1 267 138 AFFECTIVE AND COGNITIVE BEHAVIOR IN THE ALPHA-GALACTOSIDASE A DEFICIENT MOUSE MODEL OF FABRY DISEASE. FABRY DISEASE IS AN X-LINKED INHERITED LYSOSOMAL STORAGE DISORDER WITH INTRACELLULAR ACCUMULATION OF GLOBOTRIAOSYLCERAMIDE (GB3) DUE TO ALPHA-GALACTOSIDASE A (ALPHA-GAL A) DEFICIENCY. FABRY PATIENTS FREQUENTLY REPORT OF ANXIETY, DEPRESSION, AND IMPAIRED COGNITIVE FUNCTION. WE CHARACTERIZED AFFECTIVE AND COGNITIVE PHENOTYPE OF MALE MICE WITH ALPHA-GAL A DEFICIENCY (FABRY KO) AND COMPARED RESULTS WITH THOSE OF AGE-MATCHED MALE WILDTYPE (WT) LITTERMATES. YOUNG (3 MONTHS) AND OLD (>/= 18 MONTHS) MICE WERE TESTED IN THE NAIVE STATE AND AFTER I.PL. INJECTION OF COMPLETE FREUND;S ADJUVANT (CFA) AS AN INFLAMMATORY PAIN MODEL. WE USED THE ELEVATED PLUS MAZE (EPM), THE LIGHT-DARK BOX (LDB) AND THE OPEN FIELD TEST (OF) TO INVESTIGATE ANXIETY-LIKE BEHAVIOR. THE FORCED SWIM TEST (FST) AND MORRIS WATER MAZE (MWM) WERE APPLIED TO ASSESS DEPRESSIVE-LIKE AND LEARNING BEHAVIOR. THE EPM TEST REVEALED NO INTERGROUP DIFFERENCE FOR ANXIETY-LIKE BEHAVIOR IN NAIVE YOUNG AND OLD FABRY KO MICE COMPARED TO WT LITTERMATES, EXCEPT FOR LONGER TIME SPENT IN OPEN ARMS OF THE EPM FOR YOUNG WT MICE COMPARED TO YOUNG FABRY KO MICE (P<0.05). AFTER CFA INJECTION, YOUNG FABRY KO MICE SHOWED INCREASED ANXIETY-LIKE BEHAVIOR COMPARED TO YOUNG WT LITTERMATES (P<0.05) AND NAIVE YOUNG FABRY KO MICE (P<0.05) IN THE EPM AS REFLECTED BY SHORTER TIME SPENT IN EPM OPEN ARMS. THERE WERE NO RELEVANT DIFFERENCES IN THE LDB AND THE OF TEST, EXCEPT FOR LONGER TIME SPENT IN THE CENTER ZONE OF THE OF BY YOUNG WT MICE COMPARED TO YOUNG FABRY KO MICE (P<0.05). COMPLEMENTARY TO THIS, DEPRESSION-LIKE AND LEARNING BEHAVIOR WERE NOT DIFFERENT BETWEEN GENOTYPES AND AGE-GROUPS, EXCEPT FOR THE EXPECTEDLY LOWER MEMORY PERFORMANCE IN OLDER AGE-GROUPS COMPARED TO YOUNG MICE. OUR RESULTS INDICATE THAT GENETIC INFLUENCES ON AFFECTIVE AND COGNITIVE SYMPTOMS IN FD MAY BE OF SUBORDINATE RELEVANCE, DRAWING ATTENTION TO POTENTIAL INFLUENCES OF ENVIRONMENTAL AND EPIGENETIC FACTORS. 2017 2 6413 17 THE STATE OF ART OF REGENERATIVE THERAPY IN CARDIOVASCULAR ISCHEMIC DISEASE: BIOLOGY, SIGNALING PATHWAYS, AND EPIGENETICS OF ENDOTHELIAL PROGENITOR CELLS. ISCHEMIC HEART DISEASE IS CURRENTLY A MAJOR CAUSE OF MORTALITY AND MORBIDITY WORLDWIDE. NEVERTHELESS, THE ACTUAL THERAPEUTIC SCENARIO DOES NOT TARGET MYOCARDIAL CELL REGENERATION AND CONSEQUENTLY, THE PROGRESSION TOWARD THE LATE STAGE OF CHRONIC HEART FAILURE IS COMMON. ENDOTHELIAL PROGENITOR CELLS (EPCS) ARE BONE MARROW-DERIVED STEM CELLS THAT CONTRIBUTE TO THE HOMEOSTASIS OF THE ENDOTHELIAL WALL IN ACUTE AND CHRONIC ISCHEMIC DISEASE. CALCIUM MODULATION AND OTHER MOLECULAR PATHWAYS (NOTCH, VEGFR, AND CXCR4) CONTRIBUTE TO EPC PROLIFERATION AND DIFFERENTIATION. THE PRESENT REVIEW PROVIDES A SUMMARY OF EPC BIOLOGY WITH A PARTICULAR FOCUS ON THE REGULATORY PATHWAYS OF EPCS AND DESCRIBES PROMISING APPLICATIONS FOR CARDIOVASCULAR CELL THERAPY. 2020 3 4292 33 MICRORNA PROFILES OF MATERNAL AND NEONATAL ENDOTHELIAL PROGENITOR CELLS IN PREECLAMPSIA. PREECLAMPSIA IS ASSOCIATED WITH AN INCREASED CARDIOVASCULAR MORBIDITY OF MOTHER AND OFFSPRING, THUS CONTRIBUTING TO A SUBSTANTIAL BURDEN IN WOMEN AND CHILDREN'S HEALTH. IT HAS BEEN PROVEN THAT ENDOTHELIAL PROGENITOR CELL (EPC) NUMBERS AND FUNCTIONAL CHARACTERISTICS ARE IMPAIRED IN CARDIOVASCULAR DISEASE AND PREECLAMPSIA, ALTHOUGH CAUSATIVE FACTORS FOR THE LATTER HAVE REMAINED ELUSIVE. MICRORNA (MIRNA) MODIFICATIONS ARE A POTENTIAL MECHANISM THROUGH WHICH EXPOSURE TO AN ALTERED ENVIRONMENT TRANSLATES INTO THE DEVELOPMENT OF CHRONIC DISEASE. IN THIS STUDY, WE EXAMINED WHETHER DEVELOPMENT OF PREECLAMPSIA CORRESPONDS TO ALTERATIONS OF MIRNAS IN MATERNAL- AND CORD-BLOOD-DERIVED EPC. TO TEST THIS END, WE ANALYZED MATERNAL AND NEONATAL MIRNAS VIA RNA SEQUENCING FROM ENDOTHELIAL CELLS OF PREECLAMPTIC AND HEALTHY CONTROLS IN DIFFERENT CELL CULTURE PASSAGES. WE WERE ABLE TO DEMONSTRATE DIFFERENTIALLY REPRESENTED MIRNAS IN ALL GROUPS. HSA-MIR-1270 SHOWED SIGNIFICANTLY DIFFERENT LEVELS IN CORD BLOOD EPC FROM PREECLAMPSIA VERSUS CONTROL AND WAS NEGATIVELY CORRELATED WITH MRNA LEVELS OF ITS PREDICTED TARGETS ANGPTL7 AND TFRC. TRANSFECTION WITH AN HSA-MIR-1270 INHIBITOR DECREASED THE TUBE FORMATION CAPACITY AND CHEMOTACTIC MOTILITY BUT DID NOT CHANGE PROLIFERATION IN VITRO. TARGET PREDICTIONS AND GENE SET ENRICHMENT ANALYSES IDENTIFIED ALTERNATIVE SPLICING AS A SIGNIFICANTLY ENRICHED PATHWAY FOR HSA-MIR-1270. THE TOP MIRNAS IN THREE OTHER GROUPS WERE PREDICTED TO TARGET TRANSCRIPTIONAL AND DEVELOPMENTAL PATHWAYS. HERE, WE SHOWED FOR THE FIRST TIME SIGNIFICANTLY DIFFERENT LEVELS OF MIRNAS AND DIFFERENTLY REPRESENTED MRNA LEVELS OF PREDICTED TARGET GENES IN EPC DERIVED FROM PREECLAMPSIA. UNDERSTANDING THE EFFECTS OF PREECLAMPSIA ON THE EPIGENETIC MECHANISMS OF EPC WILL BE CRUCIAL AND MAY PROVIDE INITIAL INSIGHTS FOR FURTHER EVALUATION OF THE BENEFITS OF THERAPIES TARGETING THIS CELL POPULATION. 2021 4 998 39 CHRONIC SUBCONVULSIVE ACTIVITY DURING EARLY POSTNATAL LIFE PRODUCES AUTISTIC BEHAVIOR IN THE ABSENCE OF NEUROTOXICITY IN THE JUVENILE WEANLING PERIOD. THE DIAGNOSIS OF AUTISM SPECTRUM DISORDER (ASD) VARIES FROM VERY MILD TO SEVERE SOCIAL AND COGNITIVE IMPAIRMENTS. WE HYPOTHESIZED THAT EPIGENETIC SUBCONVULSIVE ACTIVITY IN EARLY POSTNATAL LIFE MAY CONTRIBUTE TO THE DEVELOPMENT OF AUTISTIC BEHAVIOR IN A SEX-RELATED MANNER. LOW DOSES OF KAINIC ACID (KA) (25-100 MUG) WERE ADMINISTERED TO RAT PUPS FOR 15 DAYS BEGINNING ON POSTNATAL (P) DAY 6 TO CHRONICALLY ELEVATE NEURONAL ACTIVITY. A BATTERY OF CLASSICAL AND NOVEL BEHAVIORAL TESTS WAS USED, AND SEX DIFFERENCES WERE OBSERVED. OUR NOVEL OPEN HANDLING TEST REVEALED THAT ASD MALES NOSE POKED MORE OFTEN AND ASD FEMALES CLIMBED AND ESCAPED MORE FREQUENTLY WITH AGE. IN THE SOCIAL INTERACTION TEST, ASD MALES WERE LESS SOCIAL THAN ASD FEMALES WHO WERE MORE ANXIOUS IN HANDLING AND ELEVATED PLUS MAZE (EPM) TASKS. TO EVALUATE GROUP DYNAMICS, SIBLING AND NON-SIBLING CONTROL AND EXPERIMENTAL ANIMALS EXPLORED 3 DIFFERENT SHAPED NOVEL SOCIAL ENVIRONMENTS. CONTROL PUPS HUDDLED QUICKLY AND MORE FREQUENTLY IN ALL ENVIRONMENTS WHETHER THEY SOCIALIZED WITH LITTERMATES OR NON-SIBLINGS COMPARED TO ASD GROUPS. NON-SIBLING ASD PUPS WERE ERRATIC AND HUDDLED IN SMALLER GROUPS. IN THE OBJECT RECOGNITION TEST, ONLY ASD MALES SPENT LESS TIME WITH THE NOVEL OBJECT COMPARED TO CONTROL PUPS. DATA SUGGEST THAT CHRONIC SUBCONVULSIVE ACTIVITY IN EARLY POSTNATAL LIFE LEADS TO AN ASD PHENOTYPE IN THE ABSENCE OF CELL DEATH. MALES WERE MORE SUSCEPTIBLE TO DEVELOPING ASOCIAL BEHAVIORS AND COGNITIVE PATHOLOGIES, WHEREAS FEMALES WERE PRONE TO HIGHER LEVELS OF HYPERACTIVITY AND ANXIETY, VALIDATING OUR POSTNATAL ASD MODEL APPARENT IN THE PRE-JUVENILE PERIOD. 2019 5 1708 30 DYSFUNCTION OF ENDOTHELIAL PROGENITOR CELLS FROM SMOKERS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS DUE TO INCREASED DNA DAMAGE AND SENESCENCE. CARDIOVASCULAR DISEASE (CVD) IS A MAJOR CAUSE OF DEATH IN SMOKERS, PARTICULARLY IN THOSE WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). CIRCULATING ENDOTHELIAL PROGENITOR CELLS (EPC) ARE REQUIRED FOR ENDOTHELIAL HOMEOSTASIS, AND THEIR DYSFUNCTION CONTRIBUTES TO CVD. TO INVESTIGATE EPC DYSFUNCTION IN SMOKERS, WE ISOLATED AND EXPANDED BLOOD OUTGROWTH ENDOTHELIAL CELLS (BOEC) FROM PERIPHERAL BLOOD SAMPLES FROM HEALTHY NONSMOKERS, HEALTHY SMOKERS, AND COPD PATIENTS. BOEC FROM SMOKERS AND COPD PATIENTS SHOWED INCREASED DNA DOUBLE-STRAND BREAKS AND SENESCENCE COMPARED TO NONSMOKERS. SENESCENCE NEGATIVELY CORRELATED WITH THE EXPRESSION AND ACTIVITY OF SIRTUIN-1 (SIRT1), A PROTEIN DEACETYLASE THAT PROTECTS AGAINST DNA DAMAGE AND CELLULAR SENESCENCE. INHIBITION OF DNA DAMAGE RESPONSE BY SILENCING OF ATAXIA TELANGIECTASIA MUTATED (ATM) KINASE RESULTED IN UPREGULATION OF SIRT1 EXPRESSION AND DECREASED SENESCENCE. TREATMENT OF BOEC FROM COPD PATIENTS WITH THE SIRT1 ACTIVATOR RESVERATROL OR AN ATM INHIBITOR (KU-55933) ALSO RESCUED THE SENESCENT PHENOTYPE. USING AN IN VIVO MOUSE MODEL OF ANGIOGENESIS, WE DEMONSTRATED THAT SENESCENT BOEC FROM COPD PATIENTS ARE DYSFUNCTIONAL, DISPLAYING IMPAIRED ANGIOGENIC ABILITY AND INCREASED APOPTOSIS COMPARED TO CELLS FROM HEALTHY NONSMOKERS. THEREFORE, THIS STUDY IDENTIFIES EPIGENETIC REGULATION OF DNA DAMAGE AND SENESCENCE AS PATHOGENETIC MECHANISMS LINKED TO ENDOTHELIAL PROGENITORS' DYSFUNCTION IN SMOKERS AND COPD PATIENTS. THESE DEFECTS MAY CONTRIBUTE TO VASCULAR DISEASE AND CARDIOVASCULAR EVENTS IN SMOKERS AND COULD THEREFORE CONSTITUTE THERAPEUTIC TARGETS FOR INTERVENTION. 2013 6 3205 32 HDAC8, A POTENTIAL THERAPEUTIC TARGET, REGULATES PROLIFERATION AND DIFFERENTIATION OF BONE MARROW STROMAL CELLS IN FIBROUS DYSPLASIA. FIBROUS DYSPLASIA (FD) IS A DISEASE OF POSTNATAL SKELETAL STEM CELLS CAUSED BY ACTIVATING MUTATIONS OF GUANINE NUCLEOTIDE-BINDING PROTEIN ALPHA-STIMULATING ACTIVITY POLYPEPTIDE (GNAS). FD IS CHARACTERIZED BY HIGH PROLIFERATION AND OSTEOGENESIS DISORDER OF BONE MARROW STROMAL CELLS (BMSCS), RESULTING IN BONE PAIN, DEFORMITIES, AND FRACTURES. THE CAMP-CREB PATHWAY, WHICH IS ACTIVATED BY GNAS MUTATIONS, IS KNOWN TO BE CLOSELY ASSOCIATED WITH THE OCCURRENCE OF FD. HOWEVER, SO FAR THERE IS NO AVAILABLE TARGETED THERAPEUTIC STRATEGY FOR FD, AS A CRITICAL ISSUE THAT REMAINS LARGELY UNKNOWN IS HOW THIS PATHWAY IS INVOLVED IN FD. OUR PREVIOUS STUDY REVEALED THAT HISTONE DEACETYLASE 8 (HDAC8) INHIBITED THE OSTEOGENIC DIFFERENTIATION OF BMSCS VIA EPIGENETIC REGULATION. HERE, COMPARED WITH NORMAL BMSCS, FD BMSCS EXHIBITED SIGNIFICANTLY HIGH PROLIFERATION AND WEAK OSTEOGENIC CAPACITY IN RESPONSE TO HDAC8 UPREGULATION AND TUMOR PROTEIN 53 (TP53) DOWNREGULATION. MOREOVER, INHIBITION OF CAMP REDUCED HDAC8 EXPRESSION, INCREASED TP53 EXPRESSION AND RESULTED IN THE IMPROVEMENT OF FD PHENOTYPE. IMPORTANTLY, HDAC8 INHIBITION PREVENTED CAMP-INDUCED CELL PHENOTYPE AND PROMOTED OSTEOGENESIS IN NUDE MICE THAT WERE IMPLANTED WITH FD BMSCS. MECHANISTICALLY, HDAC8 WAS IDENTIFIED AS A TRANSCRIPTIONAL TARGET GENE OF CREB1 AND ITS TRANSCRIPTION WAS DIRECTLY ACTIVATED BY CREB1 IN FD BMSCS. IN SUMMARY, OUR STUDY REVEALS THAT HDAC8 ASSOCIATES WITH FD PHENOTYPE AND DEMONSTRATES THE MECHANISMS REGULATED BY CAMP-CREB1-HDAC8 PATHWAY. THESE RESULTS PROVIDE INSIGHTS INTO THE MOLECULAR REGULATION OF FD PATHOGENESIS, AND OFFER NOVEL CLUES THAT SMALL MOLECULE INHIBITORS TARGETING HDAC8 ARE PROMISING CLINICAL TREATMENT FOR FD. STEM CELLS TRANSLATIONAL MEDICINE 2019;8:148&14. 2019 7 3517 33 IFNG/IFNG-AS1 EXPRESSION LEVEL BALANCE: IMPLICATIONS FOR AUTISM SPECTRUM DISORDER. AUTISM SPECTRUM DISORDER (ASD) IS A NEURODEVELOPMENTAL DISORDER ASSOCIATED WITH DIFFERENT EPIDEMIOLOGICAL, GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. ALTHOUGH ITS ETIOLOGY IS NOT FULLY UNDERSTOOD, IMMUNE DYSFUNCTION IS IMPLICATED IN THIS DISEASE. RECENTLY, A LARGE NUMBER OF GENES ENCODING LONG NONCODING RNAS (LNCRNAS) WERE DISCOVERED WHICH ACT AS POSITIVE OR NEGATIVE REGULATORS OF NEIGHBORING TARGET GENES. THE LNCRNA, INTERFERON GAMMA-ANTISENSE RNA (IFNG-AS1), REGULATES EXPRESSION LEVELS OF THE INTERFERON GAMMA (IFNG) GENE. IN THE PRESENT STUDY, WE INVESTIGATED EXPRESSION OF IFNG AND IFNG-AS1 IN 50 CHILDREN WITH ASD (15 FEMALES AND 35 MALES, MEAN AGE: 6 +/- 1.4 YEARS) AND 50 HEALTHY CONTROLS (14 FEMALES AND 36 MALES, MEAN AGE: 6 +/- 1.74 YEARS) BY REAL TIME PCR TECHNIQUE. THE RESULTS SHOWED SIGNIFICANT UP-REGULATION OF IFNG AND DOWN-REGULATION OF IFNG-AS1 EXPRESSION IN CHILDREN WITH ASD COMPARED TO CONTROLS (FOLD CHANGE = 1.5, P < 0.0001; FOLD CHANGE = -0.143, P = 0.013, RESPECTIVELY). THE IFNG EXPRESSION LEVEL INCREASE WAS MORE PRONOUNCED IN MALE ASD CHILDREN (FOLD CHANGE = 1.621; P < 0.0001). OUR DATA REVEAL A FUNCTIONAL DISRUPTION IN THE INTERACTIVE NETWORK OF IFNG/IFNG-AS1 REGULATION, WHICH COULD BE A CONTRIBUTING FACTOR IN THE CHRONIC INFLAMMATORY ASPECT OF ASD. OUR FINDINGS CAN HELP UNDERSTANDING THE UNDERLYING CONTRIBUTORS TO ASD PATHOGENESIS AND FIND NOVEL TREATMENT OPTIONS FOR CHILDREN WITH ASD. 2020 8 5334 22 QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EPIGENETIC PROFILE IN ADVANCED COPD. EPIGENETIC MECHANISMS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE DYSFUNCTION AND ATROPHY. WE ASSESSED WHETHER QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EXPRESSION PROFILE OF EPIGENETIC EVENTS IN PATIENTS WITH ADVANCED COPD (CHRONIC OBSTRUCTIVE PULMONARY DISEASE). IN VASTUS LATERALIS (VL) OF SEDENTARY SEVERE COPD PATIENTS (N=41), WHO WERE FURTHER SUBDIVIDED INTO THOSE WITH (N=25) AND WITHOUT (N=16) MUSCLE WEAKNESS AND HEALTHY CONTROLS (N=19), EXPRESSION OF MUSCLE-ENRICHED MIRNAS, HISTONE ACETYLTRANSFERASES (HATS) AND DEACETYLASES (HDACS), GROWTH AND ATROPHY SIGNALLING MARKERS, TOTAL PROTEIN AND HISTONE ACETYLATION, TRANSCRIPTION FACTORS, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED WITH CONTROLS, IN VL OF ALL COPD TOGETHER AND IN MUSCLE-WEAKNESS PATIENTS, EXPRESSION OF MIR-1, MIR-206 AND MIR-27A, LEVELS OF LYSINE-ACETYLATED PROTEINS AND HISTONES AND ACETYLATED HISTONE 3 WERE INCREASED, WHEREAS EXPRESSION OF HDAC3, HDAC4, SIRTUIN-1 (SIRT-1), IGF-1 (INSULIN-LIKE GROWTH FACTOR-1) WERE DECREASED, AKT (V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOGUE 1) EXPRESSION DID NOT DIFFER, FOLLISTATIN EXPRESSION WAS GREATER, WHEREAS MYOSTATIN EXPRESSION WAS LOWER, SERUM REPONSE FACTOR (SRF) EXPRESSION WAS INCREASED AND FIBRE SIZE OF FAST-TWITCH FIBRES WAS SIGNIFICANTLY REDUCED. IN VL OF SEVERE COPD PATIENTS WITH MUSCLE WEAKNESS AND ATROPHY, EPIGENETIC EVENTS REGULATE MUSCLE DIFFERENTIATION RATHER THAN PROLIFERATION AND MUSCLE GROWTH AND ATROPHY SIGNALLING, PROBABLY AS FEEDBACK MECHANISMS TO PREVENT THOSE MUSCLES FROM UNDERGOING FURTHER ATROPHY. LYSINE-HYPERACETYLATION OF HISTONES MAY DRIVE ENHANCED PROTEIN CATABOLISM IN THOSE MUSCLES. THESE FINDINGS MAY HELP DESIGN NOVEL THERAPEUTIC STRATEGIES (ENHANCERS OF MIRNAS PROMOTING MYOGENESIS AND ACETYLATION INHIBITORS) TO SELECTIVELY TARGET MUSCLE WEAKNESS AND ATROPHY IN SEVERE COPD. 2015 9 1633 30 DO EPIGENETIC EVENTS TAKE PLACE IN THE VASTUS LATERALIS OF PATIENTS WITH MILD CHRONIC OBSTRUCTIVE PULMONARY DISEASE? MUSCLE DYSFUNCTION IS A MAJOR COMORBIDITY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SEVERAL BIOLOGICAL MECHANISMS INCLUDING EPIGENETIC EVENTS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE ATROPHY. INVESTIGATIONS CONDUCTED SO FAR HAVE FOCUSED ON THE ELUCIDATION OF BIOLOGICAL MECHANISMS INVOLVED IN MUSCLE DYSFUNCTION IN ADVANCED COPD. WE ASSESSED WHETHER THE EPIGENETIC PROFILE MAY BE ALTERED IN THE VASTUS LATERALIS OF PATIENTS WITH MILD COPD, NORMAL BODY COMPOSITION, AND MILDLY IMPAIRED MUSCLE FUNCTION AND EXERCISE CAPACITY. IN VASTUS LATERALIS (VL) OF MILD COPD PATIENTS WITH WELL-PRESERVED BODY COMPOSITION AND IN HEALTHY AGE-MATCHED CONTROLS, EXPRESSION OF DNA METHYLATION, MUSCLE-ENRICHED MICRORNAS, HISTONE ACETYLTRANSFERASES (HTAS) AND DEACETYLASES (HDACS), PROTEIN ACETYLATION, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES, AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED TO HEALTHY CONTROLS, IN THE VL OF MILD COPD PATIENTS, MUSCLE FUNCTION AND EXERCISE CAPACITY WERE MODERATELY REDUCED, DNA METHYLATION LEVELS DID NOT DIFFER, MIR-1 EXPRESSION LEVELS WERE INCREASED AND POSITIVELY CORRELATED WITH BOTH FORCED EXPIRATORY VOLUME IN ONE SECOND (FEV1) AND QUADRICEPS FORCE, HDAC4 PROTEIN LEVELS WERE INCREASED, AND MUSCLE FIBER TYPES AND SIZES WERE NOT DIFFERENT. MODERATE SKELETAL MUSCLE DYSFUNCTION IS A RELEVANT FEATURE IN PATIENTS WITH MILD COPD AND PRESERVED BODY COMPOSITION. SEVERAL EPIGENETIC EVENTS ARE DIFFERENTIALLY EXPRESSED IN THE LIMB MUSCLES OF THESE PATIENTS, PROBABLY AS AN ATTEMPT TO COUNTERBALANCE THE UNDERLYING MECHANISMS THAT ALTER MUSCLE FUNCTION AND MASS. THE STUDY OF PATIENTS AT EARLY STAGES OF THEIR DISEASE IS OF INTEREST AS THEY ARE A TARGET FOR TIMELY THERAPEUTIC INTERVENTIONS THAT MAY SLOW DOWN THE COURSE OF THE DISEASE AND PREVENT THE DELETERIOUS EFFECTS OF MAJOR COMORBIDITIES. 2014 10 509 26 ASSOCIATION OF NUTRACEUTICAL SUPPLEMENTS WITH LONGER TELOMERE LENGTH. TELOMERES ARE NUCLEOTIDE TANDEM REPEATS LOCATED AT THE TIP OF EUKARYOTIC CHROMOSOMES THAT MAINTAIN GENOMIC INTEGRITY. THE GRADUAL SHORTENING OF TELOMERES LEADS TO CELLULAR SENESCENCE AND APOPTOSIS, A KEY MECHANISM OF AGING AND AGE?RELATED CHRONIC DISEASES. EPIGENETIC FACTORS, SUCH AS NUTRITION, EXERCISE AND TOBACCO CAN AFFECT THE RATE AT WHICH TELOMERES SHORTEN AND CAN MODIFY THE RISK OF DEVELOPING CHRONIC DISEASES. IN THIS STUDY, WE EVALUATED THE EFFECTS OF A COMBINATION OF NUTRACEUTICAL SUPPLEMENTS (NS) ON TELOMERE LENGTH (TL) IN HEALTHY VOLUNTEERS WITH NO MEDICAL HISTORY OF ANY DISEASE. PARTICIPANTS (N=47) WERE SELECTED FROM HEALTHY OUTPATIENTS VISITING A PRIVATE CLINIC AND WERE DIVIDED INTO THE EXPERIMENTAL GROUP (N=16), THAT RECEIVED THE NS AND THE CONTROL GROUP (N=31). WE ESTIMATED THE LENGTH OF SINGLE TELOMERES IN METAPHASE SPREAD LEUKOCYTES, ISOLATED FROM PERIPHERAL BLOOD, USING QUANTITATIVE?FLUORESCENT IN SITU HYBRIDIZATION (Q?FISH) ANALYSIS. THE LENGTH OF THE WHOLE TELOMERE GENOME WAS SIGNIFICANTLY INCREASED (P<0.05) FOR THE MEAN, 1ST QUARTILE AND MEDIAN MEASUREMENTS IN THE EXPERIMENTAL GROUP. SIMILAR FINDINGS WERE OBSERVED FOR SHORT TL (20TH PERCENTILE) (P<0.05) FOR THE MEDIAN AND 3RD QUARTILE MEASUREMENTS IN THE NS GROUP, COMPARED TO THE CONTROL GROUP. THE BENEFICIAL EFFECTS OF THE SUPPLEMENTS ON THE LENGTH OF SHORT TELOMERES REMAINED SIGNIFICANT (P<0.05) FOLLOWING ADJUSTMENT FOR AGE AND SEX. TELOMERES WERE MODERATELY LONGER IN FEMALE PATIENTS COMPARED TO THE MALE PATIENTS. ON THE WHOLE, THE FINDINGS OF THIS STUDY SUGGEST THAT THE ADMINISTRATION OF NS MAY BE LINKED TO SUSTAINING THE TL. 2019 11 2051 28 EPIGENETIC CONDITIONING INDUCES INTERGENERATIONAL RESILIENCE TO DEMENTIA IN A MOUSE MODEL OF VASCULAR COGNITIVE IMPAIRMENT. INTRODUCTION: EPIGENETIC STIMULI INDUCE BENEFICIAL OR DETRIMENTAL CHANGES IN GENE EXPRESSION, AND CONSEQUENTLY, PHENOTYPE. SOME OF THESE PHENOTYPES CAN MANIFEST ACROSS THE LIFESPAN-AND EVEN IN SUBSEQUENT GENERATIONS. HERE, WE USED A MOUSE MODEL OF VASCULAR COGNITIVE IMPAIRMENT AND DEMENTIA (VCID) TO DETERMINE WHETHER EPIGENETICALLY INDUCED RESILIENCE TO SPECIFIC DEMENTIA-RELATED PHENOTYPES IS HERITABLE BY FIRST-GENERATION PROGENY. METHODS: OUR SYSTEMIC EPIGENETIC THERAPY CONSISTED OF 2 MONTHS OF REPETITIVE HYPOXIC "CONDITIONING" (RHC) PRIOR TO CHRONIC CEREBRAL HYPOPERFUSION IN ADULT C57BL/6J MICE. RESULTANT CHANGES IN OBJECT RECOGNITION MEMORY AND HIPPOCAMPAL LONG-TERM POTENTIATION (LTP) WERE ASSESSED 3 AND 4 MONTHS LATER, RESPECTIVELY. RESULTS: HYPOPERFUSION-INDUCED MEMORY/PLASTICITY DEFICITS WERE ABROGATED BY RHC. MOREOVER, SIMILARLY ROBUST DEMENTIA RESILIENCE WAS DOCUMENTED IN UNTREATED CEREBRAL HYPOPERFUSED ANIMALS DERIVED FROM RHC-TREATED PARENTS. CONCLUSIONS: OUR RESULTS IN EXPERIMENTAL VCID UNDERSCORE THE EFFICACY OF EPIGENETICS-BASED TREATMENTS TO PREVENT MEMORY LOSS, AND DEMONSTRATE FOR THE FIRST TIME THE HERITABILITY OF AN INDUCED RESILIENCE TO DEMENTIA. 2022 12 5768 30 SPECIFIC ALTERATIONS IN THE CIRCULATING LEVELS OF THE SIRT1, TLR4, AND IL7 PROTEINS IN PATIENTS WITH DEMENTIA. SIRTUINS HAVE GAINED CONSIDERABLE ATTENTION AS EPIGENETIC REGULATORS FOR SLOWING AGING AND AGE-RELATED DISORDERS. THE GROWING ASSOCIATION BETWEEN NEURODEGENERATION AND INFLAMMATION HAS LED RESEARCHERS TO INVESTIGATE INTERACTIONS OF SIRTUINS WITH INFLAMMATORY MARKERS IN NEURODEGENERATIVE DISEASES. WE ANALYZED SIRT1'S ASSOCIATION WITH CHRONIC INFLAMMATION IN DEMENTIA AS AN AGE-RELATED NEURODEGENERATIVE CONDITION THROUGH TOLL-LIKE RECEPTOR 4 (TLR4) AND INTERLEUKIN-7 (IL7) FOR THE FIRST TIME. IN THE PRESENT STUDY, WE OBSERVED A SIGNIFICANT INCREASE IN THE LEVEL OF SIRT1 IN PATIENTS WITH ALL TYPES OF DEMENTIA. INTERESTINGLY, THE LEVEL OF TLR4 PROTEIN WAS SIGNIFICANTLY LOWER IN ONLY THE PATIENTS WITH ALZHEIMER'S DISEASE (AD) COMPARED TO THE HEALTHY ELDERLY SUBJECTS. THERE WAS NO SIGNIFICANT CHANGE IN THE LEVEL OF IL7 BETWEEN THE DISEASED AND HEALTHY ELDERLY SUBJECTS. A SIGNIFICANT POSITIVE CORRELATION BETWEEN SIRT1 LEVEL AND AGE IN HEALTHY ELDERLY SUBJECTS WAS EVIDENT ACCORDING TO PEARSON'S CORRELATION TEST. HOWEVER, THIS CORRELATION WAS NOT OBSERVED IN THE DEMENTIA PATIENTS. FURTHERMORE, THE POSITIVE CORRELATION BETWEEN THE LEVELS OF IL7 AND TLR4 IN THE HEALTHY ELDERLY SUBJECTS WAS ABSENT IN THE DEMENTIA PATIENTS. HOWEVER, THERE WAS NO DIRECT ASSOCIATION BETWEEN THE EXAMINED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AND DEMENTIA AT THE MOLECULAR LEVEL. ACCORDING TO LOGISTIC REGRESSION ANALYSIS, DEMENTIA RISK INCREASES 1.16 TIMES DUE TO AN INCREASE IN THE SIRT1 LEVEL AND 24.23 TIMES DUE TO A DECREASE IN THE TLR4 LEVEL. INTERESTINGLY, A HIGH LEVEL IN THE TOTAL ANTIOXIDANT STATUS (TAS) INCREASES THE RISK OF DEMENTIA APPROXIMATELY 33.32 TIMES. THEREFORE, THE CURRENT STUDY, FOR THE FIRST TIME, PROVIDES A MUCH BETTER MOLECULAR UNDERSTANDING OF THE INTERACTION BETWEEN DECREASING TLR4 LEVELS AND INCREASING SIRT1 LEVELS IN DEMENTIA, ESPECIALLY IN AD. FURTHERMORE, IT HIGHLIGHTS THE IMPORTANCE OF EPIGENETICS IN SEVERAL AGE-RELATED DISEASES AND SUGGESTS THAT DEVELOPING NOVEL THERAPIES TO PREVENT OR SLOW DOWN THE PROGRESSION OF DEMENTIA MAY SUPPORT HEALTHY AGING. 2018 13 1785 25 EFFECT OF APABETALONE ON CARDIOVASCULAR EVENTS IN DIABETES, CKD, AND RECENT ACUTE CORONARY SYNDROME: RESULTS FROM THE BETONMACE RANDOMIZED CONTROLLED TRIAL. BACKGROUND AND OBJECTIVES: CKD AND TYPE 2 DIABETES MELLITUS INTERACT TO INCREASE THE RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (I.E., CARDIOVASCULAR DEATH, NONFATAL MYOCARDIAL INFARCTION, OR STROKE) AND CONGESTIVE HEART FAILURE. A MALADAPTIVE EPIGENETIC RESPONSE MAY BE A CARDIOVASCULAR RISK DRIVER AND AMENABLE TO MODIFICATION WITH APABETALONE, A SELECTIVE MODULATOR OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN TRANSCRIPTION SYSTEM. WE EXAMINED THIS QUESTION IN A PRESPECIFIED ANALYSIS OF BETONMACE, A PHASE 3 TRIAL. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BETONMACE WAS AN EVENT-DRIVEN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING EFFECTS OF APABETALONE VERSUS PLACEBO ON MAJOR ADVERSE CARDIOVASCULAR EVENTS AND HEART FAILURE HOSPITALIZATIONS IN 2425 PARTICIPANTS WITH TYPE 2 DIABETES AND A RECENT ACUTE CORONARY SYNDROME, INCLUDING 288 PARTICIPANTS WITH CKD WITH EGFR <60 ML/MIN PER 1.73 M(2) AT BASELINE. THE PRIMARY END POINT IN BETONMACE WAS THE TIME TO THE FIRST MAJOR ADVERSE CARDIOVASCULAR EVENT, WITH A SECONDARY END POINT OF TIME TO HOSPITALIZATION FOR HEART FAILURE. RESULTS: MEDIAN FOLLOW-UP WAS 27 MONTHS (INTERQUARTILE RANGE, 20-32 MONTHS). IN PARTICIPANTS WITH CKD, APABETALONE COMPARED WITH PLACEBO WAS ASSOCIATED WITH FEWER MAJOR ADVERSE CARDIOVASCULAR EVENTS (13 EVENTS IN 124 PATIENTS [11%] VERSUS 35 EVENTS IN 164 PATIENTS [21%]; HAZARD RATIO, 0.50; 95% CONFIDENCE INTERVAL, 0.26 TO 0.96) AND FEWER HEART FAILURE-RELATED HOSPITALIZATIONS (THREE HOSPITALIZATIONS IN 124 PATIENTS [3%] VERSUS 14 HOSPITALIZATIONS IN 164 PATIENTS [9%]; HAZARD RATIO, 0.48; 95% CONFIDENCE INTERVAL, 0.26 TO 0.86). IN THE NON-CKD GROUP, THE CORRESPONDING HAZARD RATIO VALUES WERE 0.96 (95% CONFIDENCE INTERVAL, 0.74 TO 1.24) FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND 0.76 (95% CONFIDENCE INTERVAL, 0.46 TO 1.27) FOR HEART FAILURE-RELATED HOSPITALIZATION. INTERACTION OF CKD ON TREATMENT EFFECT WAS P=0.03 FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND P=0.12 FOR HEART FAILURE-RELATED HOSPITALIZATION. PARTICIPANTS WITH CKD SHOWED SIMILAR NUMBERS OF ADVERSE EVENTS, REGARDLESS OF RANDOMIZATION TO APABETALONE OR PLACEBO (119 [73%] VERSUS 88 [71%] PATIENTS), AND THERE WERE FEWER SERIOUS ADVERSE EVENTS (29% VERSUS 43%; P=0.02) IN THE APABETALONE GROUP. CONCLUSIONS: APABETALONE MAY REDUCE THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH CKD AND TYPE 2 DIABETES WHO HAVE A HIGH BURDEN OF CARDIOVASCULAR DISEASE. 2021 14 4092 32 MATERNAL REPETITIVE HYPOXIA PRIOR TO MATING CONFERS EPIGENETIC RESILIENCE TO MEMORY IMPAIRMENT IN MALE PROGENY. WE SHOWED PREVIOUSLY IN A MOUSE MODEL OF VASCULAR COGNITIVE IMPAIRMENT AND DEMENTIA INVOLVING CHRONIC CEREBRAL HYPOPERFUSION (CCH) THAT REPETITIVE HYPOXIC CONDITIONING (RHC) OF BOTH PARENTS RESULTS IN THE EPIGENETIC, INTERGENERATIONAL TRANSMISSION OF RESILIENCE TO RECOGNITION MEMORY LOSS IN ADULT PROGENY, AS ASSESSED BY THE NOVEL OBJECT RECOGNITION TEST. THE PRESENT STUDY WAS UNDERTAKEN IN THE SAME MODEL TO DETERMINE WHETHER RHC TREATMENT OF ONE OR BOTH PARENTS IS REQUIRED TO CONFER DEMENTIA RESILIENCE INTERGENERATIONALLY. WE FOUND INHERITED RESILIENCE TO 3 MONTHS OF CCH IN MALES IS MATERNALLY MEDIATED (P = .006). STATISTICALLY, WE OBSERVED A STRONG TREND FOR THE PATERNAL GERMLINE TO CONTRIBUTE AS WELL (P = .052). WE ALSO FOUND THAT, IN CONTRAST TO WHAT IS WIDELY OBSERVED IN MALES, FEMALES DISPLAY INTACT RECOGNITION MEMORY (P = .001) AFTER 3 MONTHS OF CCH, REVEALING A HERETOFORE UNIDENTIFIED SEXUAL DIMORPHISM WITH RESPECT TO COGNITIVE IMPACT DURING DISEASE PROGRESSION. OVERALL, RESULTS OF OUR STUDY STRONGLY IMPLICATE EPIGENETIC CHANGES IN MATERNAL GERM CELLS, INDUCED BY OUR REPETITIVE SYSTEMIC HYPOXIC STIMULUS, CONTRIBUTING TO A MODIFIED DIFFERENTIATION PROGRAM CAPABLE OF ESTABLISHING A DEMENTIA-RESILIENT PHENOTYPE IN ADULT MALE FIRST-GENERATION PROGENY. (PSYCINFO DATABASE RECORD (C) 2023 APA, ALL RIGHTS RESERVED). 2023 15 6312 29 THE RELATIONSHIP BETWEEN CEREBRAL SMALL VESSEL DISEASE, HIPPOCAMPAL VOLUME AND COGNITIVE FUNCTIONING IN PATIENTS WITH COPD: AN MRI STUDY. THE NEURAL CORRELATES OF COGNITIVE IMPAIRMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE NOT YET UNDERSTOOD. STRUCTURAL BRAIN ABNORMALITIES COULD POSSIBLY BE ASSOCIATED WITH THE PRESENCE OF COGNITIVE IMPAIRMENT THROUGH CIGARETTE SMOKE, INFLAMMATION, VASCULAR DISEASE, OR HYPOXEMIA IN THESE PATIENTS. THIS STUDY AIMED TO INVESTIGATE WHETHER MACROSTRUCTURAL BRAIN MAGNETIC RESONANCE IMAGING (MRI) FEATURES OF CEREBRAL SMALL VESSEL DISEASE (SVD) AND HIPPOCAMPAL VOLUME (HCV) ARE RELATED TO COGNITIVE PERFORMANCE IN PATIENTS WITH COPD. A SUBGROUP OF COGNITIVELY HIGH AND LOW-PERFORMING COPD PATIENTS OF THE COGNITIVE-PD STUDY, UNDERWENT A BRAIN 3T MRI. SVD AS A MARKER OF VASCULAR DAMAGE WAS ASSESSED USING QUALITATIVE VISUAL RATING SCALES. HCV AS A MARKER OF NEURODEGENERATION WAS ASSESSED USING THE LEARNING EMBEDDING FOR ATLAS PROPAGATION (LEAP) METHOD. FEATURES OF SVD AND HCV WERE COMPARED BETWEEN COGNITIVELY HIGH AND LOW-PERFORMING INDIVIDUALS USING MANN WHITNEY U TESTS AND INDEPENDENT SAMPLES T-TESTS, RESPECTIVELY. NO GROUP DIFFERENCES WERE REPORTED BETWEEN 25 HIGH-PERFORMING (MEAN AGE 60.3 (STANDARD DEVIATION [SD] 9.7) YEARS; 40.0% MEN; FORCED EXPIRATORY VOLUME IN FIRST SECOND [FEV(1)] 50.1% PREDICTED) AND 30 LOW-PERFORMING PATIENTS WITH COPD (MEAN AGE 60.6 (SD 6.8) YEARS; 53.3% MEN; FEV(1) 55.6% PREDICTED) REGARDING DEMOGRAPHICS, CLINICAL CHARACTERISTICS, COMORBIDITIES AND THE PRESENCE OF THE SVD FEATURES AND HCV. TO CONCLUDE, THE CURRENT STUDY DOES NOT PROVIDE EVIDENCE FOR A RELATIONSHIP BETWEEN CEREBRAL SVD AND HCV AND COGNITIVE FUNCTIONING IN PATIENTS WITH COPD. ADDITIONAL STUDIES WILL BE NEEDED TO DETERMINE OTHER POSSIBLE MECHANISMS OF COGNITIVE IMPAIRMENT IN PATIENTS WITH COPD, INCLUDING MICROSTRUCTURAL BRAIN CHANGES AND INFLAMMATORY-, HORMONAL-, METABOLIC- AND (EPI)GENETIC FACTORS. 2017 16 5186 26 PREMATURITY IN MICE LEADS TO REDUCTION IN NEPHRON NUMBER, HYPERTENSION, AND PROTEINURIA. THE NEPHRON NUMBER AT BIRTH IS A QUANTITATIVE TRAIT THAT CORRELATES INVERSELY WITH THE RISK OF HYPERTENSION AND CHRONIC KIDNEY DISEASE LATER IN LIFE. DURING KIDNEY DEVELOPMENT, THE NEPHRON NUMBER IS CONTROLLED BY MULTIPLE FACTORS INCLUDING GENETIC, EPIGENETIC, AND ENVIRONMENTAL MODIFIERS. PREMATURE BIRTH, WHICH REPRESENTS MORE THAN 12% OF ANNUAL LIVE BIRTHS IN THE UNITED STATES, HAS BEEN LINKED TO LOW NEPHRON NUMBER AND THE DEVELOPMENT OF HYPERTENSION LATER IN LIFE. IN THIS REPORT, WE DESCRIBE THE DEVELOPMENT OF A MOUSE MODEL OF PREMATURITY-INDUCED REDUCTION OF NEPHRON NUMBER. PREMATURE MICE, DELIVERED 1 AND 2 DAYS EARLY, HAVE 17.4 +/- 2.3% (N = 6) AND 23.6 +/- 2% (N = 10) FEWER NEPHRONS, RESPECTIVELY, WHEN COMPARED WITH FULL-TERM ANIMALS (12,252 +/- 571 NEPHRONS/KIDNEY, N = 10). AFTER 5 WEEKS OF AGE, THE MICE DELIVERED 2 DAYS PREMATURE SHOW LOWER REAL-TIME GLOMERULAR FILTRATION RATE (GFR, 283 +/- 13 VS 389 +/- 26 MUL/MIN). THE PREMATURE MICE ALSO DEVELOP HYPERTENSION (MEAN ARTERIAL PRESSURE [MAP], 134 +/- 18 VS 120 +/- 14 MM HG) AND ALBUMINURIA (286 +/- 83 VS 176 +/- 59 MUG ALBUMIN/MG CREATININE). THIS MOUSE MODEL PROVIDES A PROOF OF CONCEPT THAT PREMATURITY LEADS TO REDUCED NEPHRON NUMBER AND HYPERTENSION, AND THIS MODEL WILL BE USEFUL IN STUDYING THE PATHOPHYSIOLOGY OF PREMATURITY-INDUCED NEPHRON NUMBER REDUCTIONS AND HYPERTENSION. 2012 17 517 29 ASSOCIATION STUDY OF FOXO3A SINGLE-NUCLEOTIDE POLYMORPHISM AND BRONCHIAL ASTHMA IN EGYPTIAN CHILDREN. ASTHMA IS THE MOST COMMON CHRONIC ILLNESS IN CHILDREN AND IS A LEADING CAUSE OF CHILDHOOD HOSPITALIZATION AND SCHOOL ABSENTEEISM. ASTHMA PRESENTS WITH DIFFERENT PHENOTYPES DEPENDING ON AGE, GENDER, GENETIC BACKGROUND, ENVIRONMENTAL EXPOSURES AND EPIGENETIC FACTORS. FORKHEAD BOX O3 (FOXO3) IS A TRANSCRIPTION FACTOR INVOLVED IN THE PATHOGENESIS OF A NUMBER OF INFLAMMATORY AND RESPIRATORY DISEASES. THE STUDY AIMS TO INVESTIGATE THE ASSOCIATION BETWEEN THE SNP RS13217795 IN FOXO3 GENE AND PEDIATRIC ONSET ASTHMA IN THE EGYPTIAN POPULATION. NINETY ASTHMATICS AND 160 HEALTHY CONTROLS WERE SUBJECTED TO GENOTYPING OF FOXO3 SNP (RS13217795) USING THE PCR-RFLP METHOD. THE PROPORTION OF HOMOZYGOUS (CC) AND HETEROZYGOUS (CT) GENOTYPES WAS LOWER IN THE ASTHMATIC GROUP COMPARED TO THE CONTROL GROUP BUT STATISTICALLY INSIGNIFICANT; P > 0.05. ON THE OTHER HAND THE PROPORTION OF THE MUTANT HOMOZYGOUS (TT) GENOTYPE IN ASTHMATIC GROUP WAS HIGHER; 30 (33.3%) THAN THE CONTROL GROUP; 28(17.5%), THE DIFFERENCE WAS SIGNIFICANT IN RECESSIVE MODEL OF DISEASE PENETRANCE WITH ODDS RATIO OR (95% CI) OF 2.4(1 - 5.49) AND P=0.039. THIS ASSOCIATION WAS MORE PRONOUNCED IN MALE GENDER; OR AND 95% CI OF 5.3 (1.4- 19.3) AND P=0.01. IN CONCLUSIONS, EGYPTIAN CHILDREN CARRYING THE MUTANT (TT) GENOTYPE WERE AT HIGHER RISK TO DEVELOP ASTHMA WITH A HIGHER RISK IN MALE GENDER. 2020 18 5045 16 PHARMACOLOGIC EPIGENETIC MODULATORS OF ALKALINE PHOSPHATASE IN CHRONIC KIDNEY DISEASE. PURPOSE OF REVIEW: IN CHRONIC KIDNEY DISEASE (CKD), DISTURBANCE OF SEVERAL METABOLIC REGULATORY MECHANISMS CAUSE PREMATURE AGEING, ACCELERATED CARDIOVASCULAR DISEASE (CVD), AND MORTALITY. SINGLE-TARGET INTERVENTIONS HAVE REPEATEDLY FAILED TO IMPROVE THE PROGNOSIS FOR CKD PATIENTS. EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL TO MODULATE SEVERAL PATHOGENETIC PROCESSES SIMULTANEOUSLY. ALKALINE PHOSPHATASE (ALP) IS A ROBUST PREDICTOR OF CVD AND ALL-CAUSE MORTALITY AND IMPLICATED IN PATHOGENIC PROCESSES ASSOCIATED WITH CVD IN CKD. RECENT FINDINGS: IN EXPERIMENTAL STUDIES, EPIGENETIC MODULATION OF ALP BY MICRORNAS OR BROMODOMAIN AND EXTRATERMINAL (BET) PROTEIN INHIBITION HAS SHOWN PROMISING RESULTS FOR THE TREATMENT OF CVD AND OTHER CHRONIC METABOLIC DISEASES. THE BET INHIBITOR APABETALONE IS CURRENTLY BEING EVALUATED FOR CARDIOVASCULAR RISK REDUCTION IN A PHASE III CLINICAL STUDY IN HIGH-RISK CVD PATIENTS, INCLUDING PATIENTS WITH CKD (CLINICALTRIALS.GOV IDENTIFIER: NCT02586155). PHASE II STUDIES DEMONSTRATE AN ALP-LOWERING POTENTIAL OF APABETALONE, WHICH WAS ASSOCIATED WITH IMPROVED CARDIOVASCULAR AND RENAL OUTCOMES. SUMMARY: ALP IS A PREDICTOR OF CVD AND MORTALITY IN CKD. EPIGENETIC MODULATION OF ALP HAS THE POTENTIAL TO AFFECT SEVERAL PATHOGENETIC PROCESSES IN CKD AND THEREBY IMPROVE CARDIOVASCULAR OUTCOME. 2020 19 5422 30 REGULATION OF LUNG EPITHELIAL CELL SENESCENCE IN SMOKING-INDUCED COPD/EMPHYSEMA BY MICROR-125A-5P VIA SP1 MEDIATION OF SIRT1/HIF-1A. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AFFECTS THE HEALTH OF MORE THAN 300 MILLION PEOPLE WORLDWIDE; AT PRESENT, THERE IS NO EFFECTIVE DRUG TO TREAT COPD. SMOKING IS THE MOST IMPORTANT RISK FACTOR, BUT THE MOLECULAR MECHANISM BY WHICH SMOKING CAUSES THE DISEASE IS UNCLEAR. THE SENESCENCE OF LUNG EPITHELIAL CELLS IS RELATED TO DEVELOPMENT OF COPD. REGULATION OF MIRNAS IS THE MAIN EPIGENETIC MECHANISM RELATED TO AGING. BETA-GALACTOSE STAINING SHOWED THAT THE LUNG TISSUES OF SMOKERS HAVE A HIGHER DEGREE OF CELLULAR SENESCENCE, AND THE EXPRESSION OF MIR-125A-5P IS HIGH. THIS EFFECT IS OBVIOUS FOR SMOKERS WITH COPD/EMPHYSEMA, AND THERE IS A NEGATIVE CORRELATION BETWEEN MIR-125A-5P LEVELS AND VALUES FOR FORCED EXPIRATORY VOLUME IN ONE SECOND (FEV1)/FORCED VITAL CAPACITY (FVC). AFTER BALB/C MICE WERE CHRONICALLY EXPOSED TO VARIOUS CONCENTRATIONS OF CIGARETTE SMOKE (CS), PLETHYSMOGRAPHY SHOWED THAT LUNG FUNCTION WAS IMPAIRED, LUNG TISSUE SENESCENCE WAS INCREASED, AND THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) IN BRONCHOALVEOLAR LAVAGE FLUID WAS INCREASED. FOR MOUSE LUNG EPITHELIAL (MLE)-12 CELLS TREATED WITH CIGARETTE SMOKE EXTRACT (CSE), SP1 AND SIRT1 LEVELS WERE LOW, HIF-1ALPHA ACETYLATION LEVELS WERE HIGH, AND CELL SENESCENCE AND SECRETION OF SASP FACTORS WERE ELEVATED. DOWN-REGULATION OF MIR-125A-5P OR UP-REGULATION OF SP1 REVERSED THESE EFFECTS. IN ADDITION, COMPARED WITH MICE EXPOSED TO CS, KNOCKDOWN OF MIR-125A-5P REDUCED LUNG EPITHELIAL CELL SENESCENCE AND COPD/EMPHYSEMA. THEREFORE, IN SMOKING-INDUCED COPD, ELEVATED MIR-125A-5P PARTICIPATES IN THE SENESCENCE OF LUNG EPITHELIAL CELLS THROUGH SP1/SIRT1/HIF-1ALPHA. THESE FINDINGS PROVIDE EVIDENCE RELATED TO THE PATHOGENESIS OF COPD/EMPHYSEMA CAUSED BY CHRONIC SMOKING. 2022 20 5703 21 SINGLE-CELL MULTIOMICS REVEAL THE SCALE OF MULTILAYERED ADAPTATIONS ENABLING CLL RELAPSE DURING VENETOCLAX THERAPY. VENETOCLAX (VEN) INHIBITS THE PROSURVIVAL PROTEIN BCL2 TO INDUCE APOPTOSIS AND IS A STANDARD THERAPY FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), DELIVERING HIGH COMPLETE REMISSION RATES AND PROLONGED PROGRESSION-FREE SURVIVAL IN RELAPSED CLL BUT WITH EVENTUAL LOSS OF EFFICACY. A SPECTRUM OF SUBCLONAL GENETIC CHANGES ASSOCIATED WITH VEN RESISTANCE HAS NOW BEEN DESCRIBED. TO FULLY UNDERSTAND CLINICAL RESISTANCE TO VEN, WE COMBINED SINGLE-CELL SHORT- AND LONG-READ RNA-SEQUENCING TO REVEAL THE PREVIOUSLY UNAPPRECIATED SCALE OF GENETIC AND EPIGENETIC CHANGES UNDERPINNING ACQUIRED VEN RESISTANCE. THESE APPEAR TO BE MULTILAYERED. ONE LAYER COMPRISES CHANGES IN THE BCL2 FAMILY OF APOPTOSIS REGULATORS, ESPECIALLY THE PROSURVIVAL FAMILY MEMBERS. THIS INCLUDES PREVIOUSLY DESCRIBED MUTATIONS IN BCL2 AND AMPLIFICATION OF THE MCL1 GENE BUT IS HETEROGENEOUS ACROSS AND WITHIN INDIVIDUAL PATIENT LEUKEMIAS. CHANGES IN THE PROAPOPTOTIC GENES ARE NOTABLY UNCOMMON, EXCEPT FOR SINGLE CASES WITH SUBCLONAL LOSSES OF BAX OR NOXA. MUCH MORE PROMINENT WAS UNIVERSAL MCL1 GENE UPREGULATION. THIS WAS DRIVEN BY AN OVERLYING LAYER OF EMERGENT NF-KAPPAB (NUCLEAR FACTOR KAPPA B) ACTIVATION, WHICH PERSISTED IN CIRCULATING CELLS DURING VEN THERAPY. WE DISCOVERED THAT MCL1 COULD BE A DIRECT TRANSCRIPTIONAL TARGET OF NF-KAPPAB. BOTH THE SWITCH TO ALTERNATIVE PROSURVIVAL FACTORS AND NF-KAPPAB ACTIVATION LARGELY DISSIPATE FOLLOWING VEN DISCONTINUATION. OUR STUDIES REVEAL THE EXTENT OF PLASTICITY OF CLL CELLS IN THEIR ABILITY TO EVADE VEN-INDUCED APOPTOSIS. IMPORTANTLY, THESE FINDINGS PINPOINT NEW APPROACHES TO CIRCUMVENT VEN RESISTANCE AND PROVIDE A SPECIFIC BIOLOGICAL JUSTIFICATION FOR THE STRATEGY OF VEN DISCONTINUATION ONCE A MAXIMAL RESPONSE IS ACHIEVED RATHER THAN MAINTAINING LONG-TERM SELECTIVE PRESSURE WITH THE DRUG. 2022