-INDUCED COGNITION IMPAIRMENT. 2019 18 5614 28 SAFETY AND EFFICACY OF EPIGENETICALLY CONVERTED HUMAN FIBROBLASTS INTO INSULIN-SECRETING CELLS: A PRECLINICAL STUDY. TYPE 1 DIABETES MELLITUS (T1DM) IS A CHRONIC DISEASE THAT LEADS TO LOSS OF INSULIN SECRETING BETA-CELLS, CAUSING HIGH LEVELS OF BLOOD GLUCOSE. EXOGENOUS INSULIN ADMINISTRATION IS NOT SUFFICIENT TO MIMIC THE NORMAL FUNCTION OF BETA-CELLS AND, CONSEQUENTLY, DIABETES MELLITUS OFTEN PROGRESSES AND CAN LEAD TO MAJOR CHRONIC COMPLICATIONS AND MORBIDITY. THE PHYSIOLOGICAL CONTROL OF GLUCOSE LEVELS CAN ONLY BE RESTORED BY REPLACING THE BETA-CELL MASS.WE RECENTLY DEVELOPED A NEW STRATEGY THAT ALLOWS FOR EPIGENETIC CONVERSION OF DERMAL FIBROBLASTS INTO INSULIN-SECRETING CELLS (EPICC), USING A BRIEF EXPOSURE TO THE DEMETHYLATING AGENT 5-AZA-CYTIDINE (5-AZA-CR), FOLLOWED BY A PANCREATIC INDUCTION PROTOCOL. THIS METHOD HAS NOTABLE ADVANTAGES COMPARED TO THE ALTERNATIVE AVAILABLE PROCEDURES AND MAY REPRESENT A PROMISING TOOL FOR CLINICAL TRANSLATION AS A THERAPY FOR T1DM. HOWEVER, A THOUGHT EVALUATION OF ITS THERAPEUTIC SAFETY AND EFFICACY IS MANDATORY TO SUPPORT PRECLINICAL STUDIES BASED ON EPICC TREATMENT.WE HERE REPORT THE DATA OBTAINED USING HUMAN FIBROBLASTS ISOLATED FROM DIABETIC AND HEALTHY INDIVIDUALS, BELONGING THE TWO GENDERS. EPICC WERE INJECTED INTO 650 DIABETIC SEVERE COMBINED IMMUNODEFICIENCY (SCID) MICE AND DEMONSTRATED TO BE ABLE TO RESTORE AND MAINTAIN GLYCEMIC LEVELS WITHIN THE PHYSIOLOGICAL RANGE. CELLS HAD THE ABILITY TO SELF-REGULATE AND NOT TO CAUSE HYPOGLYCEMIA, WHEN TRANSPLANTED IN HEALTHY ANIMALS. EFFICACY TESTS SHOWED THAT EPICC SUCCESSFULLY RE-ESTABLISHED NORMOGLYCEMIA IN DIABETIC MICE, USING A DOSE RANGE THAT APPEARED CLINICALLY RELEVANT TO THE CONCENTRATION 0.6 X 10(6) EPICC. NECROPSY AND HISTOPATHOLOGICAL INVESTIGATIONS DEMONSTRATED THE ABSENCE OF MALIGNANT TRANSFORMATION AND CELL MIGRATION TO ORGANS AND LYMPH NODES.THE PRESENT PRECLINICAL STUDY DEMONSTRATES SAFETY AND EFFICACY OF HUMAN EPICC IN DIABETIC MICE AND SUPPORTS THE USE OF EPIGENETIC CONVERTED CELLS FOR REGENERATIVE MEDICINE OF DIABETES MELLITUS. 2018 19 1898 21 ENDOTHELINS IN CARDIOVASCULAR BIOLOGY AND THERAPEUTICS. CARDIOVASCULAR DISEASE IS A MAJOR CONTRIBUTOR TO GLOBAL MORBIDITY AND MORTALITY AND IS THE COMMON END POINT OF MANY CHRONIC DISEASES. THE ENDOTHELINS COMPRISE THREE STRUCTURALLY SIMILAR PEPTIDES OF 21 AMINO ACIDS IN LENGTH. ENDOTHELIN 1 (ET-1) AND ET-2 ACTIVATE TWO G PROTEIN-COUPLED RECEPTORS - ENDOTHELIN RECEPTOR TYPE A (ET(A)) AND ENDOTHELIN RECEPTOR TYPE B (ET(B)) - WITH EQUAL AFFINITY, WHEREAS ET-3 HAS A LOWER AFFINITY FOR ET(A). ET-1 IS THE MOST POTENT VASOCONSTRICTOR IN THE HUMAN CARDIOVASCULAR SYSTEM AND HAS REMARKABLY LONG-LASTING ACTIONS. ET-1 CONTRIBUTES TO VASOCONSTRICTION, VASCULAR AND CARDIAC HYPERTROPHY, INFLAMMATION, AND TO THE DEVELOPMENT AND PROGRESSION OF CARDIOVASCULAR DISEASE. ENDOTHELIN RECEPTOR ANTAGONISTS HAVE REVOLUTIONIZED THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION. CLINICAL TRIALS CONTINUE TO EXPLORE NEW APPLICATIONS OF ENDOTHELIN RECEPTOR ANTAGONISTS, PARTICULARLY IN TREATMENT-RESISTANT HYPERTENSION, CHRONIC KIDNEY DISEASE AND PATIENTS RECEIVING ANTIANGIOGENIC THERAPIES. TRANSLATIONAL STUDIES HAVE IDENTIFIED IMPORTANT ROLES FOR THE ENDOTHELIN ISOFORMS AND NEW THERAPEUTIC TARGETS DURING DEVELOPMENT, IN FLUID-ELECTROLYTE HOMEOSTASIS, AND IN CARDIOVASCULAR AND NEURONAL FUNCTION. NOVEL PHARMACOLOGICAL STRATEGIES ARE EMERGING IN THE FORM OF SMALL-MOLECULE EPIGENETIC MODULATORS, BIOLOGICS (SUCH AS MONOCLONAL ANTIBODIES FOR ET(B)) AND POSSIBLY SIGNALLING PATHWAY-BIASED AGONISTS AND ANTAGONISTS. 2019 20 5474 28 RESTORATION OF HISTONE ACETYLATION AMELIORATES DISEASE AND METABOLIC ABNORMALITIES IN A FUS MOUSE MODEL. DYSREGULATION OF EPIGENETIC MECHANISMS IS EMERGING AS A CENTRAL EVENT IN NEURODEGENERATIVE DISORDERS, INCLUDING AMYOTROPHIC LATERAL SCLEROSIS (ALS). IN MANY MODELS OF NEURODEGENERATION, GLOBAL HISTONE ACETYLATION IS DECREASED IN THE AFFECTED NEURONAL TISSUES. HISTONE ACETYLATION IS CONTROLLED BY THE ANTAGONISTIC ACTIONS OF TWO PROTEIN FAMILIES -THE HISTONE ACETYLTRANSFERASES (HATS) AND THE HISTONE DEACETYLASES (HDACS). DRUGS INHIBITING HDAC ACTIVITY ARE ALREADY USED IN THE CLINIC AS ANTI-CANCER AGENTS. THE AIM OF THIS STUDY WAS TO EXPLORE THE THERAPEUTIC POTENTIAL OF HDAC INHIBITION IN THE CONTEXT OF ALS. WE DISCOVERED THAT TRANSGENIC MICE OVEREXPRESSING WILD-TYPE FUS ("TG FUS+/+"), WHICH RECAPITULATE MANY ASPECTS OF HUMAN ALS, SHOWED REDUCED GLOBAL HISTONE ACETYLATION AND ALTERATIONS IN METABOLIC GENE EXPRESSION, RESULTING IN A DYSREGULATED METABOLIC HOMEOSTASIS. CHRONIC TREATMENT OF TG FUS+/+ MICE WITH ACY-738, A POTENT HDAC INHIBITOR THAT CAN CROSS THE BLOOD-BRAIN BARRIER, AMELIORATED THE MOTOR PHENOTYPE AND SUBSTANTIALLY EXTENDED THE LIFE SPAN OF THE TG FUS+/+ MICE. AT THE MOLECULAR LEVEL, ACY-738 RESTORED GLOBAL HISTONE ACETYLATION AND METABOLIC GENE EXPRESSION, THEREBY RE-ESTABLISHING METABOLITE LEVELS IN THE SPINAL CORD. TAKEN TOGETHER, OUR FINDINGS LINK EPIGENETIC ALTERATIONS TO METABOLIC DYSREGULATION IN ALS PATHOLOGY, AND HIGHLIGHT ACY-738 AS A POTENTIAL THERAPEUTIC STRATEGY TO TREAT THIS DEVASTATING DISEASE. 2019