1   245 129 ADRENERGIC REPRESSION OF THE EPIGENETIC READER MECP2 FACILITATES CARDIAC ADAPTATION IN CHRONIC HEART FAILURE. RATIONALE: IN CHRONIC HEART FAILURE, INCREASED ADRENERGIC ACTIVATION CONTRIBUTES TO STRUCTURAL REMODELING AND ALTERED GENE EXPRESSION. ALTHOUGH ADRENERGIC SIGNALING ALTERS HISTONE MODIFICATIONS, IT IS UNKNOWN, WHETHER IT ALSO AFFECTS OTHER EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION AND ITS RECOGNITION. OBJECTIVE: THE AIM OF THIS STUDY WAS TO IDENTIFY THE MECHANISM OF REGULATION OF THE METHYL-CPG-BINDING PROTEIN 2 (MECP2) AND ITS FUNCTIONAL SIGNIFICANCE DURING CARDIAC PRESSURE OVERLOAD AND UNLOADING. METHODS AND RESULTS: MECP2 WAS IDENTIFIED AS A REVERSIBLY REPRESSED GENE IN MOUSE HEARTS AFTER TRANSVERSE AORTIC CONSTRICTION AND WAS NORMALIZED AFTER REMOVAL OF THE CONSTRICTION. SIMILARLY, MECP2 REPRESSION IN HUMAN FAILING HEARTS RESOLVED AFTER UNLOADING BY A LEFT VENTRICULAR ASSIST DEVICE. THE CLUSTER MIR-212/132 WAS UPREGULATED AFTER TRANSVERSE AORTIC CONSTRICTION OR ON ACTIVATION OF ALPHA1- AND BETA1-ADRENOCEPTORS AND MIR-212/132 LED TO REPRESSION OF MECP2. PREVENTION OF MECP2 REPRESSION BY A CARDIOMYOCYTE-SPECIFIC, DOXYCYCLINE-REGULATABLE TRANSGENIC MOUSE MODEL AGGRAVATED CARDIAC HYPERTROPHY, FIBROSIS, AND CONTRACTILE DYSFUNCTION AFTER TRANSVERSE AORTIC CONSTRICTION. ABLATION OF MECP2 IN CARDIOMYOCYTES FACILITATED RECOVERY OF FAILING HEARTS AFTER REVERSIBLE TRANSVERSE AORTIC CONSTRICTION. GENOME-WIDE EXPRESSION ANALYSIS, CHROMATIN IMMUNOPRECIPITATION EXPERIMENTS, AND DNA METHYLATION ANALYSIS IDENTIFIED MITOCHONDRIAL GENES AND THEIR TRANSCRIPTIONAL REGULATORS AS MECP2 TARGET GENES. COINCIDENT WITH ITS REPRESSION, MECP2 WAS REMOVED FROM ITS TARGET GENES, WHEREAS DNA METHYLATION OF MECP2 TARGET GENES REMAINED STABLE DURING PRESSURE OVERLOAD. CONCLUSIONS: THESE DATA CONNECT ADRENERGIC ACTIVATION WITH A MICRORNA-MECP2 EPIGENETIC PATHWAY THAT IS IMPORTANT FOR CARDIAC ADAPTATION DURING THE DEVELOPMENT AND RECOVERY FROM HEART FAILURE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  6713  28 VISCERAL ADIPOSITY SYNDROME. THE ASSOCIATION OF ANTHROPOMETRIC (WAIST CIRCUMFERENCE) AND HEMODYNAMIC (BLOOD PRESSURE) CHANGES WITH ABNORMALITIES IN GLUCOSE AND LIPID METABOLISM HAS BEEN MOTIVATION FOR A LOT OF DISCUSSIONS IN THE LAST 30 YEARS. NOWADAYS, BLOOD PRESSURE, BODY MASS INDEX/ABDOMINAL CIRCUMFERENCE, GLYCEMIA, TRIGLYCERIDEMIA, AND HDL-CHOLESTEROL CONCENTRATIONS ARE CONSIDERED IN THE DEFINITION OF METABOLIC SYNDROME, REFERRED AS VISCERAL ADIPOSITY SYNDROME (VAS) IN THE PRESENT REVIEW. HOWEVER, MORE THAN 250 YEARS AGO AN ASSOCIATION BETWEEN VISCERAL AND MEDIASTINAL OBESITY WITH HYPERTENSION, GOUT, AND OBSTRUCTIVE APNEA HAD ALREADY BEEN RECOGNIZED. EXPANSION OF VISCERAL ADIPOSE TISSUE SECONDARY TO CHRONIC OVER-CONSUMPTION OF CALORIES STIMULATES THE RECRUITMENT OF MACROPHAGES, WHICH ASSUME AN INFLAMMATORY PHENOTYPE AND PRODUCE CYTOKINES THAT DIRECTLY INTERFERE WITH INSULIN SIGNALING, RESULTING IN INSULIN RESISTANCE. IN TURN, INSULIN RESISTANCE (IR) MANIFESTS ITSELF IN VARIOUS TISSUES, CONTRIBUTING TO THE OVERALL PHENOTYPE OF VAS. FOR EXAMPLE, IN WHITE ADIPOSE TISSUE, IR RESULTS IN LIPOLYSIS, INCREASED FREE FATTY ACIDS RELEASE AND WORSENING OF INFLAMMATION, SINCE FATTY ACIDS CAN BIND TO TOLL-LIKE RECEPTORS. IN THE LIVER, IR RESULTS IN INCREASED HEPATIC GLUCOSE PRODUCTION, CONTRIBUTING TO HYPERGLYCEMIA; IN THE VASCULAR ENDOTHELIUM AND KIDNEY, IR RESULTS IN VASOCONSTRICTION, SODIUM RETENTION AND, CONSEQUENTLY, ARTERIAL HYPERTENSION. OTHER PLAYERS HAVE BEEN RECOGNIZED IN THE DEVELOPMENT OF VAS, SUCH AS GENETIC PREDISPOSITION, EPIGENETIC FACTORS ASSOCIATED WITH EXPOSURE TO AN UNFAVOURABLE INTRAUTERINE ENVIRONMENT AND THE GUT MICROBIOTA. MORE RECENTLY, EXPERIMENTAL AND CLINICAL STUDIES HAVE SHOWN THE AUTONOMIC NERVOUS SYSTEM PARTICIPATES IN MODULATING VISCERAL ADIPOSE TISSUE. THE SYMPATHETIC NERVOUS SYSTEM IS RELATED TO ADIPOSE TISSUE FUNCTION AND DIFFERENTIATION THROUGH BETA1, BETA2, BETA3, ALPHA1, AND ALPHA2 ADRENERGIC RECEPTORS. THE RELATION IS BIDIRECTIONAL: SYMPATHETIC DENERVATION OF ADIPOSE TISSUE BLOCKS LIPOLYSIS TO A VARIETY OF LIPOLYTIC STIMULI AND ADIPOSE TISSUE SEND INPUTS TO THE BRAIN. AN IMBALANCE OF SYMPATHETIC/PARASYMPATHETIC AND ALPHA2 ADRENERGIC/BETA3 RECEPTOR IS RELATED TO VISCERAL ADIPOSE TISSUE STORAGE AND INSULIN SENSITIVITY. THUS, IN ADDITION TO THE WELL-KNOWN FACTORS CLASSICALLY ASSOCIATED WITH VAS, ABNORMAL AUTONOMIC ACTIVITY ALSO EMERGES AS AN IMPORTANT FACTOR REGULATING WHITE ADIPOSE TISSUE, WHICH HIGHLIGHTS COMPLEX ROLE OF ADIPOSE TISSUE IN THE VAS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  4611  27 NEONATAL IMMUNE CHALLENGE FOLLOWED BY ADULT IMMUNE CHALLENGE INDUCES EPIGENETIC-SUSCEPTIBILITY TO AGGRAVATED VISCERAL HYPERSENSITIVITY. BACKGROUND: ABDOMINAL PAIN IS ONE OF THE MAJOR SYMPTOMS OF INFLAMMATORY BOWEL DISEASE (IBD). THE INFLAMMATORY MEDIATORS RELEASED BY COLON INFLAMMATION ARE KNOWN TO SENSITIZE THE AFFERENT NEURONS, WHICH IS ONE OF THE CONTRIBUTORS TO ABDOMINAL PAIN. HOWEVER, NOT ALL IBD PATIENTS HAVE ABDOMINAL PAIN, AND SOME PATIENTS REPORT ABDOMINAL PAIN DURING REMISSION, SUGGESTING CONTRIBUTIONS OF OTHER PATHOLOGICAL FACTORS TO ABDOMINAL PAIN IN IBD. EPIDEMIOLOGICAL STUDIES FOUND EARLY-LIFE GASTROINTESTINAL INFECTIONS A RISK FACTOR FOR IBD SYMPTOMS AND ADULT-LIFE GASTROINTESTINAL INFECTIONS MAY TRIGGER THE ONSET OF IBD. WE INVESTIGATED THE HYPOTHESIS THAT NEONATAL COLON IMMUNE CHALLENGE FOLLOWED BY AN ADULT COLON IMMUNE CHALLENGE UPREGULATES SPINAL CORD BDNF THAT AGGRAVATES VISCERAL SENSITIVITY OVER AND ABOVE THAT INDUCED BY ADULT COLON IMMUNE CHALLENGE ALONE. METHODS: WE INDUCED NEONATAL AND ADULT COLON IMMUNE CHALLENGES BY INTRALUMINAL ADMINISTRATION OF TRINITROBENZENE SULFONIC ACID TO THE RAT COLON. KEY RESULTS: WE FOUND THAT NEONATAL IMMUNE CHALLENGE TRIGGERS EPIGENETIC PROGRAMMING THAT UPREGULATES TYROSINE HYDROXYLASE IN THE LOCUS CERULEUS WHEN THESE RATS ARE SUBJECTED TO AN ADULT COLON IMMUNE CHALLENGE. THE UPREGULATION OF LOCUS CERULEUS TYROSINE HYDROXYLASE, UPREGULATES NOREPINEPHRINE IN THE CEREBROSPINAL FLUID THAT ACTS ON ADRENERGIC RECEPTORS TO ENHANCE PCREB BINDING TO THE CAMP RESPONSE ELEMENT, WHICH RECRUITS HISTONE ACETYLENE TRANSFERASE (HAT) TO THE BDNF GENE TO ENHANCE ITS TRANSCRIPTION RESULTING IN AGGRAVATED VISCEROMOTOR RESPONSE TO COLORECTAL DISTENSION. HAT AND ADRENERGIC RECEPTOR ANTAGONISTS BLOCK THE AGGRAVATION OF VISCERAL SENSITIVITY. CONCLUSION & INFERENCES: HAT AND ADRENERGIC RECEPTOR INHIBITORS MAY SERVE AS ALTERNATES TO OPIOIDS AND NSAIDS IN SUPPRESSING ABDOMINAL PAIN IN IBD.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4  6150  29 THE FETAL CEREBRAL CIRCULATION: THREE DECADES OF EXPLORATION BY THE LLU CENTER FOR PERINATAL BIOLOGY. FOR MORE THAN THREE DECADES, RESEARCH PROGRAMS IN THE CENTER OF PERINATAL BIOLOGY HAVE FOCUSED ON THE VASCULAR BIOLOGY OF THE FETAL CEREBRAL CIRCULATION. IN THE 1980S, RESEARCH IN THE CENTER DEMONSTRATED THAT CEREBRAL AUTOREGULATION OPERATED OVER A NARROWER PRESSURE RANGE, AND WAS MORE VULNERABLE TO INSULTS, IN FETUSES THAN IN ADULTS. OTHER STUDIES WERE AMONG THE FIRST TO ESTABLISH THAT COMPARED TO ADULT CEREBRAL ARTERIES, FETAL CEREBRAL ARTERIES WERE MORE HYDRATED, CONTAINED SMALLER SMOOTH MUSCLE CELLS AND LESS CONNECTIVE TISSUE, AND HAD ENDOTHELIUM LESS CAPABLE OF PRODUCING NO. WORK IN THE 1990S REVEALED THAT PREGNANCY DEPRESSED REACTIVITY TO NO IN EXTRA-CEREBRAL ARTERIES, BUT ELEVATED IT IN CEREBRAL ARTERIES THROUGH EFFECTS INVOLVING CHANGES IN CGMP METABOLISM. COMPARATIVE STUDIES VERIFIED THAT FETAL LAMB CEREBRAL ARTERIES WERE AN EXCELLENT MODEL FOR CEREBRAL ARTERIES FROM HUMAN INFANTS. BIOCHEMICAL STUDIES DEMONSTRATED THAT CGMP METABOLISM WAS DRAMATICALLY UPREGULATED, BUT THAT CONTRACTION WAS FAR MORE DEPENDENT ON CALCIUM INFLUX, IN FETAL COMPARED TO ADULT CEREBRAL ARTERIES. FURTHER STUDIES ESTABLISHED THAT CHRONIC HYPOXIA ACCELERATES FUNCTIONAL MATURATION OF FETAL CEREBRAL ARTERIES, AS INDICATED BY INCREASED CONTRACTILE RESPONSES TO ADRENERGIC AGONISTS AND PERIVASCULAR ADRENERGIC NERVES. IN THE 2000S, STUDIES OF SIGNAL TRANSDUCTION ESTABLISHED AGE-DEPENDENT ROLES FOR PKG, PKC, PKA, ERK, ODC, IP3, MYOFILAMENT CALCIUM SENSITIVITY, AND MANY OTHER MECHANISMS. THESE DIVERSE STUDIES CLEARLY DEMONSTRATED THAT FETAL CEREBRAL ARTERIES WERE FUNCTIONALLY QUITE DISTINCT COMPARED TO ADULT CEREBRAL ARTERIES. IN THE CURRENT DECADE, RESEARCH IN THE CENTER HAS EXPANDED TO A MORE MOLECULAR FOCUS ON EPIGENETIC MECHANISMS AND THEIR ROLE IN FETAL VASCULAR ADAPTATION TO CHRONIC HYPOXIA, MATERNAL DRUG ABUSE, AND NUTRIENT DEPRIVATION. OVERALL, THE PAST THREE DECADES HAVE TRANSFORMED THINKING ABOUT, AND UNDERSTANDING OF, THE FETAL CEREBRAL CIRCULATION DUE IN NO SMALL PART TO THE SUSTAINED RESEARCH EFFORTS BY FACULTY AND STAFF IN THE CENTER FOR PERINATAL BIOLOGY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  3443  26 HYPERMETHYLATION IN THE PROMOTER REGION OF THE ADRA1A GENE IS ASSOCIATED WITH OPIOID USE DISORDER IN HAN CHINESE. OPIOID USE DISORDER IS A CHRONIC BRAIN DISEASE INFLUENCED BY GENETIC AND EPIGENETIC FACTORS, ACCOUNTING FOR APPROXIMATELY 50% OF THE LIABILITY. ADRENERGIC SIGNALING IS INVOLVED IN OPIOID USE DISORDER. TO DEMONSTRATE THE ASSOCIATIONS BETWEEN METHYLATION ALTERATIONS IN THE ALPHA-1-ADRENERGIC RECEPTOR (ADRA1A) GENE AND OPIOID USE DISORDER, IN THE PRESENT STUDY, WE FIRST EXAMINED AND COMPARED THE METHYLATION LEVELS OF 97 CPG SITES IN THE PROMOTER REGION OF THE ADRA1A GENE IN THE PERIPHERAL BLOOD IN 120 PATIENTS WITH HEROIN USE DISORDER AND 111 HEALTHY CONTROLS. CORRELATIONS BETWEEN METHYLATION LEVELS AND DURATION OF HEROIN/METHADONE USE WERE THEN ANALYZED. FINALLY, THE PREDICTED BINDING TRANSCRIPTION FACTORS (TFS) AND THEIR TARGET SEQUENCES IN THE PROMOTER REGION OF THE ADRA1A GENE, WHICH INCLUDE THE SELECTED CPG SITES, WERE SCREENED IN THE JASPAR DATABASE. OUR RESULTS DEMONSTRATED THAT HYPERMETHYLATION IN THE PROMOTER REGION OF THE ADRA1A GENE IN THE BLOOD WAS ASSOCIATED WITH OPIOID USE DISORDER. CORRELATIONS BETWEEN METHYLATION LEVELS OF SEVERAL CPG SITES AND DURATION OF HEROIN/METHADONE USE WERE OBSERVED. TFS TFAP2A AND RUNX1 WERE PREDICTED TO BIND TO THE TARGET SEQUENCES, WHICH INCLUDE THE CPG SITES SELECTED IN THE CURRENT STUDY, IN THE PROMOTER REGION OF THE ADRA1A GENE. OUR FINDINGS FURTHER EXTEND THE ASSOCIATIONS BETWEEN METHYLATION ALTERATIONS IN THE ADRA1A GENE AND OPIOID USE DISORDER POTENTIALLY THROUGH MECHANISMS OF GENE EXPRESSION REGULATIONS IN THE ADRA1A GENE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  6291  28 THE POTENTIAL TO FIGHT OBESITY WITH ADIPOGENESIS MODULATING COMPOUNDS. OBESITY IS AN INCREASINGLY SEVERE PUBLIC HEALTH PROBLEM, WHICH BRINGS HUGE SOCIAL AND ECONOMIC BURDENS. INCREASED BODY ADIPOSITY IN OBESITY IS NOT ONLY TIGHTLY ASSOCIATED WITH TYPE 2 DIABETES, BUT ALSO SIGNIFICANTLY INCREASES THE RISKS OF OTHER CHRONIC DISEASES INCLUDING CARDIOVASCULAR DISEASES, FATTY LIVER DISEASES AND CANCERS. ADIPOGENESIS DESCRIBES THE PROCESS OF THE DIFFERENTIATION AND MATURATION OF ADIPOCYTES, WHICH ACCUMULATE IN DISTRIBUTED ADIPOSE TISSUE AT VARIOUS SITES IN THE BODY. THE MAJOR FUNCTIONS OF WHITE ADIPOCYTES ARE TO STORE ENERGY AS FAT DURING PERIODS WHEN ENERGY INTAKE EXCEEDS EXPENDITURE AND TO MOBILIZE THIS STORED FUEL WHEN ENERGY EXPENDITURE EXCEEDS INTAKE. BROWN/BEIGE ADIPOCYTES CONTRIBUTE TO NON-SHIVERING THERMOGENESIS UPON COLD EXPOSURE AND ADRENERGIC STIMULATION, AND THEREBY PROMOTE ENERGY CONSUMPTION. THE IMBALANCE OF ENERGY INTAKE AND EXPENDITURE CAUSES OBESITY. RECENT INTEREST IN EPIGENETICS AND SIGNALING PATHWAYS HAS UTILIZED SMALL MOLECULE TOOLS AIMED AT MODIFYING OBESITY-SPECIFIC GENE EXPRESSION. IN THIS REVIEW, WE DISCUSS COMPOUNDS WITH ADIPOGENESIS-RELATED SIGNALING PATHWAYS AND EPIGENETIC MODULATING PROPERTIES THAT HAVE BEEN IDENTIFIED AS POTENTIAL THERAPEUTIC AGENTS WHICH CAST SOME LIGHT ON THE FUTURE TREATMENT OF OBESITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7  1091  31 COGNITIVE ENHANCERS AS A TREATMENT FOR HEROIN RELAPSE AND ADDICTION. HEROIN ADDICTION IS A DISORDER THAT STEMS FROM MALADAPTIVE PLASTICITY WITHIN NEURAL CIRCUITS AND PRODUCES BROAD COGNITIVE DEFICITS. DESPITE CONSIDERABLE ADVANCES IN PSYCHOTHERAPY AND PHARMACOTHERAPY FOR HEROIN RELAPSE AND ADDICTION, EFFECTIVE TREATMENTS FOR HEROIN USE DISORDER ARE STILL LACKING. INCREASING PRECLINICAL EVIDENCE INDICATES THAT HEROIN SEEKING BEHAVIOR IS PERSISTENT AFTER WITHDRAWAL, WHILE COGNITIVE DYSFUNCTIONS ASSOCIATED WITH CHRONIC HEROIN USE ARE AN IMPORTANT CONTRIBUTING FACTOR TO RISK OF HEROIN RELAPSE AND ADDICTION. COGNITIVE ENHANCERS MAY BE USED TO STIMULATE TREATMENT SUCCESS AND ENHANCE TREATMENT EFFICACY. THE PURPOSE OF THIS REVIEW IS TO OUTLINE THE LITERATURE THAT DEMONSTRATES THE COGNITIVE DEFICITS DURING THE DEVELOPMENT OF HEROIN ADDICTION AND WITHDRAWAL PROCESS, AND SEVERAL FACTORS THAT UNDERLINE THE EFFICACY OF COGNITIVE ENHANCERS FOR HEROIN USE DISORDERS. THE REVIEW, THEN, EXAMINES THE POTENTIAL USE AND PHARMACOLOGICAL MECHANISMS OF COGNITIVE ENHANCERS THAT ACT ON CHOLINERGIC, GLUTAMATERGIC, DOPAMINERGIC OR ADRENERGIC PATHWAYS. IT ALSO EXAMINES THE EFFECTS OF COMPOUNDS THAT ALTER CREB SIGNALING AND EPIGENETIC MECHANISMS IN ANIMAL MODEL OF HEROIN RELAPSE. THE CURRENT BODY OF RESEARCH REVEALS THE NEW INSIGHTS INTO THE PHARMACOLOGICAL MECHANISMS UNDERLYING HEROIN ADDICTION AND HOLDS A SIGNIFICANT PROMISE FOR COGNITIVE ENHANCERS AS AN IMPROVED APPROACH TO TREAT HEROIN USE DISORDER IN A MORE EFFICIENT AND PERSISTENT WAY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8  1023  35 CIRCULATING MICRORNA PROFILES FOR PREMATURE CARDIOVASCULAR DEATH IN PATIENTS WITH KIDNEY FAILURE WITH REPLACEMENT THERAPY. INTRODUCTION: PATIENTS WITH KIDNEY FAILURE WITH REPLACEMENT THERAPY (KFRT) SUFFER FROM A DISPROPORTIONATELY HIGH CARDIOVASCULAR DISEASE BURDEN. CIRCULATING SMALL NON-CODING RNAS (C-SNCRNAS) HAVE EMERGED AS NOVEL EPIGENETIC REGULATORS AND ARE SUGGESTED AS NOVEL BIOMARKERS AND THERAPEUTIC TARGETS FOR CARDIOVASCULAR DISEASE; HOWEVER, LITTLE IS KNOWN ABOUT THE ASSOCIATIONS OF C-SNCRNAS WITH PREMATURE CARDIOVASCULAR DEATH IN KFRT. METHODS: IN A PILOT CASE-CONTROL STUDY OF 50 HEMODIALYSIS PATIENTS WHO DIED OF CARDIOVASCULAR EVENTS AS CASES, AND 50 MATCHED HEMODIALYSIS CONTROLS WHO REMAINED ALIVE DURING A MEDIAN FOLLOW-UP OF 2.0 YEARS, WE PERFORMED C-SNCRNAS PROFILES USING NEXT-GENERATION SEQUENCING TO IDENTIFY DIFFERENTIALLY EXPRESSED CIRCULATING MICRORNAS (C-MIRNAS) BETWEEN THE PLASMA OF CASES AND THAT OF CONTROLS. MRNA TARGET PREDICTION AND PATHWAY ENRICHMENT ANALYSIS WERE PERFORMED TO EXAMINE THE FUNCTIONAL RELEVANCE OF DIFFERENTIALLY EXPRESSED C-MIRNAS TO CARDIOVASCULAR PATHOPHYSIOLOGY. THE ASSOCIATION OF DIFFERENTIALLY EXPRESSED C-MIRNAS WITH CARDIOVASCULAR MORTALITY WAS EXAMINED USING MULTIVARIABLE CONDITIONAL LOGISTIC REGRESSION. RESULTS: THE PATIENT CHARACTERISTICS WERE SIMILAR BETWEEN CASES AND CONTROLS, WITH A MEAN AGE OF 63 YEARS, 48% MALE, AND 54% AFRICAN AMERICAN IN BOTH GROUPS. WE DETECTED A TOTAL OF 613 MIRNAS IN THE PLASMA, AMONG WHICH FIVE MIRNAS (I.E., MIR-129-1-5P, MIR-500B-3P, MIR-125B-1-3P, MIR-3648-2-5P, AND MIR-3150B-3P) WERE IDENTIFIED TO BE DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS WITH CUT-OFFS OF P < 0.05 AND LOG2 FOLD-CHANGE (LOG2FC) > 1. WHEN USING MORE STRINGENT CUT-OFFS OF P-ADJUSTED < 0.05 AND LOG2FC > 1, ONLY MIR-129-1-5P REMAINED SIGNIFICANTLY DIFFERENTIALLY EXPRESSED, WITH HIGHER LEVELS OF MIR-129-1-5P IN THE CASES THAN IN THE CONTROLS. THE PATHWAY ENRICHMENT ANALYSIS USING PREDICTED MIR-129-1-5P MRNA TARGETS DEMONSTRATED ENRICHMENT IN ADRENERGIC SIGNALING IN CARDIOMYOCYTES, ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY, AND OXYTOCIN SIGNALING PATHWAYS. IN PARALLEL, THE CIRCULATING MIR-129-1-5P LEVELS WERE SIGNIFICANTLY ASSOCIATED WITH THE RISK OF CARDIOVASCULAR DEATH (ADJUSTED OR [95% CI], 1.68 [1.01-2.81] FOR ONE INCREASE IN LOG-TRANSFORMED MIR-129-1-5P COUNTS), INDEPENDENT OF POTENTIAL CONFOUNDERS. CONCLUSIONS: CIRCULATING MIR-129-1-5P MAY SERVE AS A NOVEL BIOMARKER FOR PREMATURE CARDIOVASCULAR DEATH IN KFRT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                           
9  5754  27 SOCIAL PSYCHOGENIC STRESS PROMOTES THE DEVELOPMENT OF ENDOMETRIOSIS IN MOUSE. EXPOSURE TO CHRONIC STRESS BEFORE AND WELL AFTER THE INDUCTION OF ENDOMETRIOSIS IS REPORTED TO INCREASE LESION SIZES IN RATS, BUT IT IS UNCLEAR WHETHER STRESS, EXPOSED SHORTLY AFTER THE INDUCTION OF ENDOMETRIOSIS, WOULD ALSO PROMOTE THE DEVELOPMENT OF ENDOMETRIOSIS, NOR IS IT CLEAR WHAT THE UNDERLYING POSSIBLE MOLECULAR MECHANISM IS. THIS STUDY WAS UNDERTAKEN TO TEST THE HYPOTHESIS THAT CHRONIC STRESS CAN PROMOTE THE DEVELOPMENT OF ENDOMETRIOSIS. A PROSPECTIVE RANDOMIZED MOUSE EXPERIMENT WAS CONDUCTED THAT SUBJECTED MICE WITH INDUCED ENDOMETRIOSIS TO PREDATOR STRESS. IN ADDITION, A CROSS-SECTIONAL IMMUNOHISTOCHEMISTRY STUDY WAS PERFORMED IN ECTOPIC AND EUTOPIC ENDOMETRIAL TISSUE SAMPLES FROM AGE- AND ROUGHLY MENSTRUAL PHASE-MATCHED WOMEN WITH OVARIAN ENDOMETRIOMAS. IT WAS FOUND THAT THE CHRONIC PSYCHOGENIC STRESS INDUCED EPIGENETIC CHANGES IN THE HIPPOCAMPUS IN MOUSE INDEPENDENT OF ENDOMETRIOSIS. IT WAS ALSO FOUND THAT CHRONIC PSYCHOGENIC STRESS INDUCED EPIGENETIC CHANGES IN THE HIPPOCAMPUS OF MICE WITH ENDOMETRIOSIS, AND SEEMINGLY ACTIVATED THE ADRENERGIC SIGNALLING IN ECTOPIC ENDOMETRIUM, RESULTING IN INCREASED ANGIOGENESIS AND ACCELERATED GROWTH OF ENDOMETRIOTIC LESIONS. THUS, CHRONIC PSYCHOGENIC STRESS PROMOTES ENDOMETRIOSIS DEVELOPMENT, RAISING THE POSSIBILITY THAT THE USE OF ANTI-DEPRESSANTS IN CASES OF PROLONGED AND INTENSE STRESS MIGHT FORESTALL THE NEGATIVE IMPACT OF STRESS ON THE DEVELOPMENT OF ENDOMETRIOSIS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  4309  34 MICRORNAS 29B AND 181A DOWN-REGULATE THE EXPRESSION OF THE NOREPINEPHRINE TRANSPORTER AND GLUCOCORTICOID RECEPTORS IN PC12 CELLS. MICRORNAS ARE SHORT NON-CODING RNAS THAT PROVIDE GLOBAL REGULATION OF GENE EXPRESSION AT THE POST-TRANSCRIPTIONAL LEVEL. SUCH REGULATION HAS BEEN FOUND TO PLAY A ROLE IN STRESS-INDUCED EPIGENETIC RESPONSES IN THE BRAIN. THE NOREPINEPHRINE TRANSPORTER (NET) AND GLUCOCORTICOID RECEPTORS ARE CLOSELY RELATED TO THE HOMEOSTATIC INTEGRATION AND REGULATION AFTER STRESS. OUR PREVIOUS STUDIES DEMONSTRATED THAT NET MRNA AND PROTEIN LEVELS IN RATS ARE REGULATED BY CHRONIC STRESS AND BY ADMINISTRATION OF CORTICOSTERONE, WHICH IS MEDIATED THROUGH GLUCOCORTICOID RECEPTORS. WHETHER MIRNAS ARE INTERMEDIARIES IN THE REGULATION OF THESE PROTEINS REMAINS TO BE ELUCIDATED. THIS STUDY WAS UNDERTAKEN TO DETERMINE POSSIBLE REGULATORY EFFECTS OF MIRNAS ON THE EXPRESSION OF NET AND GLUCOCORTICOID RECEPTORS IN THE NORADRENERGIC NEURONAL CELL LINE. USING COMPUTATIONAL TARGET PREDICTION, WE IDENTIFIED SEVERAL CANDIDATE MIRNAS POTENTIALLY TARGETING NET AND GLUCOCORTICOID RECEPTORS. WESTERN BLOT RESULTS SHOWED THAT OVER-EXPRESSION OF MIR-181A AND MIR-29B SIGNIFICANTLY REPRESSED PROTEIN LEVELS OF NET, WHICH IS ACCOMPANIED BY A REDUCED [(3) H] NOREPINEPHRINE UPTAKE, AND GLUCOCORTICOID RECEPTORS IN PC12 CELLS. LUCIFERASE REPORTER ASSAYS VERIFIED THAT BOTH MIR-181A AND MIR-29B BIND THE 3'UTR OF MRNA OF NET AND GLUCOCORTICOID RECEPTORS. FURTHERMORE, EXPOSURE OF PC12 CELLS TO CORTICOSTERONE MARKEDLY REDUCED THE ENDOGENOUS LEVELS OF MIR-29B, WHICH WAS NOT REVERSED BY THE APPLICATION OF GLUCOCORTICOID RECEPTOR ANTAGONIST MIFEPRISTONE. THESE OBSERVATIONS INDICATE THAT MIR-181A AND MIR-29B CAN FUNCTION AS THE NEGATIVE REGULATORS OF NET AND GLUCOCORTICOID RECEPTOR TRANSLATION IN VITRO. THIS REGULATORY EFFECT MAY BE RELATED TO STRESS-INDUCED UP-REGULATION OF THE NORADRENERGIC PHENOTYPE, A PHENOMENON OBSERVED IN STRESS MODELS AND DEPRESSIVE PATIENTS. THIS STUDY DEMONSTRATED THAT MIR-29B AND MIR-181A, TWO SHORT NON-CODING RNAS THAT PROVIDE GLOBAL REGULATION OF GENE EXPRESSION, MARKEDLY REPRESSED PROTEIN LEVELS OF NOREPINEPHRINE (NE) TRANSPORTER AND GLUCOCORTICOID RECEPTOR (GR), AS WELL AS NE UPTAKE BY BINDING THE 3'UTR OF THEIR MRNAS IN PC12 CELLS. ALSO, EXPOSURE OF CELLS TO CORTICOSTERONE SIGNIFICANTLY REDUCED MIR-29B LEVELS THROUGH A GR-INDEPENDENT WAY.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11  5970  15 TESTOSTERONE ACTS WITHIN THE MEDIAL AMYGDALA OF RATS TO REDUCE INNATE FEAR TO PREDATOR ODOR AKIN TO THE EFFECTS OF TOXOPLASMA GONDII INFECTION. RATS INFECTED WITH THE PROTOZOAN TOXOPLASMA GONDII EXHIBIT A REDUCED AVERSION TO CAT ODOR. THIS BEHAVIORAL CHANGE IS THOUGHT TO INCREASE TROPHIC TRANSMISSION OF THE PARASITE. INFECTED MALE RATS ALSO SHOW A GREATER TESTICULAR SYNTHESIS OF TESTOSTERONE AND EPIGENETIC CHANGE IN ARGININE VASOPRESSIN WITHIN THE MEDIAL AMYGDALA. HERE, WE SHOW THAT EXOGENOUS SUPPLY OF TESTOSTERONE WITHIN MEA OF UNINFECTED CASTRATES RECAPITULATES REDUCTION IN INNATE FEAR AKIN TO BEHAVIORAL CHANGE ATTRIBUTED TO THE PARASITE. WE ALSO SHOW THAT CASTRATION POST ESTABLISHMENT OF CHRONIC INFECTION PRECLUDES CHANGES IN FEAR AND MEDIAL AMYGDALA ARGININE VASOPRESSIN IN THE INFECTED MALE RATS. THESE OBSERVATIONS SUPPORT THE ROLE OF GONADAL HORMONES AND PURSUANT NEUROENDOCRINE CHANGES IN MEDIATING THE LOSS OF FEAR IN THE INFECTED RATS. THIS WORK ALSO DEMONSTRATES THAT TESTOSTERONE ACTING SPECIFICALLY WITHIN THE MEDIAL AMYGDALA SUFFICIENTLY EXPLAINS REDUCED DEFENSIVE BEHAVIORS OFTEN OBSERVED DURING THE APPETITIVE COMPONENT OF REPRODUCTIVE BEHAVIORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12  5075  31 PHYSIOLOGICAL ADAPTATION OF THE GROWTH-RESTRICTED FETUS. THE GROWTH-RESTRICTED FETUS IN UTERO IS EXPOSED TO A HOSTILE ENVIRONMENT AND SUFFERS UNDERNUTRITION AND HYPOXIA. TO COPE WITH THE STRESS, THE FETUS CHANGES ITS PHYSIOLOGICAL FUNCTIONS. THESE ADAPTIVE CHANGES AID INTRAUTERINE SURVIVAL; HOWEVER, THEY CAN LEAD TO PERMANENT FUNCTIONAL AND STRUCTURAL CHANGES THAT CAN CONTRIBUTE TO THE DEVELOPMENT OF SERIOUS CHRONIC DISEASES LATER IN LIFE. EPIGENETIC MECHANISMS ARE AN IMPORTANT PART OF THE PATHOPHYSIOLOGICAL PROCESSES BEHIND THIS "DEVELOPMENTAL ORIGIN OF ADULT DISEASES." THE DOMINANT CARDIOVASCULAR ADAPTIVE CHANGE IS THE REDISTRIBUTION OF BLOOD FLOW IN HYPOXIC FETUSES, WITH PREFERENTIAL SUPPLY OF BLOOD TO THE FETAL BRAIN, MYOCARDIUM, AND ADRENAL GLANDS. THE PROPORTION OF BLOOD FROM THE UMBILICAL VEIN TO THE DUCTUS VENOSUS AND FORAMEN OVALE INCREASES, WHICH INCREASES THE CARDIAC OUTPUT OF THE LEFT HEART VENTRICLE. THE INCREASED PERFUSION OF FETAL BRAIN CAN BE FOLLOWED WITH DOPPLER ULTRASOUND AS INCREASED DIASTOLIC VELOCITIES AND DECREASED PULSATILITY INDEX IN THE MIDDLE CEREBRAL ARTERY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13   982  37 CHRONIC PRENATAL HYPOXIA INDUCES EPIGENETIC PROGRAMMING OF PKCEPSILON GENE REPRESSION IN RAT HEARTS. RATIONALE: EPIDEMIOLOGICAL STUDIES DEMONSTRATE A CLEAR ASSOCIATION OF ADVERSE INTRAUTERINE ENVIRONMENT WITH AN INCREASED RISK OF ISCHEMIC HEART DISEASE IN ADULTHOOD. HYPOXIA IS A COMMON STRESS TO THE FETUS AND RESULTS IN DECREASED PROTEIN KINASE C EPSILON (PKCEPSILON) EXPRESSION IN THE HEART AND INCREASED CARDIAC VULNERABILITY TO ISCHEMIA AND REPERFUSION INJURY IN ADULT OFFSPRING IN RATS. OBJECTIVES: THE PRESENT STUDY TESTED THE HYPOTHESIS THAT FETAL HYPOXIA-INDUCED METHYLATION OF CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDES AT THE PKCEPSILON PROMOTER IS REPRESSIVE AND CONTRIBUTES TO PKCEPSILON GENE REPRESSION IN THE HEART OF ADULT OFFSPRING. METHODS AND RESULTS: HYPOXIC TREATMENT OF PREGNANT RATS FROM DAYS 15 TO 21 OF GESTATION RESULTED IN SIGNIFICANT DECREASES IN PKCEPSILON PROTEIN AND MRNA IN FETAL HEARTS. SIMILAR RESULTS WERE OBTAINED IN EX VIVO HYPOXIC TREATMENT OF ISOLATED FETAL HEARTS AND RAT EMBRYONIC VENTRICULAR MYOCYTE CELL LINE H9C2. INCREASED METHYLATION OF PKCEPSILON PROMOTER AT SP1 BINDING SITES, -346 AND -268, WERE DEMONSTRATED IN BOTH FETAL HEARTS OF MATERNAL HYPOXIA AND H9C2 CELLS TREATED WITH 1% O(2) FOR 24 HOURS. WHEREAS HYPOXIA HAD NO SIGNIFICANT EFFECT ON THE BINDING AFFINITY OF SP1 TO THE UNMETHYLATED SITES IN H9C2 CELLS, HEARTS OF FETUSES AND ADULT OFFSPRING, METHYLATION OF BOTH SP1 SITES REDUCED SP1 BINDING. THE ADDITION OF 5-AZA-2'-DEOXYCYTIDINE BLOCKED THE HYPOXIA-INDUCED INCREASE IN METHYLATION OF BOTH SP1 BINDING SITES AND RESTORED PKCEPSILON MRNA AND PROTEIN TO THE CONTROL LEVELS. IN HEARTS OF BOTH FETUSES AND ADULT OFFSPRING, HYPOXIA-INDUCED METHYLATION OF SP1 SITES WAS SIGNIFICANTLY GREATER IN MALES THAN IN FEMALES, AND DECREASED PKCEPSILON MRNA WAS SEEN ONLY IN MALES. IN FETAL HEARTS, THERE WAS SIGNIFICANTLY HIGHER ABUNDANCE OF ESTROGEN RECEPTOR ALPHA AND BETA ISOFORMS IN FEMALES THAN IN MALES. BOTH ESTROGEN RECEPTOR ALPHA AND BETA INTERACTED WITH THE SP1 BINDING SITES IN THE FETAL HEART, WHICH MAY EXPLAIN THE SEX DIFFERENCES IN SP1 METHYLATION IN THE FETAL HEART. ADDITIONALLY, SELECTIVE ACTIVATION OF PKCEPSILON RESTORED THE HYPOXIA-INDUCED CARDIAC VULNERABILITY TO ISCHEMIC INJURY IN OFFSPRING. CONCLUSIONS: THE FINDINGS DEMONSTRATE A DIRECT EFFECT OF HYPOXIA ON EPIGENETIC MODIFICATION OF DNA METHYLATION AND PROGRAMMING OF CARDIAC PKCEPSILON GENE REPRESSION IN A SEX-DEPENDENT MANNER, LINKING FETAL HYPOXIA AND PATHOPHYSIOLOGICAL CONSEQUENCES IN THE HEARTS OF ADULT OFFSPRING.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                               
14   701  32 BROWN FAT DNMT3B DEFICIENCY AMELIORATES OBESITY IN FEMALE MICE. OBESITY RESULTS FROM A CHRONIC ENERGY IMBALANCE DUE TO ENERGY INTAKE EXCEEDING ENERGY EXPENDITURE. ACTIVATION OF BROWN FAT THERMOGENESIS HAS BEEN SHOWN TO COMBAT OBESITY. EPIGENETIC REGULATION, INCLUDING DNA METHYLATION, HAS EMERGED AS A KEY REGULATOR OF BROWN FAT THERMOGENIC FUNCTION. HERE WE AIMED TO STUDY THE ROLE OF DNMT3B, A DNA METHYLTRANSFERASE INVOLVED IN DE NOVO DNA METHYLATION, IN THE REGULATION OF BROWN FAT THERMOGENESIS AND OBESITY. WE FOUND THAT THE SPECIFIC DELETION OF DNMT3B IN BROWN FAT PROMOTES THE THERMOGENIC AND MITOCHONDRIAL PROGRAM IN BROWN FAT, ENHANCES ENERGY EXPENDITURE, AND DECREASES ADIPOSITY IN FEMALE MICE FED A REGULAR CHOW DIET. WITH A LEAN PHENOTYPE, THE FEMALE KNOCKOUT MICE ALSO EXHIBIT INCREASED INSULIN SENSITIVITY. IN ADDITION, DNMT3B DEFICIENCY IN BROWN FAT ALSO PREVENTS DIET-INDUCED OBESITY AND INSULIN RESISTANCE IN FEMALE MICE. INTERESTINGLY, OUR RNA-SEQ ANALYSIS REVEALED AN UPREGULATION OF THE PI3K-AKT PATHWAY IN THE BROWN FAT OF FEMALE DNMT3B KNOCKOUT MICE. HOWEVER, MALE DNMT3B KNOCKOUT MICE HAVE NO CHANGE IN THEIR BODY WEIGHT, SUGGESTING THE EXISTENCE OF SEXUAL DIMORPHISM IN THE BROWN FAT DNMT3B KNOCKOUT MODEL. OUR DATA DEMONSTRATE THAT DNMT3B PLAYS AN IMPORTANT ROLE IN THE REGULATION OF BROWN FAT FUNCTION, ENERGY METABOLISM AND OBESITY IN FEMALE MICE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15  5878  33 SYNERGISTIC EFFECTS OF HYPERANDROGENEMIA AND OBESOGENIC WESTERN-STYLE DIET ON TRANSCRIPTION AND DNA METHYLATION IN VISCERAL ADIPOSE TISSUE OF NONHUMAN PRIMATES. POLYCYSTIC OVARY SYNDROME (PCOS) IS A MAJOR REPRODUCTIVE DISORDER THAT IS RESPONSIBLE FOR 80% OF ANOVULATORY INFERTILITY AND THAT IS ASSOCIATED WITH HYPERANDROGENEMIA, INCREASED RISK OF OBESITY, AND WHITE ADIPOSE TISSUE (WAT) DYSFUNCTION. WE HAVE PREVIOUSLY DEMONSTRATED THAT THE COMBINATION OF CHRONIC TESTOSTERONE (T) TREATMENT AND AN OBESOGENIC WESTERN-STYLE DIET (WSD) EXERTS SYNERGISTIC FUNCTIONAL EFFECTS ON WAT, LEADING TO INCREASED LIPID ACCUMULATION IN VISCERAL ADIPOCYTES BY AN UNKNOWN MECHANISM. IN THIS STUDY, WE EXAMINED THE WHOLE-GENOME TRANSCRIPTIONAL RESPONSE IN VISCERAL WAT TO T AND WSD, ALONE AND IN COMBINATION. WE OBSERVED A SYNERGISTIC EFFECT OF T AND WSD ON GENE EXPRESSION, RESULTING IN UPREGULATION OF LIPID STORAGE GENES CONCOMITANT WITH ADIPOCYTE HYPERTROPHY. BECAUSE DNA METHYLATION IS KNOWN TO BE ASSOCIATED WITH BODY FAT DISTRIBUTION AND THE ETIOLOGY OF PCOS, WE CONDUCTED WHOLE-GENOME DNA METHYLATION ANALYSIS OF VISCERAL WAT. WHILE ONLY A FRACTION OF DIFFERENTIALLY EXPRESSED GENES ALSO EXHIBITED DIFFERENTIAL DNA METHYLATION, IN SILICO ANALYSIS SHOWED THAT DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED IN TRANSCRIPTION FACTOR BINDING MOTIFS, SUGGESTING A POTENTIAL GENE REGULATORY ROLE FOR THESE REGIONS. IN SUMMARY, THIS STUDY DEMONSTRATES THAT HYPERANDROGENEMIA ALONE DOES NOT INDUCE GLOBAL TRANSCRIPTIONAL AND EPIGENETIC RESPONSE IN YOUNG FEMALE MACAQUES UNLESS COMBINED WITH AN OBESOGENIC DIET.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  6267  27 THE NEUROENDOCRINOLOGY OF STRESS: A NEVER ENDING STORY. EVOLUTIONARY SUCCESS DEPENDS ON OUR ABILITY TO ADAPT TO CHANGING CIRCUMSTANCES. THE NEUROENDOCRINE RESPONSE TO STRESS IS AN EXCELLENT EXAMPLE OF A PLASTIC SYSTEM THAT RESPONDS TO THREATS TO HOMEOSTASIS AND ALTERS ITS OUTPUT TO MEET CURRENT AND EXPECTED FUTURE DEMANDS. AT THE LEVEL OF THE HYPOTHALAMUS, THE CORTICOTROPH SECRETAGOGUES CORTICOTROPHIN-RELEASING HORMONE (CRH) AND ARGININE VASOPRESSIN (AVP) RESPOND RAPIDLY TO AN ACUTE STRESSOR BUT, FOLLOWING CHRONIC STRESS, THEY ADAPT WITH A REDUCTION OF CRH BUT A MAJOR INCREASE IN AVP. THE RELEASE OF CRH AND AVP ACTIVATES PRO-OPIOMELANOCORTIN IN ANTERIOR PITUITARY CORTICOTROPH CELLS AND THE RELEASE OF ADRENOCORTICOTROPHIC HORMONE INTO PERIPHERAL BLOOD FROM WHERE IT TARGETS RECEPTORS IN THE ADRENAL CORTEX TO RELEASE GLUCOCORTICOID HORMONES. THESE HORMONES (I.E. CORTICOSTERONE IN THE RAT AND CORTISOL IN MAN) ARE RELEASED IN A PULSATILE ULTRADIAN PATTERN WHICH DEFINES THE NORMAL CIRCADIAN RHYTHM. THE FREQUENCY OF THE PULSES IS INCREASED UNDER STATES OF CHRONIC STRESS, AND IN RATS WITH GENETICALLY DETERMINED HYPER-RESPONSIVENESS OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. INTERESTINGLY, NEONATAL INFLUENCES CAN ALSO PROGRAMME ALTERATIONS IN ULTRADIAN RHYTHMICITY, IMPLICATING EPIGENETIC FACTORS IN ITS REGULATION. AT THE LEVEL OF TISSUE RECEPTORS, THE ALTERATION IN PATTERN OF GLUCOCORTICOID ULTRADIAN RHYTHM HAS DIFFERENTIAL EFFECTS ON MINERALOCORTICOID RECEPTOR AND GLUCOCORTICOID RECEPTOR (GR) BINDING TO DNA AND OFFERS A MECHANISM FOR TISSUE SPECIFIC RESPONSES TO ALTERED GLUCOCORTICOID DYNAMICS. THE EFFECTS OF NEONATAL EXPERIENCE ARE NOT ONLY SEEN AT THE LEVEL OF CRH AND GR REGULATION, BUT ALSO ARE EVIDENT IN BEHAVIOURAL RESPONSES TO STRESS AND IN THE RESPONSIVENESS OF BRAIN STEM SEROTONERGIC PATHWAYS, AS MEASURED BY TRYPTOPHAN HYDROXYLASE MRNA IN THE BRAIN STEM.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  6418  38 THE TEMPORAL EXPRESSION OF CIRCULATING MICRORNAS AFTER ACUTE EXPERIMENTAL PAIN IN HUMANS. BACKGROUND: MICRORNAS (MIRNAS) CAN MODULATE SEVERAL BIOLOGICAL SYSTEMS, INCLUDING THE PAIN SYSTEM. THIS STUDY AIMED TO EVALUATE THE TEMPORAL EXPRESSION OF CIRCULATING MIRNAS IN THE PLASMA OF HEALTHY VOLUNTEERS AS A MARKER FOR EPIGENETIC CHANGES BEFORE AND AFTER AN ACUTE, EXPERIMENTAL, PAIN PROVOCATION BY INTRAMUSCULAR HYPERTONIC SALINE INJECTION. METHODS: TWENTY VOLUNTEERS WERE RANDOMLY ALLOCATED INTO TWO GROUPS AND RECEIVED EITHER HYPERTONIC (PAIN) OR ISOTONIC (CONTROL) SALINE INJECTION IN THE FIRST DORSAL INTEROSSEOUS MUSCLE OF THEIR DOMINANT HAND. PAIN INTENSITY WAS CONTINUOUSLY RECORDED FOR 20 MINUTES AFTER INJECTION ON A VAS SCALE FROM 0 TO 100 (0 INDICATES NO PAIN AND 100 THE WORST IMAGINABLE PAIN). BLOOD SAMPLES WERE TAKEN AT BASELINE, 30 MINUTES, 3 HOURS, AND 24 HOURS POST-INJECTION, AND PLASMA WAS SEPARATED. MIRNA EXTRACTS WERE USED FOR RNA SEQUENCING WITH THE ILLUMINA NEXTSEQ PLATFORM. MIRNA TRANSCRIPTS WERE COMPARED BETWEEN THE PAIN AND THE NO-PAIN, CONTROL GROUP AT EVERY TIME POINT. SIGNIFICANT DIFFERENCES WERE CONSIDERED WHEN FOLDS WERE >2 AND THE FALSE DISCOVERY RATE WAS P < 0.05. RESULTS: AFTER 30 MINUTES, 4 MIRNAS WERE SIGNIFICANTLY ALTERED IN THE PAIN GROUP COMPARED TO CONTROLS, WHICH INCREASED TO 24 AFTER 3 HOURS AND TO 42 AFTER 24 HOURS FROM BASELINE (P < 0.0001). TWO MIRNAS WERE CONSISTENTLY UPREGULATED THROUGHOUT THE EXPERIMENT. ENRICHMENT ANALYSIS SHOWED SIGNIFICANT MIRNAS INVOLVED IN BRAIN PERCEPTION OF PAIN, BRAIN SIGNALLING AND RESPONSE TO STIMULI. CONCLUSIONS: THIS EXPLORATORY STUDY IS THE FIRST TO REPORT ON THE TEMPORAL EXPRESSION OF CIRCULATING MIRNAS AFTER AN ACUTE, HUMAN EXPERIMENTAL MUSCLE PAIN MODEL. SIGNIFICANCE: THIS EXPLORATORY STUDY EVALUATED THE TEMPORAL PROFILE OF CIRCULATING MIRNAS IN THE PLASMA OF HEALTHY SUBJECTS AFTER ACUTE EXPERIMENTAL PAIN. SEVERAL MIRNAS WERE ALTERED IN SUBJECTS AT THE TIMES OF FOLLOW-UP AFTER THE ACUTE PAIN MODEL WHEN COMPARED TO CONTROLS. MIRNAS PREVIOUSLY ASSOCIATED WITH PAIN PROCESSES WERE ALTERED IN THE PAIN GROUP. OUR RESULTS, BY SHOWING THE FAST AND PROLONGED MODIFICATIONS OF MIRNA ELICITED BY THE ACUTE EXPERIMENTAL PAIN MODEL, ADD NEW PERSPECTIVES TO THE TOPIC OF EPIGENETICS AND PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
18  4949  26 PATERNAL TRANSMISSION OF STRESS-INDUCED PATHOLOGIES. BACKGROUND: THERE HAS BEEN RECENT INTEREST IN THE POSSIBILITY THAT EPIGENETIC MECHANISMS MIGHT CONTRIBUTE TO THE TRANSGENERATIONAL TRANSMISSION OF STRESS-INDUCED VULNERABILITY. HERE, WE FOCUSED ON POSSIBLE PATERNAL TRANSMISSION WITH THE SOCIAL DEFEAT STRESS PARADIGM. METHODS: ADULT MALE MICE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS OR CONTROL NONDEFEATED MICE WERE BRED WITH NORMAL FEMALE MICE, AND THEIR OFFSPRING WERE ASSESSED BEHAVIORALLY FOR DEPRESSIVE- AND ANXIETY-LIKE MEASURES. PLASMA LEVELS OF CORTICOSTERONE AND VASCULAR ENDOTHELIAL GROWTH FACTOR WERE ALSO ASSAYED. TO DIRECTLY ASSESS THE ROLE OF EPIGENETIC MECHANISMS, WE USED IN VITRO FERTILIZATION (IVF); BEHAVIORAL ASSESSMENTS WERE CONDUCTED ON OFFSPRING OF MICE FROM IVF-CONTROL AND IVF-DEFEATED FATHERS. RESULTS: WE SHOW THAT BOTH MALE AND FEMALE OFFSPRING FROM DEFEATED FATHERS EXHIBIT INCREASED MEASURES OF SEVERAL DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. THE MALE OFFSPRING OF DEFEATED FATHERS ALSO DISPLAY INCREASED BASELINE PLASMA LEVELS OF CORTICOSTERONE AND DECREASED LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR. HOWEVER, MOST OF THESE BEHAVIORAL CHANGES WERE NOT OBSERVED WHEN OFFSPRING WERE GENERATED THROUGH IVF. CONCLUSIONS: THESE RESULTS SUGGEST THAT, ALTHOUGH BEHAVIORAL ADAPTATIONS THAT OCCUR AFTER CHRONIC SOCIAL DEFEAT STRESS CAN BE TRANSMITTED FROM THE FATHER TO HIS MALE AND FEMALE F1 PROGENY, ONLY VERY SUBTLE CHANGES MIGHT BE TRANSMITTED EPIGENETICALLY UNDER THE CONDITIONS TESTED.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19  5166  37 PRECONCEPTION PATERNAL ALCOHOL EXPOSURE EXERTS SEX-SPECIFIC EFFECTS ON OFFSPRING GROWTH AND LONG-TERM METABOLIC PROGRAMMING. BACKGROUND: ALTHOUGH CLINICAL DATA SUPPORT AN ASSOCIATION BETWEEN PATERNAL ALCOHOL USE AND DEFICITS IN CHILD NEUROCOGNITIVE DEVELOPMENT, THE RELATIONSHIP BETWEEN PATERNAL DRINKING AND ALCOHOL-INDUCED GROWTH PHENOTYPES REMAINS CHALLENGING TO DEFINE. USING AN ESTABLISHED MOUSE MODEL OF CHRONIC EXPOSURE, PREVIOUS WORK BY OUR GROUP HAS LINKED PRECONCEPTION PATERNAL ALCOHOL USE TO SEX-SPECIFIC PATTERNS OF FETAL GROWTH RESTRICTION AND PLACENTAL DYSFUNCTION. THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE THE LONG-TERM IMPACT OF CHRONIC PRECONCEPTION PATERNAL ALCOHOL USE ON OFFSPRING GROWTH AND METABOLIC PROGRAMMING. RESULTS: PRECONCEPTION PATERNAL ALCOHOL EXPOSURE INDUCED A PROLONGED PERIOD OF FETAL GESTATION AND AN INCREASED INCIDENCE OF INTRAUTERINE GROWTH RESTRICTION, WHICH AFFECTED THE MALE OFFSPRING TO A GREATER EXTENT THAN THE FEMALES. WHILE THE FEMALE OFFSPRING OF ETHANOL-EXPOSED MALES WERE ABLE TO MATCH THE BODY WEIGHTS OF THE CONTROLS WITHIN THE FIRST 2 WEEKS OF POSTNATAL LIFE, MALE OFFSPRING CONTINUED TO DISPLAY AN 11% REDUCTION IN WEIGHT AT 5 WEEKS OF AGE AND A 6% REDUCTION AT 8 WEEKS OF AGE. THE OBSERVED GROWTH DEFICITS ASSOCIATED WITH INSULIN HYPERSENSITIVITY IN THE MALE OFFSPRING, WHILE IN CONTRAST, FEMALES DISPLAYED A MODEST LAG IN THEIR GLUCOSE TOLERANCE TEST. THESE METABOLIC DEFECTS WERE ASSOCIATED WITH AN UP-REGULATION OF GENES WITHIN THE PRO-FIBROTIC TGF-BETA SIGNALING PATHWAY AND INCREASED LEVELS OF CELLULAR HYDROXYPROLINE WITHIN THE LIVERS OF THE MALE OFFSPRING. WE OBSERVED SUPPRESSED CYTOKINE PROFILES WITHIN THE LIVER AND PANCREAS OF BOTH THE MALE AND FEMALE OFFSPRING, WHICH CORRELATED WITH THE UP-REGULATION OF GENES IN THE LIVERX/RETINOIDX/FARNESOIDX RECEPTOR PATHWAYS. HOWEVER, PATTERNS OF GENE EXPRESSION WERE HIGHLY VARIABLE BETWEEN THE OFFSPRING OF ALCOHOL-EXPOSED SIRES. IN THE ADULT OFFSPRING OF ALCOHOL-EXPOSED MALES, WE DID NOT OBSERVE ANY DIFFERENCES IN THE ALLELIC EXPRESSION OF IGF2 OR ANY OTHER IMPRINTED GENES. CONCLUSIONS: THE IMPACT OF PATERNAL ALCOHOL USE ON CHILD DEVELOPMENT IS POORLY EXPLORED AND REPRESENTS A SIGNIFICANT GAP IN OUR UNDERSTANDING OF THE TERATOGENIC EFFECTS OF ETHANOL. OUR STUDIES IMPLICATE PATERNAL EXPOSURE HISTORY AS AN ADDITIONAL AND IMPORTANT MODIFIER OF ALCOHOL-INDUCED GROWTH PHENOTYPES AND CHALLENGE THE CURRENT MATERNAL-CENTRIC EXPOSURE PARADIGM.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20  4075  31 MATERNAL HIGH-FAT DIET IMPAIRS LEPTIN SIGNALING AND UP-REGULATES TYPE-1 CANNABINOID RECEPTOR WITH SEX-SPECIFIC EPIGENETIC CHANGES IN THE HYPOTHALAMUS OF NEWBORN RATS. MATERNAL NUTRITIONAL IMBALANCES TRIGGER DEVELOPMENTAL ADAPTATIONS INVOLVING EARLY EPIGENETIC MECHANISMS ASSOCIATED WITH ADULT CHRONIC DISEASE. MATERNAL HIGH-FAT (HF) DIET PROMOTES OBESITY AND HYPOTHALAMIC LEPTIN RESISTANCE IN MALE RAT OFFSPRING AT WEANING AND ADULTHOOD. LEPTIN RESISTANCE IS ASSOCIATED WITH OVER ACTIVATION OF THE ENDOCANNABINOID SYSTEM (ECS). THE ECS MAINLY CONSISTS OF ENDOCANNABINOIDS DERIVED FROM N-6 FATTY ACIDS AND CANNABINOID RECEPTORS (CB1 CODED BY CNR1 AND CB2 CODED BY CNR2). THE CB1 ACTIVATION IN HYPOTHALAMUS STIMULATES FEEDING AND APPETITE FOR FAT WHILE CB2 ACTIVATION SEEMS TO PLAY AN IMMUNOMODULATORY ROLE. WE DEMONSTRATED THAT MATERNAL HF DIET INCREASES HYPOTHALAMIC CB1 IN MALE OFFSPRING WHILE INCREASES CB2 IN FEMALE OFFSPRING AT BIRTH, PRIOR TO OBESITY DEVELOPMENT. HOWEVER, THE MOLECULAR MECHANISMS BEHIND THESE CHANGES REMAIN UNEXPLORED. WE HYPOTHESIZED THAT MATERNAL HF DIET WOULD DOWN-REGULATE LEPTIN SIGNALING AND UP-REGULATE CNR1 MRNA LEVELS IN THE HYPOTHALAMUS OF THE OFFSPRING AT BIRTH, ASSOCIATED WITH SEX-SPECIFIC CHANGES IN EPIGENETIC MARKERS AND SEX STEROID SIGNALING. TO TEST OUR HYPOTHESIS, WE USED PROGENITOR FEMALE RATS THAT RECEIVED CONTROL DIET (C, 9% FAT) OR ISOCALORIC HIGH-FAT DIET (HF, 28% FAT) FROM 8 WEEKS BEFORE MATING UNTIL DELIVERY. BLOOD, HYPOTHALAMUS AND CARCASS FROM C AND HF MALE AND FEMALE OFFSPRING WERE COLLECTED FOR BIOCHEMICAL AND MOLECULAR ANALYSES AT BIRTH. MATERNAL HF DIET DOWN-REGULATED THE TRANSCRIPTIONAL FACTOR STAT3 IN THE HYPOTHALAMUS OF MALE AND FEMALE OFFSPRING, BUT INDUCED HYPOLEPTINEMIA ONLY IN MALES AND DECREASED PHOSPHORYLATED STAT3 ONLY IN FEMALE OFFSPRING. BECAUSE LEPTIN ACTS THROUGH STAT3 PATHWAY TO INHIBIT CENTRAL ECS, OUR RESULTS SUGGEST THAT LEPTIN PATHWAY IMPAIRMENT MIGHT CONTRIBUTE TO INCREASED LEVELS OF CRN1 MRNA IN HYPOTHALAMUS OF BOTH SEX OFFSPRING. BESIDES, MATERNAL HF DIET INCREASED THE HISTONE ACETYLATION PERCENTAGE OF CNR1 PROMOTER IN MALE OFFSPRING AND INCREASED THE ANDROGEN RECEPTOR BINDING TO THE CNR1 PROMOTER, WHICH CAN CONTRIBUTE TO HIGHER EXPRESSION OF CNR1 IN NEWBORN HF OFFSPRING. MATERNAL HF DIET INCREASED PLASMA N6 TO N3 FATTY ACID RATIO IN MALE OFFSPRING, WHICH IS AN IMPORTANT RISK FACTOR TO METABOLIC DISEASES AND MIGHT INDICATE AN OVER ACTIVATION OF ENDOCANNABINOID SIGNALING. THUS, ALTHOUGH MATERNAL HF DIET PROGRAMS A SIMILAR PHENOTYPE IN ADULT OFFSPRING OF BOTH SEXES (OBESITY, HYPERPHAGIA AND HIGHER PREFERENCE FOR FAT), HERE WE SHOWED THAT MOLECULAR MECHANISMS INVOLVING LEPTIN SIGNALING, ECS, EPIGENETIC MARKERS AND SEX HORMONE SIGNALING WERE MODIFIED PRIOR TO OBESITY DEVELOPMENT AND CAN DIFFER BETWEEN NEWBORN MALE AND FEMALE OFFSPRING. THESE OBSERVATIONS MAY PROVIDE MOLECULAR INSIGHTS INTO SEX-SPECIFIC TARGETS FOR ANTI-OBESITY THERAPIES.	2019