1 5845 151 STUDY PROTOCOL FOR THE EPIGENETIC CHARACTERIZATION OF ANGOR PECTORIS ACCORDING TO THE AFFECTED CORONARY COMPARTMENT: GLOBAL AND COMPREHENSIVE ASSESSMENT OF THE RELATIONSHIP BETWEEN INVASIVE CORONARY PHYSIOLOGY AND MICRORNAS. BACKGROUND: MICRORNAS (MIRNAS) ARE NONCODING RNAS INVOLVED IN POST-TRANSCRIPTIONAL GENETIC REGULATION WITH A PROPOSED ROLE IN INTERCELLULAR COMMUNICATION. MIRNAS ARE CONSIDERED PROMISING BIOMARKERS IN ISCHEMIC HEART DISEASE. INVASIVE PHYSIOLOGICAL EVALUATION ALLOWS A PRECISE ASSESSMENT OF EACH AFFECTED CORONARY COMPARTMENT. ALTHOUGH SOME STUDIES HAVE ASSOCIATED THE EXPRESSION OF CIRCULATING MIRNAS WITH INVASIVE PHYSIOLOGICAL INDEXES, THEIR GLOBAL RELATIONSHIP WITH CORONARY COMPARTMENTS HAS NOT BEEN ASSESSED. HERE, WE WILL EVALUATE CIRCULATING MIRNAS PROFILES ACCORDING TO THE CORONARY PATTERN OF THE VASCULAR COMPARTMENT AFFECTATION. STUDY AND DESIGN: THIS IS AN INVESTIGATOR-INITIATED, MULTICENTRE, DESCRIPTIVE STUDY TO BE CONDUCTED AT THREE CENTRES IN SPAIN (NCT05374694). THE STUDY WILL INCLUDE ONE HUNDRED CONSECUTIVE PATIENTS OLDER THAN 18 YEARS WITH CHEST PAIN OF PRESUMED CORONARY CAUSE UNDERGOING INVASIVE PHYSIOLOGICAL EVALUATION, INCLUDING FRACTIONAL FLOW RESERVE (FFR) AND INDEX OF MICROVASCULAR RESISTANCE (IMR). PATIENTS WILL BE INITIALLY CLASSIFIED INTO FOUR GROUPS, ACCORDING TO FFR AND IMR: MACROVASCULAR AND MICROVASCULAR AFFECTATION (FFR/=25), ISOLATED MACROVASCULAR AFFECTATION (FFR0.80 / IMR >/=25) AND NORMAL CORONARY INDEXES (FFR>0.80 / IMR<25). PATIENTS WITH ISOLATED MICROVASCULAR AFFECTATION OR NORMAL INDEXES WILL ALSO UNDERGO THE ACETYLCHOLINE TEST AND MAY BE RECLASSIFIED AS A FIFTH GROUP IN THE PRESENCE OF SPASM. A PANEL OF MIRNAS PREVIOUSLY ASSOCIATED WITH MOLECULAR MECHANISMS LINKED TO CHRONIC CORONARY SYNDROME WILL BE ANALYSED USING RT-QPCR. CONCLUSIONS: THE RESULTS OF THIS STUDY WILL IDENTIFY MIRNA PROFILES ASSOCIATED WITH PATTERNS OF CORONARY AFFECTATION AND WILL CONTRIBUTE TO A BETTER UNDERSTANDING OF THE MECHANISTIC PATHWAYS OF CORONARY PATHOLOGY. 2023 2 3959 36 LONG NON-CODING RNAS TARGET PATHOGENETICALLY RELEVANT GENES AND PATHWAYS IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE DRIVEN BY GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. LONG NON-CODING RNAS (LNCRNAS) ARE A KEY COMPONENT OF THE EPIGENETIC MECHANISMS AND ARE KNOWN TO BE INVOLVED IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN THIS WORK WE AIMED TO IDENTIFY SIGNIFICANTLY DIFFERENTIALLY EXPRESSED LNCRNAS (DE-LNCRNAS) THAT ARE FUNCTIONALLY CONNECTED TO MODULATED GENES STRICTLY ASSOCIATED WITH RA. IN TOTAL, 542,500 TRANSCRIPTS HAVE BEEN PROFILED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM FOUR PATIENTS WITH EARLY ONSET RA PRIOR ANY TREATMENT AND FOUR HEALTHY DONORS USING CLARIOM D ARRAYS. RESULTS WERE CONFIRMED BY REAL-TIME PCR IN 20 PATIENTS AND 20 CONTROLS. SIX DE-LNCRNAS TARGET EXPERIMENTALLY VALIDATED MIRNAS ABLE TO REGULATE DIFFERENTIALLY EXPRESSED GENES (DEGS) IN RA; AMONG THEM, ONLY FTX, HNRNPU-AS1 AND RP11-498C9.15 TARGETED A LARGE NUMBER OF DEGS. MOST IMPORTANTLY, RP11-498C9.15 TARGETED THE LARGEST NUMBER OF SIGNALLING PATHWAYS THAT WERE FOUND TO BE ENRICHED BY THE GLOBAL AMOUNT OF RA-DEGS AND THAT HAVE ALREADY BEEN ASSOCIATED WITH RA AND RA-SYNOVIOCYTES. MOREOVER, RP11-498C9.15 TARGETED THE MOST HIGHLY CONNECTED GENES IN THE RA INTERACTOME, THUS SUGGESTING ITS INVOLVEMENT IN CRUCIAL GENE REGULATION. THESE RESULTS INDICATE THAT, BY MODULATING BOTH MICRORNAS AND GENE EXPRESSION, RP11-498C9.15 MAY PLAY A PIVOTAL ROLE IN RA PATHOGENESIS. 2019 3 2776 34 EXTRAUTERINE GROWTH RESTRICTION ON PULMONARY VASCULAR ENDOTHELIAL DYSFUNCTION IN ADULT MALE RATS: THE ROLE OF EPIGENETIC MECHANISMS. OBJECTIVE: EARLY POSTNATAL LIFE IS CONSIDERED AS A CRITICAL TIME WINDOW FOR THE DETERMINATION OF LONG-TERM METABOLIC STATES AND ORGAN FUNCTIONS. EXTRAUTERINE GROWTH RESTRICTION (EUGR) CAUSES THE DEVELOPMENT OF ADULT-ONSET CHRONIC DISEASES, INCLUDING PULMONARY HYPERTENSION. HOWEVER, THE EFFECTS OF NUTRITIONAL DISADVANTAGES DURING THE EARLY POSTNATAL PERIOD ON PULMONARY VASCULAR CONSEQUENCES IN LATER LIFE ARE NOT FULLY UNDERSTOOD. OUR STUDY WAS DESIGNED TO TEST WHETHER EPIGENETICS DYSREGULATION MEDIATES THE CELLULAR MEMORY OF THIS EARLY POSTNATAL EVENT. METHODS AND RESULTS: TO TEST THIS HYPOTHESIS, WE ISOLATED PULMONARY VASCULAR ENDOTHELIAL CELLS BY MAGNETIC-ACTIVATED CELL SORTING FROM EUGR AND CONTROL RATS. A POSTNATAL INSULT, NUTRITIONAL RESTRICTION-INDUCED EUGR CAUSED DEVELOPMENT OF AN INCREASED PULMONARY ARTERY PRESSURE AT 9 WEEKS OF AGE IN MALE SPRAGUE-DAWLEY RATS. METHYL-DNA IMMUNE PRECIPITATION CHIP, GENOME-SCALE MAPPING STUDIES TO SEARCH FOR DIFFERENTIALLY METHYLATED LOCI BETWEEN CONTROL AND EUGR RATS, REVEALED SIGNIFICANT DIFFERENCE IN CYTOSINE METHYLATION BETWEEN EUGR AND CONTROL RATS. EUGR CHANGES THE CYTOSINE METHYLATION AT APPROXIMATELY 500 LOCI IN MALE RATS AT 9 WEEKS OF AGE, PRECEDING THE DEVELOPMENT OF PULMONARY HYPERTENSION AND THESE REPRESENT THE CANDIDATE LOCI FOR MEDIATING THE PATHOGENESIS OF PULMONARY VASCULAR DISEASE THAT OCCURS LATER IN LIFE. GENE ONTOLOGY ANALYSIS ON DIFFERENTIALLY METHYLATED GENES SHOWED THAT HYPERMETHYLATED GENES IN EUGR ARE VASCULAR DEVELOPMENT-ASSOCIATED GENES AND HYPOMETHYLATED GENES IN EUGR ARE LATE-DIFFERENTIATION-ASSOCIATED AND SIGNAL TRANSDUCTION GENES. WE VALIDATED CANDIDATE DYSREGULATED LOCI WITH THE QUANTITATIVE ASSAYS OF CYTOSINE METHYLATION AND GENE EXPRESSIONS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT EPIGENETICS DYSREGULATION IS A STRONG MECHANISM FOR PROPAGATING THE CELLULAR MEMORY OF EARLY POSTNATAL EVENTS, CAUSING CHANGES IN THE EXPRESSION OF GENES AND LONG-TERM SUSCEPTIBILITY TO PULMONARY HYPERTENSION, AND FURTHER PROVIDING A NEW INSIGHT INTO THE PREVENTION AND TREATMENT OF EUGR-RELATED PULMONARY HYPERTENSION. 2014 4 3764 30 INTEGRATIVE ANALYSIS OF DNA METHYLATION AND GENE EXPRESSION DATA IDENTIFIES EPAS1 AS A KEY REGULATOR OF COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMPLEX DISEASE. GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO COPD RISK AND DISEASE PROGRESSION. THEREFORE WE DEVELOPED A SYSTEMATIC APPROACH TO IDENTIFY KEY REGULATORS OF COPD THAT INTEGRATES GENOME-WIDE DNA METHYLATION, GENE EXPRESSION, AND PHENOTYPE DATA IN LUNG TISSUE FROM COPD AND CONTROL SAMPLES. OUR INTEGRATIVE ANALYSIS IDENTIFIED 126 KEY REGULATORS OF COPD. WE IDENTIFIED EPAS1 AS THE ONLY KEY REGULATOR WHOSE DOWNSTREAM GENES SIGNIFICANTLY OVERLAPPED WITH MULTIPLE GENES SETS ASSOCIATED WITH COPD DISEASE SEVERITY. EPAS1 IS DISTINCT IN COMPARISON WITH OTHER KEY REGULATORS IN TERMS OF METHYLATION PROFILE AND DOWNSTREAM TARGET GENES. GENES PREDICTED TO BE REGULATED BY EPAS1 WERE ENRICHED FOR BIOLOGICAL PROCESSES INCLUDING SIGNALING, CELL COMMUNICATIONS, AND SYSTEM DEVELOPMENT. WE CONFIRMED THAT EPAS1 PROTEIN LEVELS ARE LOWER IN HUMAN COPD LUNG TISSUE COMPARED TO NON-DISEASE CONTROLS AND THAT EPAS1 GENE EXPRESSION IS REDUCED IN MICE CHRONICALLY EXPOSED TO CIGARETTE SMOKE. AS EPAS1 DOWNSTREAM GENES WERE SIGNIFICANTLY ENRICHED FOR HYPOXIA RESPONSIVE GENES IN ENDOTHELIAL CELLS, WE TESTED EPAS1 FUNCTION IN HUMAN ENDOTHELIAL CELLS. EPAS1 KNOCKDOWN BY SIRNA IN ENDOTHELIAL CELLS IMPACTED GENES THAT SIGNIFICANTLY OVERLAPPED WITH EPAS1 DOWNSTREAM GENES IN LUNG TISSUE INCLUDING HYPOXIA RESPONSIVE GENES, AND GENES ASSOCIATED WITH EMPHYSEMA SEVERITY. OUR FIRST INTEGRATIVE ANALYSIS OF GENOME-WIDE DNA METHYLATION AND GENE EXPRESSION PROFILES ILLUSTRATES THAT NOT ONLY DOES DNA METHYLATION PLAY A 'CAUSAL' ROLE IN THE MOLECULAR PATHOPHYSIOLOGY OF COPD, BUT IT CAN BE LEVERAGED TO DIRECTLY IDENTIFY NOVEL KEY MEDIATORS OF THIS PATHOPHYSIOLOGY. 2015 5 3963 46 LONG NONCODING RNA UC.98 STABILIZES ATHEROSCLEROTIC PLAQUES BY PROMOTING THE PROLIFERATION AND ADHESIVE CAPACITY IN MURINE AORTIC ENDOTHELIAL CELLS. PATHOLOGICAL STUDIES HAVE SHOWN THAT THE VULNERABILITY OF PLAQUES AFFECTS OUTCOMES IN PATIENTS WITH ATHEROSCLEROSIS (AS), A CHRONIC INFLAMMATORY DISEASE AND COMMON CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE. ALTHOUGH EMERGING TECHNOLOGIES HAVE ENABLED EARLY DIAGNOSIS OF AS WITH HIGH-RISK VULNERABLE PLAQUES, MORE ACCURATE AND NONINVASIVE DIAGNOSTIC METHODS ARE URGENTLY REQUIRED. TO THIS END, MOLECULES INVOLVED IN GENETIC OR EPIGENETIC REGULATION OF THE VULNERABILITY OF ATHEROSCLEROTIC PLAQUES HAVE BEEN EXTENSIVELY STUDIED. HERE, WE EVALUATED LONG NONCODING RNA (LNCRNA) VARIABILITY BY MICROARRAY ASSAY IN MURINE AORTIC ENDOTHELIAL CELLS (MAECS) BEARING VULNERABLE PLAQUES AND IDENTIFIED THE NOVEL FUNCTIONAL LNCRNA UC.98, WHOSE EXPRESSION PATTERN WAS ASSOCIATED WITH THE VULNERABILITY OF ATHEROSCLEROTIC PLAQUES. CONSISTENT WITH THIS, CLINICAL STATISTICS COMPARING THE PERIPHERAL BLOOD SPECIMENS FROM SETS OF PATIENTS WITH AS WITH OR WITHOUT VULNERABLE PLAQUES CONFIRMED THE LINEAR RELATIONSHIP BETWEEN THE EXPRESSION PATTERN OF UC.98 AND PLAQUE INSTABILITY. MOREOVER, MTT ASSAYS AND WESTERN BLOT ANALYSIS SHOWED THAT SILENCING OF INTRINSIC UC.98 IN MAECS NOT ONLY SUPPRESSED CELL PROLIFERATION BUT ALSO DECREASED THE EXPRESSIONS OF VASCULAR CELL ADHESION MOLECULE-1 AND INTERCELLULAR ADHESION MOLECULE-1, THEREBY INACTIVATING THE NUCLEAR FACTOR-KAPPAB PATHWAY. IN CONCLUSION, OUR RESULTS HIGHLIGHTED THE PIVOTAL ROLE OF UC.98 IN REGULATING THE VULNERABILITY OF PLAQUES DURING AS PROGRESSION AND SUGGESTED THAT UC.98 MAY BE A BIOMARKER OF THE EARLY DIAGNOSIS AND PROGNOSIS OF AS WITH VULNERABLE PLAQUES AND A POTENTIAL THERAPEUTIC TARGET FOR SLOWING AS PROGRESSION. 2020 6 2997 23 GENETIC VARIANTS IN DNMT1 AND THE RISK OF CARDIAC AUTONOMIC NEUROPATHY IN WOMEN WITH TYPE 1 DIABETES. AIMS/INTRODUCTION: EPIGENETICS PARTICIPATE IN THE PATHOGENESIS OF METABOLIC MEMORY, A SITUATION IN WHICH HYPERGLYCEMIA EXERTS PROLONGED DELETERIOUS EFFECTS EVEN AFTER ITS NORMALIZATION. WE TESTED THE HYPOTHESIS THAT GENETIC VARIANTS IN AN EPIGENETIC GENE COULD PREDISPOSE TO DIABETES COMPLICATIONS. MATERIAL AND METHODS: WE ASSESSED THE FREQUENCY OF FIVE SINGLE-NUCLEOTIDE POLYMORPHISMS IN THE GENE ENCODING DEOXYRIBONUCLEIC ACID METHYTRANSFERASE 1 (DNMT1; RS8112895, RS7254567, RS11085721, RS17291414 AND RS10854076), AND THEIR ASSOCIATIONS WITH DIABETIC KIDNEY DISEASE, RETINOPATHY, DISTAL POLYNEUROPATHY AND AUTONOMIC CARDIOVASCULAR NEUROPATHY IN 359 INDIVIDUALS WITH LONG-TERM TYPE 1 DIABETES. RESULTS: NONE OF THE SINGLE-NUCLEOTIDE POLYMORPHISMS STUDIED WAS SIGNIFICANTLY ASSOCIATED WITH THE PRESENCE OF CHRONIC COMPLICATIONS IN THE OVERALL POPULATION. HOWEVER, AFTER SEX STRATIFICATION, THE MINOR ALLELE C OF RS11085721 CONFERRED RISK FOR CARDIOVASCULAR NEUROPATHY IN WOMEN AFTER ADJUSTMENT FOR CONFOUNDING VARIABLES (ODDS RATIO 2.32; 95% CONFIDENCE INTERVAL 1.26-4.33; P = 0.006). CONCLUSIONS: THE FACT THAT HETEROZYGOUS MUTATIONS IN DNMT1 ARE ASSOCIATED WITH HEREDITARY SENSORY AUTONOMIC NEUROPATHY PROVIDES PLAUSIBILITY TO THE PRESENT FINDING. IF CONFIRMED IN INDEPENDENT SAMPLES, IT SUGGESTS THAT GENETIC VARIANTS IN EPIGENETIC GENES MIGHT PREDISPOSE TO MORE OR FEWER EPIGENETIC CHANGES IN THE FACE OF SIMILAR METABOLIC DERANGEMENTS TRIGGERED BY HYPERGLYCEMIA, CONSTITUTING THE "GENETICS OF EPIGENETICS" FOR MICROVASCULAR DIABETES COMPLICATIONS. 2019 7 5464 31 RESILIENCE IN LONG-TERM VIRAL INFECTION: GENETIC DETERMINANTS AND INTERACTIONS. VIRUS-INDUCED NEUROLOGICAL SEQUELAE RESULTING FROM INFECTION BY THEILER'S MURINE ENCEPHALOMYELITIS VIRUS (TMEV) ARE USED FOR STUDYING HUMAN CONDITIONS RANGING FROM EPILEPTIC SEIZURES TO DEMYELINATING DISEASE. MOUSE STRAINS ARE TYPICALLY CONSIDERED SUSCEPTIBLE OR RESISTANT TO TMEV INFECTION BASED ON VIRAL PERSISTENCE AND EXTREME PHENOTYPES, SUCH AS DEMYELINATION. WE HAVE IDENTIFIED A BROADER SPECTRUM OF PHENOTYPIC OUTCOMES BY INFECTING STRAINS OF THE GENETICALLY DIVERSE COLLABORATIVE CROSS (CC) MOUSE RESOURCE. WE EVALUATED THE CHRONIC-INFECTION GENE EXPRESSION PROFILES OF HIPPOCAMPI AND THORACIC SPINAL CORDS FOR 19 CC STRAINS IN RELATION TO PHENOTYPIC SEVERITY AND TMEV PERSISTENCE. STRAINS WERE CLUSTERED BASED ON SIMILAR PHENOTYPIC PROFILES AND TMEV LEVELS AT 90 DAYS POST-INFECTION, AND WE CATEGORIZED DISTINCT TMEV RESPONSE PROFILES. THE THREE MOST COMMON PROFILES INCLUDED "RESISTANT" AND "SUSCEPTIBLE," AS BEFORE, AS WELL AS A "RESILIENT" TMEV RESPONSE GROUP WHICH EXPERIENCED BOTH TMEV PERSISTENCE AND MILD NEUROLOGICAL PHENOTYPES EVEN AT 90 DAYS POST-INFECTION. EACH PROFILE HAD A DISTINCT GENE EXPRESSION SIGNATURE, ALLOWING THE IDENTIFICATION OF PATHWAYS AND NETWORKS SPECIFIC TO EACH TMEV RESPONSE GROUP. CC FOUNDER HAPLOTYPES FOR GENES INVOLVED IN THESE PATHWAYS/NETWORKS REVEALED CANDIDATE RESPONSE-SPECIFIC ALLELES. THESE ALLELES DEMONSTRATED PLEIOTROPY AND EPIGENETIC (MIRNA) REGULATION IN LONG-TERM TMEV INFECTION, WITH PARTICULAR RELEVANCE FOR RESILIENT MOUSE STRAINS. 2021 8 2967 40 GENETIC AND EPIGENETIC REGULATION OF CATECHOL-O-METHYLTRANSFERASE IN RELATION TO INFLAMMATION IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA. BACKGROUND: CATECHOL-O-METHYLTRANSFERASE (COMT) HAS BEEN SHOWN TO INFLUENCE CLINICAL PAIN, DESCENDING MODULATION, AND EXERCISE-INDUCED SYMPTOM WORSENING. COMT REGULATES NOCICEPTIVE PROCESSING AND INFLAMMATION, KEY PATHOPHYSIOLOGICAL FEATURES OF CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA (CFS/FM). WE AIMED TO DETERMINE THE INTERACTIONS BETWEEN GENETIC AND EPIGENETIC MECHANISMS REGULATING COMT AND ITS INFLUENCE ON INFLAMMATORY MARKERS AND SYMPTOMS IN PATIENTS WITH CFS/FM. METHODS: A CASE-CONTROL STUDY WITH REPEATED-MEASURES DESIGN WAS USED TO REDUCE THE CHANCE OF FALSE POSITIVE AND INCREASE THE POWER OF OUR FINDINGS. FIFTY-FOUR PARTICIPANTS (28 PATIENTS WITH CFS/FM AND 26 CONTROLS) WERE ASSESSED TWICE WITHIN 4 DAYS. THE ASSESSMENT INCLUDED CLINICAL QUESTIONNAIRES, NEUROPHYSIOLOGICAL ASSESSMENT (PAIN THRESHOLDS, TEMPORAL SUMMATION, AND CONDITIONED PAIN MODULATION), AND BLOOD WITHDRAWAL IN ORDER TO ASSESS RS4818, RS4633, AND RS4680 COMT POLYMORPHISMS AND PERFORM HAPLOTYPE ESTIMATION, DNA METHYLATION IN THE COMT GENE (BOTH MB-COMT AND S-COMT PROMOTERS), AND CYTOKINE EXPRESSION (TNF-ALPHA, IFN-GAMMA, IL-6, AND TGF-BETA). RESULTS: COMT HAPLOTYPES WERE ASSOCIATED WITH DNA METHYLATION IN THE S-COMT PROMOTER, TGF-BETA EXPRESSION, AND SYMPTOMS. HOWEVER, THIS WAS NOT SPECIFIC FOR ONE CONDITION. SIGNIFICANT BETWEEN-GROUP DIFFERENCES WERE FOUND FOR INCREASED DNA METHYLATION IN THE MB-COMT PROMOTER AND DECREASED IFN-GAMMA EXPRESSION IN PATIENTS. DISCUSSION: OUR RESULTS ARE CONSISTENT WITH BASIC AND CLINICAL RESEARCH, PROVIDING INTERESTING INSIGHTS INTO GENETIC-EPIGENETIC REGULATORY MECHANISMS. MB-COMT DNA METHYLATION MIGHT BE AN INDEPENDENT FACTOR CONTRIBUTING TO THE PATHOPHYSIOLOGY OF CFS/FM. FURTHER RESEARCH ON DNA METHYLATION IN COMPLEX CONDITIONS SUCH AS CFS/FM IS WARRANTED. WE RECOMMEND FUTURE RESEARCH TO EMPLOY A REPEATED-MEASURE DESIGN TO CONTROL FOR BIOMARKERS VARIABILITY AND WITHIN-SUBJECT CHANGES. 2022 9 5567 47 ROLE OF LNCRNAS IN REMODELING OF THE CORONARY ARTERY PLAQUES IN PATIENTS WITH ATHEROSCLEROSIS. INTRODUCTION: CARDIOVASCULAR DISEASES (CVDS) ARE THE LEADING CAUSE OF DEATH WORLDWIDE ACCORDING TO WORLD HEALTH ORGANIZATION (WHO) DATA. ATHEROSCLEROSIS IS CONSIDERED AS A CHRONIC INFLAMMATORY DISEASE THAT DEVELOPS IN RESPONSE TO DAMAGE TO THE VASCULAR INTIMA-MEDIA LAYER IN MOST CASES. IN RECENT YEARS, EPIGENETIC EVENTS HAVE EMERGED AS IMPORTANT PLAYERS IN THE DEVELOPMENT AND PROGRESSION OF CVDS. SINCE NONCODING RNA (NCRNAS) ARE IMPORTANT REGULATORS IN THE ORGANIZATION OF THE PATHOPHYSIOLOGICAL PROCESSES OF THE CARDIOVASCULAR SYSTEM, THEY HAVE THE POTENTIAL TO BE USED AS THERAPEUTIC TARGETS, DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. IN THIS STUDY LONG NONCODING RNA (LNCRNA) AND MRNA GENE EXPRESSION WERE COMPARED BETWEEN CORONARY ATHEROSCLEROTIC PLAQUES (CAP) AND THE INTERNAL MAMMARY ARTERY (IMA) WHICH HAS THE SAME GENETIC MAKEUP AND IS EXPOSED TO THE SAME ENVIRONMENTAL STRESS CONDITIONS WITH CAP IN THE SAME INDIVIDUAL. METHODS: LNCRNA AND MRNA GENE EXPRESSIONS WERE DETERMINED USING THE MICROARRAY IN THE SAMPLES. MICROARRAY RESULTS WERE VALIDATED BY RT-QPCR. DIFFERENTIALLY EXPRESSED GENES (DEGS; LNCRNAS AND MRNAS) WERE DETERMINED BY GENESPRING (VER 3.0) [P VALUES < 0.05 AND FOLD CHANGE (FC) > 2]. DAVID BIOINFORMATICS PROGRAM WAS USED FOR GENE ONTOLOGY (GO) ANNOTATION AND ENRICHMENT ANALYSES OF STATISTICALLY SIGNIFICANT GENES BETWEEN CAP AND IMA TISSUE. RESULTS AND CONCLUSIONS: IN OUR STUDY, 345 DEGS WERE FOUND TO BE STATISTICALLY SIGNIFICANT (P < 0.05; FC > 2) BETWEEN CAP AND IMA. OF THESE, 65 WERE LNCRNA AND 280 WERE MRNA. THIRTY-THREE LNCRNAS WERE UPREGULATED, WHILE 32 LNCRNAS WERE DOWNREGULATED. SOME OF THE IMPORTANT MRNAS ARE SPP1, CYP4B1, CHRDL1, MYOC, AND ALKAL2, WHILE SOME OF THE LNCRNAS ARE LOC105377123, LINC01857, DIO3OS, LOC101928134, AND KCNA3 BETWEEN CAP AND IMA TISSUE. WE ALSO IDENTIFIED GENES THAT CORRELATED WITH STATISTICALLY SIGNIFICANT LNCRNAS. THE RESULTS OF THIS STUDY ARE EXPECTED TO BE AN IMPORTANT SOURCE OF DATA IN THE DEVELOPMENT OF NEW GENETICALLY BASED DRUGS TO PREVENT ATHEROSCLEROTIC PLAQUE. IN ADDITION, THE DATA OBTAINED MAY CONTRIBUTE TO THE EXPLANATION OF THE EPIGENETIC MECHANISMS THAT PLAY A ROLE IN THE PATHOLOGICAL BASIS OF THE PROCESS THAT PROTECTS THE IMA FROM ATHEROSCLEROSIS. 2023 10 177 29 ACCELERATED EPIGENETIC AGING AND INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) IN PATIENTS WITH CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). THIS FAILURE CAN BE RELATED TO A PHENOTYPE OF ACCELERATED AGING. IN THIS WORK, WE CONSIDERED 76 PATIENTS WITH END-STAGE RENAL DISEASE (ESRD) AND 83 HEALTHY CONTROLS. WE CONCOMITANTLY EVALUATED FOR THE FIRST TIME TWO MEASURES THAT CAN BE INFORMATIVE OF THE RATE OF AGING, I.E., WHOLE BLOOD DNA METHYLATION USING THE ILLUMINA INFINIUM EPIC ARRAY AND PLASMA LEVELS OF A SELECTION OF INFLAMMATORY/IMMUNOLOGICAL PROTEINS USING MULTIPLEX IMMUNOASSAYS. FIRST OF ALL, WE DEMONSTRATED ACCELERATED AGING IN TERMS OF THE MOST COMMON EPIGENETIC AGE ESTIMATORS IN CKD PATIENTS. MOREOVER, WE DEVELOPED A NEW CLOCK/PREDICTOR OF AGE BASED ON THE INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) AND IDENTIFIED THE INFLAMMATORY/IMMUNOLOGICAL BIOMARKERS DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS. IPAGE APPEARED TO BE MORE SENSITIVE THAN EPIGENETIC CLOCKS IN QUANTIFYING THE ACCELERATED AGING PHENOTYPE OF ESRD PATIENTS. INTERESTINGLY, WE DID NOT FIND ANY CORRELATION BETWEEN THE AGE ACCELERATION EVALUATED ACCORDING TO THE EPIGENETIC CLOCKS AND IPAGE IN EITHER THE ESRD GROUP OR THE CONTROL GROUP. ON THE WHOLE, OUR DATA SHOW A CONSISTENT ACCELERATED AGING PHENOTYPE IN ESRD PATIENTS, WHICH IS BETTER APPRECIATED BY QUANTIFYING THE UNDERLYING INFLAMMATORY PROCESSES (INFLAMMAGING) BY IPAGE THAN BY USING EPIGENETIC CLOCKS. 2022 11 6081 35 THE EFFECT OF FOXO GENE FAMILY VARIANTS AND GLOBAL DNA METYLATION ON RRMS DISEASE. MULTIPLE SCLEROSIS IS A CHRONIC DISEASE THAT USUALLY OCCURS WITH EXACERBATIONS AND REMISSIONS IN YOUNG ADULTS, AFFECTS THE CENTRAL NERVOUS SYSTEM WHITE MATTER IN MULTIPLE LOCALIZATION, AND IS THOUGHT TO BE THE RESULT OF COMPLEX INTERACTIONS OF GENETIC AND ENVIRONMENTAL FACTORS, THE MOST COMMON FORM IS RELAPSING-REMITTING MS. FORKHEAD TRANSCRIPTION FACTORS O CLASS (FOXO) ARE RESPONSIBLE FOR THE REGULATION OF VARIOUS CELLULAR PROCESSES INCLUDING CELL CYCLE, APOPTOSIS, DNA REPAIR, CELLULAR RESISTANCE AND METABOLISM. DNA METHYLATION IS SUCH AN EPIGENETIC CHANGE AND HAS BEEN SHOWN TO BE ASSOCIATED WITH ALMOST ANY BIOLOGICAL PROCESS. THE AIM OF OUR STUDY TO SHOW THE RELATION BETWEEN THE GENETIC VARIANTS OF FOXO3A (RS2253310 RS4966936) AND FOXO1 (RS3900833, RS4581585) AND GLOBAL DNA METHYLATION IN RRMS. WE ANALYZED DNA OBTAINED FROM 79 RRMS PATIENTS AND 104 HEALTHY INDIVIDUALS BY PCR-RFLP METHOD FOR THE DETECTION OF GENETIC VARIANTS. FOR THE DETERMINATION OF GLOBAL DNA METHYLATION, RESULTS WERE OBTAINED USING ELISA METHOD. THE DATA WERE EVALUATED STATISTICALLY. AS A RESULT OF OUR ANALYSIS; GLOBAL DNA METHYLATION IS HIGHER IN RRMS PATIENTS COMPARED TO CONTROL INDIVIDUALS AND IT CAN BE EFFECTIVE ON THE DISEASE. IN ADDITION, IT HAS BEEN DETERMINED THAT VARIANTS OF FOXO3A (RS2253310, RS4966936) AND FOXO1 (RS3900833), WHICH HAVE BEEN GENOTYPED, MAY BE EFFECTIVE IN DISEASE PATHOGENESIS. THESE RESULTS SUGGEST THAT DNAMETHYLATION AND FOXO GENE VARIANTS MAY BE EFFECTIVE IN NEURONAL LOSS IN RRMS. 2020 12 4736 32 NOVEL EPIGENETIC BIOMARKERS MEDIATING BISPHENOL A EXPOSURE AND METABOLIC PHENOTYPES IN FEMALE MICE. THERE IS COMPELLING EVIDENCE THAT EPIGENETIC MODIFICATIONS LINK DEVELOPMENTAL ENVIRONMENTAL INSULTS TO ADULT DISEASE SUSCEPTIBILITY. ANIMAL STUDIES HAVE ASSOCIATED PERINATAL BISPHENOL A (BPA) EXPOSURE TO ALTERED DNA METHYLATION, BUT THESE STUDIES ARE OFTEN LIMITED TO CANDIDATE GENE AND GLOBAL NON-LOCI-SPECIFIC APPROACHES. BY USING AN EPIGENOME-WIDE DISCOVERY PLATFORM, WE ELUCIDATED EPIGENETIC ALTERATIONS IN LIVER TISSUE FROM ADULT MICE OFFSPRING (10 MONTHS) FOLLOWING PERINATAL BPA EXPOSURE AT HUMAN PHYSIOLOGICALLY RELEVANT DOSES (50-NG, 50-MUG, AND 50-MG BPA/KG DIET). BIOLOGICAL PATHWAY ANALYSIS IDENTIFIED AN ENRICHMENT OF SIGNIFICANT DIFFERENTIALLY METHYLATED REGIONS IN METABOLIC PATHWAYS AMONG FEMALES. FURTHERMORE, THROUGH THE USE OF TOP ENRICHED BIOLOGICAL PATHWAYS, 4 CANDIDATE GENES WERE CHOSEN TO ASSESS DNA METHYLATION AS A MEDIATING FACTOR LINKING THE ASSOCIATION OF PERINATAL BPA EXPOSURE TO METABOLIC PHENOTYPES PREVIOUSLY OBSERVED IN FEMALE OFFSPRING. DNA METHYLATION STATUS AT JANUS KINASE-2 (JAK-2), RETINOID X RECEPTOR (RXR), REGULATORY FACTOR X-ASSOCIATED PROTEIN (RFXAP), AND TRANSMEMBRANE PROTEIN 238 (TMEM238) WAS USED WITHIN A MEDIATIONAL REGRESSION ANALYSIS. DNA METHYLATION IN ALL FOUR OF THE CANDIDATE GENES WAS IDENTIFIED AS A MEDIATOR IN THE MECHANISTIC PATHWAY OF DEVELOPMENTAL BPA EXPOSURE AND FEMALE-SPECIFIC ENERGY EXPENDITURE, BODY WEIGHT, AND BODY FAT PHENOTYPES. DATA GENERATED FROM THIS STUDY ARE CRUCIAL FOR DECIPHERING THE MECHANISTIC ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC DISEASE AND THE DEVELOPMENT OF EPIGENETIC-BASED PREVENTION AND THERAPEUTIC STRATEGIES FOR COMPLEX HUMAN DISEASE. 2017 13 6911 20 [TWO GERMAN BIRTH COHORTS: GINIPLUS AND LISAPLUS]. NUMEROUS CHRONIC DISEASES IN CHILDHOOD AND ADULTHOOD HAVE THEIR ORIGINS IN PERINATAL LIFE AND ARE POTENTIALLY INFLUENCED BY TRANS-GENERATIONAL EPIGENETIC PROCESSES. THEREFORE, PROSPECTIVE BIRTH COHORTS CAN SUBSTANTIALLY CONTRIBUTE TO OUR KNOWLEDGE ABOUT THE ETIOLOGY OF DISEASES INCLUDING MODIFIABLE RISK FACTORS. THE TWO POPULATION-BASED GERMAN BIRTH COHORTS GINIPLUS AND LISAPLUS AIM TO DESCRIBE THE NATURAL COURSE OF CHRONIC DISEASES AND INTERMEDIATE PHENOTYPES IN CHILDHOOD AND ITS DETERMINANTS, AND TO IDENTIFY POTENTIAL GENETIC EFFECT MODIFICATIONS. IN THE MID-1990S, 5,991 (GINIPLUS) AND 3,097 (LISAPLUS) HEALTHY, TERM NEWBORNS WERE RECRUITED FOR LONG-TERM FOLLOW-UP IN FOUR REGIONS OF GERMANY. THE FOLLOW-UP RATE FOR THE FIRST 10 YEARS WAS ABOUT 55%. WE ANALYZED THE GROWTH AND DEVELOPMENT OF OVERWEIGHT, INFECTIONS AND ALLERGIC DISEASES, MENTAL AND ORAL HEALTH, METABOLIC AND INFLAMMATORY PARAMETERS AND THE ROLE OF POTENTIAL RISK FACTORS INCLUDING GENETICS. THE RESULTS OF THESE TWO BIRTH COHORTS SUBSTANTIALLY CONTRIBUTE TO THE CURRENT KNOWLEDGE ABOUT THE NATURAL COURSE OF THESE HEALTH PARAMETERS. THESE DATA WERE INCLUDED IN MANY INTERNATIONAL PROJECTS AND CONSORTIA FOR PURPOSES OF INTERNATIONAL COMPARISONS OF PREVALENCE AND CONSISTENCY OF FINDINGS, AND TO INCREASE THE POWER OF THE ANALYSES. 2012 14 5095 25 PLASMA PROTEOMIC BIOMARKER SIGNATURE OF AGE PREDICTS HEALTH AND LIFE SPAN. OLDER AGE IS A STRONG SHARED RISK FACTOR FOR MANY CHRONIC DISEASES, AND THERE IS INCREASING INTEREST IN IDENTIFYING AGING BIOMARKERS. HERE, A PROTEOMIC ANALYSIS OF 1301 PLASMA PROTEINS WAS CONDUCTED IN 997 INDIVIDUALS BETWEEN 21 AND 102 YEARS OF AGE. WE IDENTIFIED 651 PROTEINS ASSOCIATED WITH AGE (506 OVER-REPRESENTED, 145 UNDERREPRESENTED WITH AGE). MEDIATION ANALYSIS SUGGESTED A ROLE FOR PARTIAL CIS-EPIGENETIC CONTROL OF PROTEIN EXPRESSION WITH AGE. OF THE AGE-ASSOCIATED PROTEINS, 33.5% AND 45.3%, WERE ASSOCIATED WITH MORTALITY AND MULTIMORBIDITY, RESPECTIVELY. THERE WAS ENRICHMENT OF PROTEINS ASSOCIATED WITH INFLAMMATION AND EXTRACELLULAR MATRIX AS WELL AS SENESCENCE-ASSOCIATED SECRETORY PROTEINS. A 76-PROTEIN PROTEOMIC AGE SIGNATURE PREDICTED ACCUMULATION OF CHRONIC DISEASES AND ALL-CAUSE MORTALITY. THESE DATA SUPPORT THE USE OF PROTEOMIC BIOMARKERS TO MONITOR AGING TRAJECTORIES AND TO IDENTIFY INDIVIDUALS AT HIGHER RISK OF DISEASE TO BE TARGETED FOR IN DEPTH DIAGNOSTIC PROCEDURES AND EARLY INTERVENTIONS. 2020 15 546 34 ATTENUATED EXPRESSION OF SLCO2A1 CAUSED BY DNA METHYLATION IN PEDIATRIC INFLAMMATORY BOWEL DISEASE. BACKGROUND: SLCO2A1 ENCODES A PROSTAGLANDIN (PG) TRANSPORTER, AND AUTOSOMAL RECESSIVE PATHOGENIC VARIANTS OF THIS GENE CAUSE CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1. IT IS UNCLEAR WHETHER A HETEROZYGOUS PATHOGENIC VARIANT OF SLCO2A1 HAS A ROLE IN THE PATHOGENESIS OF OTHER TYPES OF INFLAMMATORY BOWEL DISEASE (IBD). IN THIS STUDY, WE INVESTIGATED THE POSSIBLE INVOLVEMENT OF A LOCAL EPIGENETIC ALTERATION IN SLCO2A1 IN PATIENTS WITH A HETEROZYGOUS PATHOGENIC VARIANT. METHODS: WE CONDUCTED WHOLE-EXOME SEQUENCING OF SAMPLES FROM 2 SISTERS WITH SUSPECTED MONOGENIC IBD. IN ADDITION, WE PERFORMED BISULFITE SEQUENCING USING DNA EXTRACTED FROM THEIR SMALL AND LARGE INTESTINE SAMPLES TO EXPLORE EPIGENETIC ALTERATIONS. RESULTS: A HETEROZYGOUS SPLICING SITE VARIANT, SLCO2A1:C.940 + 1G > A, WAS DETECTED IN BOTH PATIENTS. TO EXPLORE THE POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS, WE ANALYZED PROTEIN AND MESSENGER RNA EXPRESSION OF SLCO2A1, AND OBSERVED ATTENUATED SLCO2A1 EXPRESSION IN THE INFLAMED LESIONS OF THESE PATIENTS COMPARED WITH THAT IN THE CONTROL INDIVIDUALS. FURTHERMORE, BISULFITE SEQUENCING INDICATED DENSE METHYLATION IN THE PROMOTER REGION OF SLCO2A1 ONLY IN THE INFLAMED LESIONS OF BOTH PATIENTS. THE URINARY PG METABOLITE LEVELS IN THESE PATIENTS WERE COMPARABLE TO THOSE IN PATIENTS WITH CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1 AND HIGHER THAN THOSE IN THE CONTROL INDIVIDUALS. WE FOUND CONSIDERABLY HIGHER LEVELS OF THE METABOLITES IN PATIENT 1, WHO SHOWED MORE SEVERE SYMPTOMS THAN PATIENT 2. CONCLUSIONS: LOCAL DNA METHYLATION ATTENUATED SLCO2A1 EXPRESSION, WHICH MAY EVOKE LOCAL INFLAMMATION OF THE MUCOSA BY THE UNINCORPORATED PG. THESE FINDINGS MAY IMPROVE OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS UNDERLYING IBD DEVELOPMENT. 2023 16 6642 32 UNRAVELING THE PATHOGENESIS OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE OVERLAP: FOCUSING ON EPIGENETIC MECHANISMS. ASTHMA AND COPD OVERLAP (ACO) IS CHARACTERIZED BY PATIENTS PRESENTING WITH PERSISTENT AIRFLOW LIMITATION AND FEATURES OF BOTH ASTHMA AND COPD. IT IS ASSOCIATED WITH A HIGHER FREQUENCY AND SEVERITY OF EXACERBATIONS, A FASTER LUNG FUNCTION DECLINE, AND A HIGHER HEALTHCARE COST. SYSTEMIC INFLAMMATION IN COPD AND ASTHMA IS DRIVEN BY TYPE 1 T HELPER (TH1) AND TH2 IMMUNE RESPONSES, RESPECTIVELY, BOTH OF WHICH MAY CONTRIBUTE TO AIRWAY REMODELING IN ACO. ACO-RELATED BIOMARKERS CAN BE CLASSIFIED INTO FOUR CATEGORIES: NEUTROPHIL-MEDIATED INFLAMMATION, TH2 CELL RESPONSES, ARACHIDONIC ACID-EICOSANOIDS PATHWAY, AND METABOLITES. GENE-ENVIRONMENT INTERACTIONS ARE KEY CONTRIBUTORS TO THE COMPLEXITY OF ACO AND ARE REGULATED BY EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNAS. THUS, THIS REVIEW FOCUSES ON THE LINK BETWEEN EPIGENETICS AND ACO, AND OUTLINES THE FOLLOWING: (I) INHERITING EPIGENOTYPES WITHOUT CHANGE WITH ENVIRONMENTAL STIMULI, OR EPIGENETIC CHANGES IN RESPONSE TO LONG-TERM EXPOSURE TO INHALED PARTICLES PLUS INTERMITTENT EXPOSURE TO SPECIFIC ALLERGENS; (II) EPIGENETIC MARKERS DISTINGUISHING ACO FROM COPD AND ASTHMA; (III) POTENTIAL EPIGENETIC DRUGS THAT CAN REVERSE OXIDATIVE STRESS, GLUCOCORTICOID INSENSITIVITY, AND CELL INJURY. IMPROVED UNDERSTANDING OF THE EPIGENETIC REGULATIONS HOLDS GREAT VALUE TO GIVE DEEPER INSIGHT INTO THE MECHANISMS, AND CLARIFY THEIR IMPLICATIONS FOR BIOMEDICAL RESEARCH IN ACO. 2022 17 4279 36 MICRONUCLEI, INFLAMMATION AND AUTO-IMMUNE DISEASE. AUTO-IMMUNE DISEASES (AUD) ARE CHARACTERIZED BY AN IMMUNE RESPONSE TO ANTIGENIC COMPONENTS OF THE HOST ITSELF. THE ETIOLOGY OF AUD IS NOT WELL UNDERSTOOD. THE AVAILABLE EVIDENCE POINTS TO AN INTERACTION BETWEEN GENETIC, EPIGENETIC, ENVIRONMENTAL, INFECTIOUS AND LIFE-STYLE FACTORS. AUD ARE MORE PREVALENT IN WOMEN THAN IN MEN; SEX HORMONES PLAY A CRUCIAL ROLE IN THIS SEX BIAS. MICRONUCLEI (MN) EMERGED AS A NEW PLAYER IN THE INDUCTION OF AUD, BASED ON THE CAPACITY OF DNA-SENSORS TO DETECT SELF-DNA THAT LEAKS INTO THE CYTOPLASM FROM DISRUPTED MN AND INDUCE THE CGAS-STING PATHWAY TRIGGERING AN INNATE AUTO-IMMUNE RESPONSE AND CHRONIC INFLAMMATION. IT WAS FOUND THAT INFLAMMATION CAN INDUCE MN AND MN CAN INDUCE INFLAMMATION, LEADING TO A VICIOUS INFLAMMATION-OXIDATIVE-DNA DAMAGE-MN-FORMATION-CHROMOTHRIPSIS CYCLE. MN ORIGINATING FROM SEX CHROMOSOME-LOSS MAY INDUCE INFLAMMATION AND AUD. WE PERFORMED A SYSTEMATIC REVIEW OF STUDIES REPORTING MN IN PATIENTS WITH SYSTEMIC OR ORGAN-SPECIFIC AUD. A META-ANALYSIS WAS PERFORMED ON LYMPHOCYTE MN IN DIABETES MELLITUS (10 STUDIES, 457 PATIENTS/290 CONTROLS) AND BEHCET'S DISEASE (3 STUDIES, 100 PATIENTS/70 CONTROLS) AND FOR BUCCAL MN IN DIABETES MELLITUS (11 STUDIES, 507 PATIENTS/427 CONTROLS). A STATISTICALLY SIGNIFICANT INCREASE IN PATIENTS COMPARED TO CONTROLS WAS FOUND IN THE META-ANALYSES PROVIDING AN INDICATION OF AN ASSOCIATION BETWEEN MN AND AUD. A 36%-HIGHER MEAN-MRI IN BUCCAL CELLS (3.8+/-0.7) WAS FOUND COMPARED TO LYMPHOCYTES (2.8+/-0.7)(P = 0.01). THE META-MRI IN LYMPHOCYTES AND BUCCAL CELLS (1.7 AND 3.0 RESPECTIVELY) SUGGEST THAT BUCCAL CELLS MAY BE MORE SENSITIVE. TO ASSESS THEIR RELATIVE SENSITIVITY, STUDIES WITH MEASUREMENTS FROM THE SAME SUBJECTS WOULD BE DESIRABLE. IT IS IMPORTANT THAT FUTURE STUDIES (I) INVESTIGATE, IN WELL-DESIGNED POWERED STUDIES, THE PROSPECTIVE ASSOCIATION OF MN-FORMATION WITH AUD AND (II) EXPLORE THE MOLECULAR MECHANISMS BY WHICH CHROMOSOME SHATTERING IN MN AND THE RELEASE OF CHROMATIN FRAGMENTS FROM MN LEAD TO THE FORMATION OF AUTO-ANTIBODIES. 2020 18 5468 30 RESISTANCE TRAINING AND REDOX HOMEOSTASIS: CORRELATION WITH AGE-ASSOCIATED GENOMIC CHANGES. REGULAR PHYSICAL ACTIVITY IS EFFECTIVE AS PREVENTION AND TREATMENT FOR DIFFERENT CHRONIC CONDITIONS RELATED TO THE AGEING PROCESSES. IN FACT, A SEDENTARY LIFESTYLE HAS BEEN LINKED TO A WORSENING OF CELLULAR AGEING BIOMARKERS SUCH AS TELOMERE LENGTH (TL) AND/OR SPECIFIC EPIGENETIC CHANGES (E.G. DNA METHYLATION), WITH INCREASE OF THE PROPENSITY TO AGING-RELATED DISEASES AND PREMATURE DEATH. EXTENDING OUR PREVIOUS FINDINGS, WE AIMED TO TEST THE HYPOTHESIS THAT 12 WEEKS OF LOW FREQUENCY, MODERATE INTENSITY, EXPLOSIVE-TYPE RESISTANCE TRAINING (EMRT) MAY ATTENUATE AGE-ASSOCIATED GENOMIC CHANGES. TO THIS AIM, TL, GLOBAL DNA METHYLATION, TRF2, KU80, SIRT1, SIRT2 AND GLOBAL PROTEIN ACETYLATION, AS WELL AS OTHER PROTEINS INVOLVED IN APOPTOTIC PATHWAY (BCL-2, BAX AND CASPASE-3), ANTIOXIDANT RESPONSE (TRXR1 AND MNSOD) AND OXIDATIVE DAMAGE (MYELOPEROXIDASE) WERE EVALUATED BEFORE AND AFTER EMRT IN WHOLE BLOOD OR PERIPHERAL MONONUCLEAR CELLS (PBMCS) OF ELDERLY SUBJECTS. OUR FINDINGS CONFIRM THE POTENTIAL OF EMRT TO INDUCE AN ADAPTIVE CHANGE IN THE ANTIOXIDANT PROTEIN SYSTEMS AT SYSTEMIC LEVEL AND SUGGEST A PUTATIVE ROLE OF RESISTANCE TRAINING IN THE REDUCTION OF GLOBAL DNA METHYLATION. MOREOVER, WE OBSERVED THAT EMRT COUNTERACTS THE TELOMERES' SHORTENING IN A MANNER THAT PROVED TO BE DIRECTLY CORRELATED WITH THE AMELIORATION OF REDOX HOMEOSTASIS AND EFFICACY OF TRAINING REGIME, EVALUATED AS IMPROVEMENT OF BOTH MUSCLE'S POWER/STRENGTH AND FUNCTIONAL PARAMETERS. 2016 19 3648 40 INCREASED RELATIVE ABUNDANCE OF RUMINOCCOCUS IS ASSOCIATED WITH REDUCED CARDIOVASCULAR RISK IN AN OBESE POPULATION. BACKGROUND: OBESITY IS A COMPLEX DISEASE WITH UNDERLYING GENETIC, ENVIRONMENTAL, PSYCHOLOGICAL, PHYSIOLOGICAL, MEDICAL, AND EPIGENETIC FACTORS. OBESITY CAN CAUSE VARIOUS DISORDERS, INCLUDING CARDIOVASCULAR DISEASES (CVDS), THAT ARE AMONG THE MOST PREVALENT CHRONIC CONDITIONS IN QATAR. RECENT STUDIES HAVE HIGHLIGHTED THE SIGNIFICANT ROLES OF THE GUT MICROBIOME IN IMPROVING THE PATHOLOGY OF VARIOUS DISEASES, INCLUDING OBESITY. THUS, IN THIS STUDY, WE AIMED TO INVESTIGATE THE EFFECTS OF DIETARY INTAKE AND GUT MICROBIAL COMPOSITION IN MODULATING THE RISK OF CVD DEVELOPMENT IN OBESE QATARI ADULTS. METHODS: WE ENROLLED 46 ADULT SUBJECTS (18-65 YEARS OF AGE) WHO WERE CLASSIFIED BASED ON THEIR CVD RISK SCORES, CALCULATED USING THE FRAMINGHAM FORMULA, INTO A CVD NO-RISK GROUP (SCORE OF <10%, N = 36) AND CVD RISK GROUP (SCORE OF >/=10%, N = 10). FOR EACH STUDY SUBJECT, WE MEASURED THE GUT MICROBIAL COMPOSITION WITH A 16S RDNA SEQUENCING METHOD THAT TARGETED THE V3-V4 REGION USING ILLUMINA MISEQ, AND THEIR NUTRITIONAL STATUS WAS RECORDED BASED ON 24-H DIETARY RECALL. DIETARY INTAKE, BACTERIAL TAXA SUMMARY, DIVERSITY INDEX, MICROBIAL MARKERS, PATHWAY ANALYSIS, AND NETWORK CORRELATION WERE DETERMINED FOR THE STUDY SUBJECTS. RESULTS: THE CVD RISK GROUP SHOWED A LOWER INTAKE OF VITAMIN D, REDUCED RELATIVE ABUNDANCE OF GENERA RUMINOCOCCUS AND BIFIDOBACTERIUM, NO CHANGE IN BACTERIAL DIVERSITY, AND HIGHER LEVELS OF TAURINE, HYPOTAURINE, AND LIPOIC ACID METABOLISM THAN THE CVD NO-RISK GROUP. BESIDES, THE RELATIVE ABUNDANCE OF GENUS RUMINOCOCCUS WAS POSITIVELY CORRELATED WITH THE INTAKE OF PROTEIN, MONOUNSATURATED FAT, VITAMIN A, AND VITAMIN D. CONCLUSION: TAKEN TOGETHER, OUR RESULTS SUGGEST THAT THE GENUS RUMINOCOCCUS COULD BE USED AS A MICROBIAL MARKER, AND ITS REDUCED RELATIVE ABUNDANCE COULD MEDIATE THE RISK OF CVDS IN THE OBESE QATARI POPULATION. 2022 20 2568 30 EPIGENETICS OF ALCOHOL-RELATED LIVER DISEASES. ALCOHOL-RELATED LIVER DISEASE (ARLD) IS A PRIMARY CAUSE OF CHRONIC LIVER DISEASE IN THE UNITED STATES. DESPITE ADVANCES IN THE DIAGNOSIS AND MANAGEMENT OF ARLD, IT REMAINS A MAJOR PUBLIC HEALTH PROBLEM ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY, EMPHASISING THE NEED TO ADOPT NOVEL APPROACHES TO THE STUDY OF ARLD AND ITS COMPLICATIONS. EPIGENETIC CHANGES ARE INCREASINGLY BEING RECOGNISED AS CONTRIBUTING TO THE PATHOGENESIS OF MULTIPLE DISEASE STATES. HARNESSING THE POWER OF INNOVATIVE TECHNOLOGIES FOR THE STUDY OF EPIGENETICS (E.G., NEXT-GENERATION SEQUENCING, DNA METHYLATION ASSAYS, HISTONE MODIFICATION PROFILING AND COMPUTATIONAL TECHNIQUES LIKE MACHINE LEARNING) HAS RESULTED IN A SEISMIC SHIFT IN OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF ARLD. KNOWLEDGE OF THESE TECHNIQUES AND ADVANCES IS OF PARAMOUNT IMPORTANCE FOR THE PRACTICING HEPATOLOGIST AND RESEARCHERS ALIKE. ACCORDINGLY, IN THIS REVIEW ARTICLE WE WILL SUMMARISE THE CURRENT KNOWLEDGE ABOUT ALCOHOL-INDUCED EPIGENETIC ALTERATIONS IN THE CONTEXT OF ARLD, INCLUDING BUT NOT LIMITED TO, DNA HYPER/HYPO METHYLATION, HISTONE MODIFICATIONS, CHANGES IN NON-CODING RNA, 3D CHROMATIN ARCHITECTURE AND ENHANCER-PROMOTER INTERACTIONS. ADDITIONALLY, WE WILL DISCUSS THE STATE-OF-THE-ART TECHNIQUES USED IN THE STUDY OF ARLD (E.G. SINGLE-CELL SEQUENCING). WE WILL ALSO HIGHLIGHT THE EPIGENETIC REGULATION OF CHEMOKINES AND THEIR PROINFLAMMATORY ROLE IN THE CONTEXT OF ARLD. LASTLY, WE WILL EXAMINE THE CLINICAL APPLICATIONS OF EPIGENETICS IN THE DIAGNOSIS AND MANAGEMENT OF ARLD. 2022