1   119 163 A SYSTEMATIC EXAMINATION OF BRAIN VOLUMETRIC ABNORMALITIES IN RECENT-ONSET SCHIZOPHRENIA USING VOXEL-BASED, SURFACE-BASED AND REGION-OF-INTEREST-BASED MORPHOMETRIC ANALYSES. BACKGROUND: BRAIN MORPHOMETRIC ABNORMALITIES IN SCHIZOPHRENIA HAVE BEEN EXTENSIVELY REPORTED IN THE LITERATURE. WHOLE-BRAIN VOLUMETRIC REDUCTIONS ARE ALMOST UNIVERSALLY REPORTED BY MOST STUDIES IRRESPECTIVE OF THE CHARACTERISTICS OF THE SAMPLES STUDIED (E.G., CHRONIC/RECENT-ONSET; MEDICATED/NEUROLEPTIC-NAIVE ETC.). HOWEVER, THE SAME CANNOT BE SAID OF THE REPORTED REGIONAL MORPHOMETRIC ABNORMALITIES IN SCHIZOPHRENIA. WHILE CERTAIN REGIONAL MORPHOMETRIC ABNORMALITIES ARE MORE FREQUENTLY REPORTED THAN OTHERS, THERE ARE NO SUCH ABNORMALITIES THAT ARE UNIVERSALLY REPORTED ACROSS STUDIES. VARIABILITY OF SOCIO-DEMOGRAPHIC AND CLINICAL CHARACTERISTICS ACROSS STUDY SAMPLES AS WELL AS TECHNICAL AND METHODOLOGICAL ISSUES RELATED TO ACQUISITION AND ANALYSES OF BRAIN STRUCTURAL IMAGES MAY CONTRIBUTE TO INCONSISTENCY OF BRAIN MORPHOMETRIC FINDINGS IN SCHIZOPHRENIA. THE OBJECTIVE OF THE PRESENT STUDY THEREFORE WAS TO SYSTEMATICALLY EXAMINE BRAIN MORPHOMETRY IN PATIENTS WITH RECENT-ONSET SCHIZOPHRENIA TO FIND OUT IF THERE ARE SIGNIFICANT WHOLE-BRAIN OR REGIONAL VOLUMETRIC DIFFERENCES DETECTABLE AT THE APPROPRIATE SIGNIFICANCE THRESHOLD, AFTER ATTEMPTING TO CONTROL FOR VARIOUS CONFOUNDING FACTORS THAT COULD IMPACT BRAIN VOLUMES. METHODS: STRUCTURAL MAGNETIC RESONANCE IMAGES OF 90 SUBJECTS (SCHIZOPHRENIA = 45; HEALTHY SUBJECTS = 45) WERE ACQUIRED USING A 3 TESLA MAGNET. MORPHOMETRIC ANALYSES WERE CARRIED OUT FOLLOWING STANDARD ANALYSES PIPELINES OF THREE MOST COMMONLY USED STRATEGIES, VIZ., WHOLE-BRAIN VOXEL-BASED MORPHOMETRY, WHOLE-BRAIN SURFACE-BASED MORPHOMETRY, AND BETWEEN-GROUP COMPARISONS OF REGIONAL VOLUMES GENERATED BY AUTOMATED SEGMENTATION AND PARCELLATION. RESULTS: IN OUR SAMPLE OF PATIENTS HAVING RECENT-ONSET SCHIZOPHRENIA WITH LIMITED NEUROLEPTIC EXPOSURE, THERE WERE NO SIGNIFICANT WHOLE BRAIN OR REGIONAL BRAIN MORPHOMETRIC ABNORMALITIES NOTED AT THE APPROPRIATE STATISTICAL SIGNIFICANCE THRESHOLDS WITH OR WITHOUT INCLUDING AGE, GENDER AND INTRACRANIAL VOLUME OR TOTAL BRAIN VOLUME IN THE STATISTICAL ANALYSES. CONCLUSIONS: IN THE BACKGROUND OF THE CONFLICTING FINDINGS IN THE LITERATURE, OUR FINDINGS INDICATE THAT BRAIN MORPHOMETRIC ABNORMALITIES MAY NOT BE DIRECTLY RELATED TO THE SCHIZOPHRENIA PHENOTYPE. ANALYSIS OF THE REASONS FOR THE INCONSISTENT RESULTS ACROSS STUDIES AS WELL AS CONSIDERATION OF ALTERNATE SOURCES OF VARIABILITY OF BRAIN MORPHOLOGY IN SCHIZOPHRENIA SUCH AS EPISTATIC AND EPIGENETIC MECHANISMS COULD PERHAPS ADVANCE OUR UNDERSTANDING OF STRUCTURAL BRAIN ALTERATIONS IN SCHIZOPHRENIA.	2015	

2  5227  24 PRMT6 MEDIATES INFLAMMATION VIA ACTIVATION OF THE NF-KAPPAB/P65 PATHWAY ON A CIGARETTE SMOKE EXTRACT-INDUCED MURINE EMPHYSEMA MODEL. INTRODUCTION: SMOKE-DRIVEN LUNG INFLAMMATION IS CONSIDERED TO BE THE MAJOR PATHOPHYSIOLOGY MECHANISM OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA. PROTEIN ARGININE METHYLTRANSFERASE 6 (PRMT6) IS A KEY EPIGENETIC ENZYME, WHICH IS RELATED TO PROTECTING THE TRI-METHYLATION OF H3K4 (H3K4ME3). WE HYPOTHESIZED THAT PTMT6 PROTECTS LUNG INFLAMMATION THROUGH THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY. METHODS: MICE WERE INJECTED WITH CIGARETTE SMOKE EXTRACT (CSE) OR PBS TO ESTABLISH A MICE MODEL, INTRATRACHEALLY INSTILLED WITH OVEREXPRESSED PRMT6 OR NEGATIVE CONTROL VECTOR. MORPHOMETRY OF LUNG SLIDES AND LUNG FUNCTION WERE MEASURED. WE DETERMINED THE PROTEIN EXPRESSION OF PRMT6 AND ITS RELATED HISTONE TARGETS, THE ACTIVATION OF NF-KAPPAB PATHWAY, THE LEVEL OF TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) AND INTERLEUKIN-1BETA (IL-1BETA). RESULTS: AFTER PRMT6 OVEREXPRESSION, THE MORPHOMETRY INDEXES AND LUNG FUNCTION WERE IMPROVED. ALSO, THE EXPRESSION OF H3K4ME3 WAS DECREASED. OVEREXPRESSED PRMT6 COULD SUPPRESS CSE-INDUCED NF-KAPPAB ACTIVATION AND PRO-INFLAMMATION GENES EXPRESSION. CONCLUSIONS: THE OVEREXPRESSED PRMT6 COULD SERVE AS AN INFLAMMATION INHIBITOR, POTENTIALLY THROUGH BLOCKING THE NF-KAPPAB/P65 PATHWAY IN THE MURINE EMPHYSEMA MODEL.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
3  2278  37 EPIGENETIC REGULATION BY SUV4-20H1 IN CARDIOPULMONARY PROGENITOR CELLS IS REQUIRED TO PREVENT PULMONARY HYPERTENSION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: THE PATHOGENESIS OF LIFE-THREATENING CARDIOPULMONARY DISEASES SUCH AS PULMONARY HYPERTENSION (PH) AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ORIGINATES FROM A COMPLEX INTERPLAY OF ENVIRONMENTAL FACTORS AND GENETIC PREDISPOSITIONS THAT IS NOT FULLY UNDERSTOOD. LIKEWISE, LITTLE IS KNOWN ABOUT DEVELOPMENTAL ABNORMALITIES OR EPIGENETIC DYSREGULATIONS THAT MIGHT PREDISPOSE FOR PH OR COPD IN ADULT INDIVIDUALS. METHODS: TO IDENTIFY PATHOLOGY-ASSOCIATED EPIGENETIC ALTERATION IN DISEASED LUNG TISSUES, WE SCREENED A COHORT OF HUMAN PATIENTS WITH PH AND COPD FOR CHANGES OF HISTONE MODIFICATIONS BY IMMUNOFLUORESCENCE STAINING. TO ANALYZE THE FUNCTION OF H4K20ME2/3 IN LUNG PATHOGENESIS, WE DEVELOPED A SERIES OF SUV4-20H1 KNOCKOUT MOUSE LINES TARGETING CARDIOPULMONARY PROGENITOR CELLS AND DIFFERENT HEART AND LUNG CELL TYPES, FOLLOWED BY HEMODYNAMIC STUDIES AND MORPHOMETRIC ASSESSMENT OF TISSUE SAMPLES. MOLECULAR, CELLULAR, AND BIOCHEMICAL TECHNIQUES WERE APPLIED TO ANALYZE THE FUNCTION OF SUV4-20H1-DEPENDENT EPIGENETIC PROCESSES IN CARDIOPULMONARY PROGENITOR CELLS AND THEIR DERIVATIVES. RESULTS: WE DISCOVERED A STRONG REDUCTION OF THE HISTONE MODIFICATIONS OF H4K20ME2/3 IN HUMAN PATIENTS WITH COPD BUT NOT PATIENTS WITH PH THAT DEPEND ON THE ACTIVITY OF THE H4K20 DI-METHYLTRANSFERASE SUV4-20H1. LOSS OF SUV4-20H1 IN CARDIOPULMONARY PROGENITOR CELLS CAUSED A COPD-LIKE/PH PHENOTYPE IN MICE INCLUDING THE FORMATION OF PERIVASCULAR TERTIARY LYMPHOID TISSUE AND GOBLET CELL HYPERPLASIA, HYPERPROLIFERATION OF SMOOTH MUSCLE CELLS/MYOFIBROBLASTS, IMPAIRED ALVEOLARIZATION AND MATURATION DEFECTS OF THE MICROVASCULATURE LEADING TO MASSIVE RIGHT VENTRICULAR DILATATION AND PREMATURE DEATH. MECHANISTICALLY, SUV4-20H1 BINDS DIRECTLY TO THE 5'-UPSTREAM REGULATORY ELEMENT OF THE SUPEROXIDE DISMUTASE 3 (SOD3) GENE TO REPRESS ITS EXPRESSION. INCREASED LEVELS OF THE EXTRACELLULAR SOD3 ENZYME IN SUV4-20H1 MUTANTS INCREASES HYDROGEN PEROXIDE CONCENTRATIONS, CAUSING VASCULAR DEFECTS AND IMPAIRING ALVEOLARIZATION. CONCLUSIONS: OUR FINDINGS REVEAL A PIVOTAL ROLE OF THE HISTONE MODIFIER SUV4-20H1 IN CARDIOPULMONARY CODEVELOPMENT AND UNCOVER THE DEVELOPMENTAL ORIGINS OF CARDIOPULMONARY DISEASES. WE ASSUME THAT THE STUDY WILL FACILITATE THE UNDERSTANDING OF PATHOGENIC EVENTS CAUSING PH AND COPD AND AID THE DEVELOPMENT OF EPIGENETIC DRUGS FOR THE TREATMENT OF CARDIOPULMONARY DISEASES.	2021	
                                                                                                                                                        
4   386  32 AN IN VIVO IMMUNOHISTOCHEMICAL STUDY ON MACROH2A.1 IN LUNG AND LYMPH-NODE TISSUES EXPOSED TO AN ASBESTIFORM FIBER. AIMS: THE AIM OF THIS STUDY WAS TO INVESTIGATE MACROH2A.1 IMMUNOEXPRESSION IN TISSUES OF SHEEP EXPOSED TO FE. BACKGROUND: THE CORRELATION BETWEEN ASBESTIFORM FIBERS, LUNG CANCER, PLEURAL MESOTHELIOMA, AND OTHER LUNG DISEASES IS ALREADY WELL ESTABLISHED AS THE PATHOPHISIOLOGICAL PATHOPHYSIOLOGICAL RESPIRATORY MECHANISMS INVOLVED BY INHALATION OF FLUORO-EDENITE (FE). THE LATTER IS REPRESENTED BY CELL PROLIFERATION AND INDUCING THE RELEASE OF GROWTH FACTORS, CYTOKINES, AND REACTIVE OXYGEN AND NITRITE SPECIES, WITH DNA DAMAGE THAT CAUSES CHRONIC INFLAMMATION AND CARCINOGENESIS. MACROH2A.1, AND HISTONE VARIANT, SEEMS TO PLAY A ROLE IN SENSING THE METABOLIC STATE OF THE CELL AND LINKING IT WITH CHROMATIN. PHYSIOLOGICALLY, MACROH2A.1 IS EXPRESSED AT LOW LEVELS IN STEM CELLS AND IT BECAME UPREGULATED DURING DIFFERENTIATION, PREVENTING REPROGRAMMING OF INDUCED PLURIPOTENT STEM CELLS AND AFTER NUCLEAR TRANSFER. IN PARTICULAR, MACROH2A.1 HAS BEEN SHOWN TO EXPLICATE A POTENT ANTITUMOR MECHANISM IN VIVO AS IT RESULTS UPREGULATED IN SENESCENT CELLS DETERMINING A PERMANENT GROWTH-ARREST. OBJECTIVE: EVALUATE THE POSSIBLE ROLE OF THE HISTONE VARIANT IN THE ORGANISM IN RESPONSE TO DEEP INSIGHT UNDERSTANDING THE MECHANISMS OF TOXICITY AND THE CELLULAR RESPONSE TO FE. METHODS: LUNG AND LYMPH NODES OF EXPOSED SHEEP WERE SELECTED. SAMPLES WERE PROCESSED FOR HISTOLOGICAL AND IMMUNIHISTOCHEMICAL IMMUNOHISTOCHEMICAL EVALUATIONS. DENSITOMETRIC, MORPHOMETRIC, AND STATISTICAL ANALYSIS ANALYSES WERE CONDUCTED. RESULTS: TISSUE SECTIONS OF FE EXPOSED SHEEP DEMONSTRATED OVEREXPRESSION OF MACROH2A.1 VS UNEXPOSED SAMPLES. THE DATA SUGGEST AN INVOLVEMENT OF THESE THIS MOLECULE IN THE CELLULAR RESPONSE TRIGGERED BY FE DIRECTED EXPOSURE. CONCLUSION: IN THIS CONTEST, MACROH2A.1 OVEREXPRESSION SUPPORTS ITS FUNCTION AS AN EPIGENETIC STABILIZER THAT HELPS TO ESTABLISH AND MAINTAIN DIFFERENTIATED STATES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5   225  27 ACUTE STRESS-INDUCED EPIGENETIC MODULATIONS AND THEIR POTENTIAL PROTECTIVE ROLE TOWARD DEPRESSION. PSYCHIATRIC DISORDERS ENTAIL MALADAPTIVE PROCESSES IMPAIRING INDIVIDUALS' ABILITY TO APPROPRIATELY INTERFACE WITH ENVIRONMENT. AMONG THEM, DEPRESSION IS CHARACTERIZED BY DIVERSE DEBILITATING SYMPTOMS INCLUDING HOPELESSNESS AND ANHEDONIA, DRAMATICALLY IMPACTING THE PROPENSITY TO LIVE A SOCIAL AND ACTIVE LIFE AND SERIOUSLY AFFECTING WORKING CAPABILITY. RELEVANTLY, BESIDES GENETIC PREDISPOSITION, FOREMOST RISK FACTORS ARE STRESS-RELATED, SUCH AS EXPERIENCING CHRONIC PSYCHOSOCIAL STRESS-INCLUDING BULLYING, MOBBING AND ABUSE-, AND UNDERGOING ECONOMIC CRISIS OR CHRONIC ILLNESSES. IN THE LAST FEW YEARS THE FIELD OF EPIGENETICS PROMISED TO UNDERSTAND CORE MECHANISMS OF GENE-ENVIRONMENT CROSSTALK, CONTRIBUTING TO GET INTO PATHOGENIC PROCESSES OF MANY DISORDERS HIGHLY INFLUENCED BY STRESSFUL LIFE CONDITIONS. HOWEVER, STILL VERY LITTLE IS KNOWN ABOUT MECHANISMS THAT TUNE GENE EXPRESSION TO ADAPT TO THE EXTERNAL MILIEU. IN THIS PERSPECTIVE ARTICLE, WE DISCUSS A SET OF PROTECTIVE, FUNCTIONALLY CONVERGENT EPIGENETIC PROCESSES INDUCED BY ACUTE STRESS IN THE RODENT HIPPOCAMPUS AND DEVOTED TO THE NEGATIVE MODULATION OF STRESS-INDUCED IMMEDIATE EARLY GENES (IEGS) TRANSCRIPTION, HINDERING STRESS-DRIVEN MORPHOSTRUCTURAL MODIFICATIONS OF CORTICOLIMBIC CIRCUITRY. WE ALSO SUGGEST THAT CHRONIC STRESS DAMAGING PROTECTIVE EPIGENETIC MECHANISMS, COULD BIAS THE FUNCTIONAL TRAJECTORY OF STRESS-INDUCED NEURONAL MORPHOSTRUCTURAL MODIFICATION FROM ADAPTIVE TO MALADAPTIVE, CONTRIBUTING TO THE ONSET OF DEPRESSION IN VULNERABLE INDIVIDUALS. A BETTER UNDERSTANDING OF THE EPIGENETIC RESPONSE TO STRESS WILL BE PIVOTAL TO NEW AVENUES OF THERAPEUTIC INTERVENTION TO TREAT DEPRESSION, ESPECIALLY IN LIGHT OF LIMITED EFFICACY OF AVAILABLE ANTIDEPRESSANT DRUGS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6  3939  21 LNC-IL7R ALLEVIATES PM(2.5)-MEDIATED CELLULAR SENESCENCE AND APOPTOSIS THROUGH EZH2 RECRUITMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: LONG-TERM EXPOSURE TO PM(2.5) (PARTICULATE MATTER WITH AN AERODYNAMIC DIAMETER OF </= 2.5 MUM) IS ASSOCIATED WITH PULMONARY INJURY AND EMPHYSEMA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE INVESTIGATED MECHANISMS THROUGH WHICH THE LONG NONCODING RNA LNC-IL7R CONTRIBUTES TO CELLULAR DAMAGE BY INDUCING OXIDATIVE STRESS IN COPD PATIENTS EXPOSED TO PM(2.5). METHODS: ASSOCIATIONS OF SERUM LNC-IL7R LEVELS WITH LUNG FUNCTION, EMPHYSEMA, AND PREVIOUS PM(2.5) EXPOSURE IN COPD PATIENTS WERE ANALYZED. REACTIVE OXYGEN SPECIES AND LNC-IL7R LEVELS WERE MEASURED IN PM(2.5)-TREATED CELLS. THE LEVELS OF LNC-IL7R AND CELLULAR SENESCENCE-ASSOCIATED GENES, NAMELY P16(INK4A) AND P21(CIP1/WAF1), WERE DETERMINED THROUGH LUNG TISSUE SECTION STAINING. THE EFFECTS OF P16(INK4A) OR P21(CIP1/WAF1) REGULATION WERE EXAMINED BY PERFORMING LNC-IL7R OVEREXPRESSION AND KNOCKDOWN ASSAYS. THE FUNCTIONS OF LNC-IL7R-MEDIATED CELL PROLIFERATION, CELL CYCLE, SENESCENCE, COLONY FORMATION, AND APOPTOSIS WERE EXAMINED IN CELLS TREATED WITH PM(2.5). CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE CONDUCTED TO INVESTIGATE THE EPIGENETIC REGULATION OF P21(CIP1/WAF1). RESULTS: LNC-IL7R LEVELS DECREASED IN COPD PATIENTS AND WERE NEGATIVELY CORRELATED WITH EMPHYSEMA OR PM(2.5) EXPOSURE. LNC-IL7R LEVELS WERE UPREGULATED IN NORMAL LUNG EPITHELIAL CELLS BUT NOT IN COPD CELLS EXPOSED TO PM(2.5). LOWER LNC-IL7R EXPRESSION IN PM(2.5)-TREATED CELLS INDUCED P16(INK4A) AND P21(CIP1/WAF1) EXPRESSION BY INCREASING OXIDATIVE STRESS. HIGHER LNC-IL7R EXPRESSION PROTECTED AGAINST CELLULAR SENESCENCE AND APOPTOSIS, WHEREAS LOWER LNC-IL7R EXPRESSION AUGMENTED INJURY IN PM(2.5)-TREATED CELLS. LNC-IL7R AND THE ENHANCER OF ZESTE HOMOLOG 2 (EZH2) SYNERGISTICALLY SUPPRESSED P21(CIP1/WAF1) EXPRESSION THROUGH EPIGENETIC MODULATION. CONCLUSION: LNC-IL7R ATTENUATES PM(2.5)-MEDIATED P21(CIP1/WAF1) EXPRESSION THROUGH EZH2 RECRUITMENT, AND ITS DYSFUNCTION MAY AUGMENT CELLULAR INJURY IN COPD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7  4769  26 NUCLEAR MORPHOMETRY, NUCLEOMICS AND PROSTATE CANCER PROGRESSION. PROSTATE CANCER (PCA) RESULTS FROM A MULTISTEP PROCESS. THIS PROCESS INCLUDES INITIATION, WHICH OCCURS THROUGH VARIOUS AGING EVENTS AND MULTIPLE INSULTS (SUCH AS CHRONIC INFECTION, INFLAMMATION AND GENETIC INSTABILITY THROUGH REACTIVE OXYGEN SPECIES CAUSING DNA DOUBLE-STRAND BREAKS), FOLLOWED BY A MULTISTEP PROCESS OF PROGRESSION. THESE STEPS INCLUDE SEVERAL GENETIC AND EPIGENETIC ALTERATIONS, AS WELL AS ALTERATIONS TO THE CHROMATIN STRUCTURE, WHICH OCCUR IN RESPONSE TO THE CARCINOGENIC STRESS-RELATED EVENTS THAT SUSTAIN PROLIFERATIVE SIGNALING. EVENTS SUCH AS EVADING GROWTH SUPPRESSORS, RESISTING CELL DEATH, ENABLING REPLICATIVE IMMORTALITY, INDUCING ANGIOGENESIS, AND ACTIVATING INVASION AND METASTASIS ARE READILY OBSERVED. IN ADDITION, IN CONJUNCTION WITH THESE CRITICAL DRIVERS OF CARCINOGENESIS, OTHER FACTORS RELATED TO THE ETIOPATHOGENESIS OF PCA, INVOLVING ENERGY METABOLISM AND EVASION OF THE IMMUNE SURVEILLANCE SYSTEM, APPEAR TO BE INVOLVED. IN ADDITION, WHEN CANCER SPREAD AND METASTASIS OCCUR, THE 'TUMOR MICROENVIRONMENT' IN THE BONE OF PCA PATIENTS MAY PROVIDE A WAY TO SUSTAIN DORMANCY OR SENESCENCE AND EVENTUALLY ESTABLISH A 'SEED AND SOIL' SITE WHERE PCA PROLIFERATION AND GROWTH MAY OCCUR OVER TIME. WHEN PCA IS INITIATED AND PROGRESSION ENSUES, SIGNIFICANT ALTERATIONS IN NUCLEAR SIZE, SHAPE AND HETEROCHROMATIN (DNA TRANSCRIPTION) ORGANIZATION ARE FOUND, AND KEY NUCLEAR TRANSCRIPTIONAL AND STRUCTURAL PROTEINS, AS WELL AS MULTIPLE NUCLEAR BODIES CAN LEAD TO PRECANCEROUS AND MALIGNANT CHANGES. THESE SERIES OF CELLULAR AND TISSUE-RELATED MALIGNANCY-ASSOCIATED EVENTS CAN BE QUANTIFIED TO ASSESS DISEASE PROGRESSION AND MANAGEMENT.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8  1817  26 EFFECTS OF CHRONIC METAL EXPOSURE ON WILD FISH POPULATIONS REVEALED BY HIGH-THROUGHPUT CDNA SEQUENCING. GIVEN THE INHERENT VARIABILITY OF AQUATIC SYSTEMS, PREDICTING THE IN SITU EFFECTS OF CONTAMINANTS ON SUCH ECOSYSTEMS STILL REPRESENTS A MAJOR CHALLENGE FOR ECOTOXICOLOGY. IN THIS CONTEXT, TRANSCRIPTOMIC TOOLS CAN HELP IDENTIFY AND INVESTIGATE THE MECHANISMS OF TOXICITY BEYOND THE TRADITIONAL MORPHOMETRIC, PHYSIOLOGICAL AND POPULATION-LEVEL ENDPOINTS. IN THIS STUDY, WE USED THE 454 SEQUENCING TECHNOLOGY TO EXAMINE THE IN SITU EFFECTS OF CHRONIC METAL (CD, CU) EXPOSURE ON THE YELLOW PERCH (PERCA FLAVESCENS) TRANSCRIPTOME. TOTAL HEPATIC MRNA FROM FISH SAMPLED ALONG A POLYMETALLIC GRADIENT WAS EXTRACTED, REVERSE TRANSCRIBED, LABELED WITH UNIQUE BARCODE SEQUENCES AND SEQUENCED. THIS APPROACH ALLOWED US TO IDENTIFY CORRELATIONS BETWEEN THE TRANSCRIPTION LEVEL OF SINGLE GENES AND THE HEPATIC CONCENTRATIONS OF INDIVIDUAL METALS; 71% OF THE CORRELATIONS ESTABLISHED WERE NEGATIVE. CHRONIC METAL EXPOSURE WAS THUS ASSOCIATED WITH A DECREASE IN THE TRANSCRIPTION LEVELS OF NUMEROUS GENES INVOLVED IN PROTEIN BIOSYNTHESIS, IN THE IMMUNE SYSTEM, AND IN LIPID AND ENERGY METABOLISM. OUR RESULTS SUGGEST THAT THIS MARKED DECREASE COULD RESULT FROM AN IMPAIRMENT OF BILE ACID METABOLISM BY CD AND ENERGY RESTRICTION BUT ALSO FROM THE RECRUITMENT OF SEVERAL GENES INVOLVED IN EPIGENETIC MODIFICATIONS OF HISTONES AND DNA THAT LEAD TO GENE SILENCING.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9  5760  36 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10  5882  39 SYSTEMATIC REVIEW OF LUNG FUNCTION AND COPD WITH PERIPHERAL BLOOD DNA METHYLATION IN POPULATION BASED STUDIES. BACKGROUND: EPIGENETIC VARIATIONS IN PERIPHERAL BLOOD HAVE POTENTIAL AS BIOMARKERS FOR DISEASE. THIS SYSTEMATIC REVIEW ASSESSES THE ASSOCIATION OF LUNG FUNCTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) WITH DNA METHYLATION PROFILES IN PERIPHERAL BLOOD FROM POPULATION-BASED STUDIES. METHODS: ONLINE DATABASES MEDLINE, EMBASE, AND WEB OF SCIENCE WERE SEARCHED. GOOGLE SCHOLAR WAS SEARCHED TO IDENTIFY GREY LITERATURE. AFTER REMOVING DUPLICATE ARTICLES, 1155 ARTICLES WERE INDEPENDENTLY SCREENED BY TWO INVESTIGATORS. PEER REVIEWED REPORTS ON POPULATION-BASED STUDIES THAT EXAMINED PERIPHERAL BLOOD DNA METHYLATION IN PARTICIPANTS WITH MEASURED LUNG FUNCTION (FEV1, FEV1/FVC RATIO) OR KNOWN COPD STATUS WERE SELECTED FOR FULL-TEXT REVIEW. SIX ARTICLES WERE SUITABLE FOR INCLUSION. INFORMATION REGARDING STUDY CHARACTERISTICS, DESIGNS, METHODOLOGIES AND CONCLUSIONS WAS EXTRACTED. A NARRATIVE SYNTHESIS WAS PERFORMED BASED ON PUBLISHED RESULTS. RESULTS: THREE OF THE SIX ARTICLES ASSESSED THE ASSOCIATION OF COPD WITH DNA METHYLATION, AND TWO OF THESE ALSO INCLUDED ASSOCIATIONS WITH LUNG FUNCTION. OVERALL, FIVE REPORTS EXAMINED THE ASSOCIATION OF LUNG FUNCTION WITH DNA METHYLATION PROFILES. FIVE OF THE SIX ARTICLES REPORTED 'SIGNIFICANT' RESULTS. HOWEVER, NO CONSISTENT CPG SITES WERE IDENTIFIED ACROSS STUDIES FOR COPD STATUS OR LUNG FUNCTION VALUES. CONCLUSIONS: DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD FROM INDIVIDUALS WITH REDUCED LUNG FUNCTION OR COPD MAY BE DIFFERENT TO THOSE IN PEOPLE WITH NORMAL LUNG FUNCTION. HOWEVER, THIS SYSTEMATIC REVIEW DID NOT FIND ANY CONSISTENT ASSOCIATIONS OF LUNG FUNCTION OR COPD WITH DIFFERENTIALLY METHYLATED CPG SITES. LARGE STUDIES WITH A LONGITUDINAL DESIGN TO ADDRESS REVERSE CAUSALITY MAY PROVE A MORE FRUITFUL AREA OF RESEARCH. TRIAL REGISTRATION: PROSPERO 2016: CRD42016037352 .	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11  3767  25 INTEGRATIVE EPIGENOMIC ANALYSIS IN DIFFERENTIATED HUMAN PRIMARY BRONCHIAL EPITHELIAL CELLS EXPOSED TO CIGARETTE SMOKE. CIGARETTE SMOKE (CS) IS ONE OF THE MAJOR RISK FACTORS FOR MANY PULMONARY DISEASES, INCLUDING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. THE FIRST LINE OF DEFENSE FOR CS EXPOSURE IS THE BRONCHIAL EPITHELIAL CELLS. ELUCIDATION OF THE EPIGENETIC CHANGES DURING CS EXPOSURE IS KEY TO GAINING A MECHANISTIC UNDERSTANDING INTO HOW MATURE AND DIFFERENTIATED BRONCHIAL EPITHELIAL CELLS RESPOND TO CS. THEREFORE, WE PERFORMED EPIGENOMIC PROFILING IN CONJUNCTION WITH TRANSCRIPTIONAL PROFILING IN WELL-DIFFERENTIATED HUMAN BRONCHIAL EPITHELIAL (HBE) CELLS CULTURED IN AIR-LIQUID INTERFACE (ALI) EXPOSED TO THE VAPOR PHASE OF CS. THE GENOME-WIDE ENRICHMENT OF HISTONE 3 LYSINE 27 ACETYLATION WAS DETECTED BY CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) IN HBE CELLS AND SUGGESTED THE PLAUSIBLE BINDING OF SPECIFIC TRANSCRIPTION FACTORS RELATED TO CS EXPOSURE. ADDITIONALLY, INTERROGATION OF CHIP-SEQ DATA WITH GENE EXPRESSION PROFILING OF HBE CELLS AFTER CS EXPOSURE FOR DIFFERENT DURATIONS (3 HOURS, 2 DAYS, 4 DAYS) SUGGESTED THAT EARLIER EPIGENETIC CHANGES (3 HOURS AFTER CS EXPOSURE) MAY BE ASSOCIATED WITH LATER GENE EXPRESSION CHANGES INDUCED BY CS EXPOSURE (4 DAYS). THE INTEGRATION OF EPIGENETICS AND GENE EXPRESSION DATA REVEALED SIGNALING PATHWAYS RELATED TO CS-INDUCED EPIGENETIC CHANGES IN HBE CELLS THAT MAY IDENTIFY NOVEL REGULATORY PATHWAYS RELATED TO CS-INDUCED COPD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12  6078  29 THE EFFECT OF CHRONIC ARSENIC EXPOSURE IN ZEBRAFISH. ARSENIC IS A PREVALENT ENVIRONMENTAL TOXIN AND A GROUP ONE HUMAN CARCINOGENIC AGENT. CHRONIC ARSENIC EXPOSURE HAS BEEN ASSOCIATED WITH MANY HUMAN DISEASES. THE AIM OF THIS STUDY IS TO EVALUATE ZEBRAFISH AS AN ANIMAL MODEL TO ASSESS ARSENIC TOXICITY IN ELEVATED LONG-TERM ARSENIC EXPOSURE. WITH PROLONGED EXPOSURE (6 MONTHS) TO VARIOUS CONCENTRATIONS OF ARSENIC FROM 50 PPB TO 300 PPB, EFFECTS OF ARSENIC ACCUMULATION IN ZEBRAFISH TISSUES, AND PHENOTYPES WERE INVESTIGATED. RESULTS SHOWED THAT THERE ARE NO SIGNIFICANT CHANGES OF ARSENIC RETENTION IN ZEBRAFISH TISSUES, AND ZEBRAFISH DID NOT EXHIBIT ANY VISIBLE TUMOR FORMATION UNDER ARSENIC EXPOSURE CONDITIONS. HOWEVER, THE ZEBRAFISH DEMONSTRATE A DYSFUNCTION IN THEIR NEUROLOGICAL SYSTEM, WHICH IS REFLECTED BY A REDUCTION OF LOCOMOTIVE ACTIVITY. MOREOVER, ELEVATED LEVELS OF THE SUPEROXIDE DISMUTASE (SOD2) PROTEIN WERE DETECTED IN THE EYE AND LIVER, SUGGESTING INCREASED OXIDATIVE STRESS. IN ADDITION, THE PROGENIES OF ARSENIC-TREATED PARENTS DISPLAYED A SMALLER BIOMASS (FOUR-FOLD REDUCTION IN BODY WEIGHT) COMPARED WITH THOSE FROM THEIR PARENTAL CONTROLS. THIS RESULT INDICATES THAT ARSENIC MAY INDUCE GENETIC OR EPIGENETIC CHANGES THAT ARE THEN PASSED ON TO THE NEXT GENERATION. OVERALL, THIS STUDY DEMONSTRATES THAT ZEBRAFISH IS A CONVENIENT VERTEBRATE MODEL WITH ADVANTAGES IN THE EVALUATION OF ARSENIC-ASSOCIATED NEUROLOGICAL DISORDERS AS WELL AS ITS INFLUENCES ON THE OFFSPRING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13   219  32 ACUTE IMMOBILIZATION STRESS FOLLOWING CONTEXTUAL FEAR CONDITIONING REDUCES FEAR MEMORY: TIMING IS ESSENTIAL. BACKGROUND: HISTONE ACETYLATION IS REGULATED IN RESPONSE TO STRESS AND PLAYS AN IMPORTANT ROLE IN LEARNING AND MEMORY. CHRONIC STRESS IS KNOWN TO DETERIORATE COGNITION, WHEREAS ACUTE STRESS FACILITATES MEMORY FORMATION. HOWEVER, WHETHER ACUTE STRESS FACILITATES MEMORY FORMATION WHEN IT IS APPLIED AFTER FEAR STIMULATION IS NOT YET KNOWN. THEREFORE, THIS STUDY AIMED TO INVESTIGATE THE EFFECT OF ACUTE STRESS APPLIED AFTER FEAR TRAINING ON MEMORY FORMATION, MRNA EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), EPIGENETIC REGULATION OF BDNF EXPRESSION, AND CORTICOSTERONE LEVEL IN MICE IN VIVO. METHODS: MICE WERE SUBJECTED TO ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 OR 90 MIN AFTER CONTEXTUAL FEAR CONDITIONING TRAINING, AND ACETYLATION OF HISTONE 3 AT LYSINE 14 (H3K14) AND LEVEL OF CORTICOSTERONE WERE MEASURED USING WESTERN BLOT ANALYSIS AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. A FREEZING BEHAVIOR TEST WAS PERFORMED 24 H AFTER TRAINING, AND MRNA EXPRESSION OF BDNF WAS MEASURED USING REAL-TIME POLYMERASE CHAIN REACTIONS. DIFFERENT GROUPS OF MICE WERE USED FOR EACH TEST. RESULTS: FREEZING BEHAVIOR SIGNIFICANTLY DECREASED WITH THE DOWN-REGULATION OF BDNF MRNA EXPRESSION CAUSED BY ACUTE IMMOBILIZATION STRESS AT 60 MIN AFTER FEAR CONDITIONING TRAINING OWING TO THE REDUCTION OF H3K14 ACETYLATION. HOWEVER, BDNF MRNA EXPRESSION AND H3K14 ACETYLATION WERE NOT REDUCED IN ANIMALS SUBJECTED TO IMMOBILIZATION STRESS AT 90 MIN AFTER THE TRAINING. FURTHER, THE CORTICOSTERONE LEVEL WAS SIGNIFICANTLY HIGH IN MICE SUBJECTED TO IMMOBILIZATION STRESS AT 60 MIN AFTER THE TRAINING. CONCLUSION: ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 MIN AFTER FEAR CONDITIONING TRAINING IMPAIRED MEMORY FORMATION AND REDUCED BDNF MRNA EXPRESSION AND H3K14 ACETYLATION IN THE HIPPOCAMPUS OF MICE OWING TO THE HIGH LEVEL OF CORTICOSTERONE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  4947  38 PATERNAL SEPSIS INDUCES ALTERATIONS OF THE SPERM METHYLOME AND DAMPENS OFFSPRING IMMUNE RESPONSES-AN ANIMAL STUDY. BACKGROUND: SEPSIS REPRESENTS THE UTMOST SEVERE CONSEQUENCE OF INFECTION, INVOLVING A DYSREGULATED AND SELF-DAMAGING IMMUNE RESPONSE OF THE HOST. WHILE DIFFERENT ENVIRONMENTAL EXPOSURES LIKE CHRONIC STRESS OR MALNUTRITION HAVE BEEN WELL DESCRIBED TO REPROGRAM THE GERMLINE AND SUBSEQUENTLY OFFSPRING ATTRIBUTES, THE INTERGENERATIONAL IMPACT OF SEPSIS AS A TREMENDOUS IMMUNOLOGICAL STRESSOR HAS NOT BEEN EXAMINED YET. METHODS: POLYMICROBIAL SEPSIS IN 12-WEEK-OLD MALE C57BL/6 MICE WAS INDUCED BY CECAL LIGATION AND PUNCTURE (CLP), FOLLOWED BY A MATING OF THE MALE SURVIVORS (OR APPROPRIATE SHAM CONTROL ANIMALS) 6 WEEKS LATER WITH HEALTHY FEMALES. ALVEOLAR MACROPHAGES OF OFFSPRING ANIMALS WERE ISOLATED AND STIMULATED WITH EITHER LPS OR ZYMOSAN, AND SUPERNATANT LEVELS OF TNF-ALPHA WERE QUANTIFIED BY ELISA. FURTHERMORE, SYSTEMIC CYTOKINE RESPONSE TO INTRAPERITONEALLY INJECTED LPS WAS ASSESSED AFTER 24 H. ALSO, MORPHOLOGY, MOTILITY, AND GLOBAL DNA METHYLATION OF THE SEPSIS SURVIVORS' SPERM WAS EXAMINED. RESULTS: COMPARATIVE REDUCED REDUCTION BISULFITE SEQUENCING (RRBS) OF SPERM REVEALED CHANGES OF DNA METHYLATION (N = 381), MOST PRONOUNCED IN THE INTERGENIC GENOME AS WELL AS WITHIN INTRONS OF DEVELOPMENTALLY RELEVANT GENES. OFFSPRING OF SEPSIS FATHERS EXHIBITED A SLIGHT DECREASE IN BODY WEIGHT, WITH A MORE PRONOUNCED WEIGHT DIFFERENCE IN MALE ANIMALS (CLP VS. SHAM). MALE DESCENDANTS OF SEPSIS FATHERS, BUT NOT FEMALE DESCENDANTS, EXHIBITED LOWER PLASMA CONCENTRATIONS OF IL-6, TNF-ALPHA, AND IL-10 24 H AFTER INJECTION OF LPS. IN LINE, ONLY ALVEOLAR MACROPHAGES OF MALE DESCENDANTS OF SEPSIS FATHERS PRODUCED LESS TNF-ALPHA UPON ZYMOSAN STIMULATION COMPARED TO SHAM DESCENDANTS, WHILE LPS RESPONSES KEPT UNCHANGED. CONCLUSION: WE CAN PROVE THAT MALE-BUT SURPRISINGLY NOT FEMALE-DESCENDANTS OF POST-SEPSIS FATHERS SHOW A DAMPENED SYSTEMIC AS WELL AS PULMONARY IMMUNE RESPONSE. BASED ON THIS OBSERVATION OF AN IMMUNE HYPO-RESPONSIVITY, WE PROPOSE THAT MALE DESCENDANTS OF SEPSIS FATHERS ARE AT RISK TO DEVELOP FUNGAL AND BACTERIAL INFECTIONS AND MIGHT BENEFIT FROM THERAPEUTIC IMMUNE MODULATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15   642  35 BIOMARKERS OF PARTICULATE MATTER EXPOSURE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: A SYSTEMATIC REVIEW. BACKGROUND: IN RECENT YEARS, AMBIENT PARTICULATE MATTER (PM) EXPOSURE HAS BEEN STRONGLY LINKED WITH HEALTH EFFECTS. ELEVATED LEVELS OF PM IN POLLUTED AIR HAVE BEEN CORRELATED WITH THE ONSET AND DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS SYSTEMATIC REVIEW WAS CONDUCTED TO EVALUATE BIOMARKERS THAT COULD REFLECT THE EFFECTS OF PM EXPOSURE IN PATIENTS WITH COPD. METHODS: WE PERFORMED A SYSTEMATIC REVIEW OF STUDIES PUBLISHED ON BIOMARKERS ASSOCIATED WITH PM EXPOSURE IN PATIENTS WITH COPD BETWEEN JANUARY 01, 2012 AND JUNE 30, 2022 IN PUBMED/MEDLINE, EMBASE, AND COCHRANE DATABASES. STUDIES THAT INCLUDED DATA ON BIOMARKERS WITH COPD EXPOSED PM WERE ELIGIBLE FOR INCLUSION. BIOMARKERS WERE CLASSIFIED INTO 4 GROUPS ACCORDING TO THEIR MECHANISMS. RESULTS: OF THE 105 STUDIES IDENTIFIED, 22 WERE INCLUDED IN THIS STUDY. NEARLY 50 BIOMARKERS HAVE BEEN PROPOSED IN THE STUDIES INCLUDED IN THIS REVIEW, AND THE MOST STUDIED IN RELATION TO PM ARE SEVERAL INTERLEUKINS. VARIOUS MECHANISMS HAVE BEEN REPORTED BY WHICH PM INDUCES AND AGGRAVATES COPD. SIX STUDIES RELATED TO OXIDATIVE STRESS, ONE RELATED TO DIRECT EFFECT OF INNATE AND ADAPTIVE IMMUNE SYSTEMS, 16 ASSOCIATED WITH GENETIC REGULATION OF INFLAMMATION, AND TWO RELATED TO EPIGENETIC REGULATION OF PHYSIOLOGY AND SUSCEPTIBILITY WERE FOUND. BIOMARKERS RELATED TO THESE MECHANISMS WERE DETECTED IN SERUM, SPUTUM, URINE, EXHALED BREATH CONCENTRATION (EBC), AND SHOWED VARIOUS CORRELATIONS WITH PM IN COPD. CONCLUSIONS: VARIOUS BIOMARKERS HAVE SHOWN POTENTIAL IN PREDICTING THE EXTENT OF PM EXPOSURE IN COPD PATIENTS. FUTURE STUDIES ARE NEEDED TO ESTABLISH RECOMMENDATIONS FOR REGULATION TO REDUCE AIRBORNE PM, WHICH COULD BE USED TO DEVELOP STRATEGIES FOR PREVENTION AND MANAGEMENT OF ENVIRONMENTAL RESPIRATORY DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16  5743  25 SMOKING SUPPRESSES THE THERAPEUTIC POTENTIAL OF ADIPOSE STEM CELLS IN CROHN'S DISEASE PATIENTS THROUGH EPIGENETIC CHANGES. PATIENTS WITH CROHN'S DISEASE (CD) WHO SMOKE ARE KNOWN TO HAVE A WORSE PROGNOSIS THAN NEVER-SMOKERS AND A HIGHER RISK FOR POST-SURGICAL RECURRENCE, WHEREAS PATIENTS WHO QUIT SMOKING AFTER SURGERY HAVE SIGNIFICANTLY LOWER POST-OPERATIVE RECURRENCE. THE HYPOTHESIS WAS THAT SMOKING INDUCES EPIGENETIC CHANGES THAT IMPAIR THE CAPACITY OF ADIPOSE STEM CELLS (ASCS) TO SUPPRESS THE IMMUNE SYSTEM. IT WAS ALSO QUESTIONED WHETHER THIS IMPAIRMENT REMAINS IN EX-SMOKERS WITH CD. ASCS WERE ISOLATED FROM NON-SMOKERS, SMOKERS AND EX-SMOKERS WITH CD AND THEIR INTERACTIONS WITH IMMUNE CELLS WERE STUDIED. THE ASCS FROM BOTH SMOKERS AND EX-SMOKERS PROMOTED MACROPHAGE POLARIZATION TO AN M1 PRO-INFLAMMATORY PHENOTYPE, WERE NOT ABLE TO INHIBIT T- AND B-CELL PROLIFERATION IN VITRO AND ENHANCED THE GENE AND PROTEIN EXPRESSION OF INFLAMMATORY MARKERS INCLUDING INTERLEUKIN-1B. GENOME-WIDE EPIGENETIC ANALYSIS USING TWO DIFFERENT BIOINFORMATIC APPROACHES REVEALED SIGNIFICANT CHANGES IN THE METHYLATION PATTERNS OF GENES THAT ARE CRITICAL FOR WOUND HEALING, IMMUNE AND METABOLIC RESPONSE AND P53-MEDIATED DNA DAMAGE RESPONSE IN ASCS FROM SMOKERS AND EX-SMOKERS WITH CD. IN CONCLUSION, CIGARETTE SMOKING INDUCES A PRO-INFLAMMATORY EPIGENETIC SIGNATURE IN ASCS THAT LIKELY COMPROMISES THEIR THERAPEUTIC POTENTIAL.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
17  4989  30 PCSK9 IS INCREASED IN CEREBROSPINAL FLUID OF INDIVIDUALS WITH ALCOHOL USE DISORDER. BACKGROUND: RECENT STUDIES HAVE SHOWN THAT ALCOHOL USE AFFECTS THE REGULATION AND EXPRESSION OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN 9 (PCSK9). WHILE A MAJOR ROLE OF PCSK9 IN HEPATIC FUNCTION AND LIPID REGULATION HAS BEEN CLEARLY ESTABLISHED, OTHER PLEIOTROPIC EFFECTS REMAIN POORLY UNDERSTOOD. EXISTING RESEARCH SUGGESTS A POSITIVE ASSOCIATION BETWEEN PCSK9 EXPRESSION IN THE BRAIN AND PSYCHOPATHOLOGY, WITH INCREASED LEVELS OF PCSK9 IN THE CEREBROSPINAL FLUID (CSF) OF INDIVIDUALS WITH DEMENTIA AND EPIGENETIC MODIFICATIONS OF PCSK9 ASSOCIATED WITH ALCOHOL USE DISORDER (AUD). IN THIS STUDY, WE HYPOTHESIZED THAT CHRONIC ALCOHOL USE WOULD INCREASE PCSK9 EXPRESSION IN CSF. METHODS: PCSK9 LEVELS IN CSF WERE MEASURED IN INDIVIDUALS WITH AUD (N = 42) ADMITTED TO AN INPATIENT REHABILITATION PROGRAM AND CONTROLS (N = 25). CSF SAMPLES IN AUD WERE ASSESSED AT 2 TIME POINTS, AT DAY 5 AND DAY 21 AFTER ADMISSION. FURTHERMORE, PLASMA SAMPLES WERE COLLECTED AND MEASURED FROM THE INDIVIDUALS WITH AUD. RESULTS: PCSK9 IN CSF WAS SIGNIFICANTLY INCREASED IN THE AUD GROUP AT DAY 5 AND DAY 21 COMPARED TO THE CONTROLS (P < 0.0001). PLASMA PCSK9 LEVELS WERE CORRELATED POSITIVELY WITH CSF PCSK9 LEVELS IN AUD (P = 0.0493). CONCLUSIONS: OUR DATA SUGGEST THAT PCSK9 IS ELEVATED IN THE CSF OF INDIVIDUALS WITH AUD, WHICH MAY INDICATE A POTENTIAL ROLE OF PCSK9 IN AUD. ADDITIONAL STUDIES ARE NECESSARY TO FURTHER ELUCIDATE THE FUNCTIONS OF PCSK9 IN THE BRAIN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18   849  37 CHILDHOOD TRAUMATIZATION IS ASSOCIATED WITH DIFFERENCES IN TRPA1 PROMOTER METHYLATION IN FEMALE PATIENTS WITH MULTISOMATOFORM DISORDER WITH PAIN AS THE LEADING BODILY SYMPTOM. BACKGROUND: THE CONSTRUCT OF MULTISOMATOFORM DISORDER (MSD) IS A COMMON POINT OF REFERENCE FOR PATIENTS IN DIFFERENT SOMATIC AND PSYCHOSOMATIC SPECIALTIES AND THEREFORE USEFUL IN STUDYING LARGE WELL-CHARACTERIZED COHORTS OF A PROTOTYPE OF A SOMATOFORM DISORDER AND IN PARALLEL AS A FUNCTIONAL SOMATIC SYNDROME (FSS). THIS DISORDER IS CHARACTERIZED BY DISTRESSING AND FUNCTIONALLY DISABLING SOMATIC SYMPTOMS WITH CHRONIC PAIN AS THE MOST FREQUENT AND CLINICALLY RELEVANT COMPLAINT. PAIN IS PERCEIVED BY NOCICEPTIVE NERVE FIBERS AND TRANSFERRED THROUGH THE GENERATION OF ACTION POTENTIALS BY DIFFERENT RECEPTOR MOLECULES KNOWN TO DETERMINE PAIN SENSITIVITY IN PATHOPHYSIOLOGICAL PROCESSES. PREVIOUS STUDIES HAVE SHOWN THAT FOR THE TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1), RECEPTOR METHYLATION OF A PARTICULAR CPG DINUCLEOTIDE IN THE PROMOTER REGION IS INVERSELY ASSOCIATED WITH BOTH HEAT PAIN AND PRESSURE PAIN THRESHOLDS. IN THIS STUDY, WE HYPOTHESIZED THAT TRPA1 PROMOTER METHYLATION REGULATES PAIN SENSITIVITY OF PATIENTS WITH MULTISOMATOFORM DISORDER (MSD). A COHORT OF 151 PATIENTS WITH MSD AND 149 MATCHED HEALTHY VOLUNTEERS WERE EVALUATED USING QUANTITATIVE SENSORY TESTING, CLINICAL AND PSYCHOMETRIC ASSESSMENT, AND METHYLATION ANALYSIS USING DNA ISOLATED FROM WHOLE BLOOD. RESULTS: WE FOUND CPG -628 TO BE CORRELATED WITH MECHANICAL PAIN THRESHOLD AND CPG -411 TO BE CORRELATED WITH MECHANICAL PAIN THRESHOLD IN FEMALE VOLUNTEERS, I.E., HIGHER METHYLATION LEVELS LEAD TO HIGHER PAIN THRESHOLDS. A NOVEL FINDING IS THAT METHYLATION LEVELS WERE SIGNIFICANTLY DIFFERENT BETWEEN PATIENTS WITH NO AND SEVERE LEVELS OF CHILDHOOD TRAUMA. CPG METHYLATION ALSO CORRELATED WITH PSYCHOMETRIC ASSESSMENT OF PAIN AND PAIN LEVELS RATED ON A VISUAL ANALOG SCALE. CONCLUSION: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT EPIGENETIC REGULATION OF TRPA1 PLAYS A ROLE IN MECHANICAL PAIN SENSITIVITIES IN HEALTHY VOLUNTEERS. THEY FURTHER PROVIDE EVIDENCE FOR THE POSSIBLE INFLUENCE OF CHILDHOOD TRAUMATIC EXPERIENCES ON THE EPIGENETIC REGULATION OF TRPA1 IN PATIENTS WITH MSD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19  5479  23 RESVERATROL ATTENUATES CIGARETTE SMOKE EXTRACT INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY ACCELERATED LUNG AGING. SMOKING IS THE CRITICAL RISK FACTOR FOR COPD. CELLULAR SENESCENCE OF AIRWAY EPITHELIAL CELLS IS THE CYTOLOGICAL BASIS OF ACCELERATED LUNG AGING IN COPD, AND THE REGULATION OF MICRORNAS (MIRNAS) IS THE CENTRAL EPIGENETIC MECHANISM OF CELLULAR SENESCENCE. RESVERATROL (RES) IS A POLYPHENOL WITH ANTI-AGING PROPERTIES. THIS STUDY INVESTIGATED WHETHER RES ATTENUATES CIGARETTE SMOKE EXTRACT (CSE)-INDUCED CELLULAR SENESCENCE IN HUMAN AIRWAY EPITHELIAL CELLS (BEAS-2B) THROUGH THE MIR-34A/SIRT1/NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) PATHWAY. BEAS-2B CELLS WERE TREATED WITH RES, CSE AND TRANSFECTED WITH MIR-34A-5P MIMICS. CELLULAR SENESCENCE WAS EVALUATED BY SENESCENCE -RELATED BETA-GALACTOSIDASE (SA-BETA-GAL) STAINING AND EXPRESSION OF SENESCENCE-RELATED GENES (P16, P21, AND P53). THE EXPRESSIONS OF MIR-34A-5P, SIRT1, AND NF-KAPPAB P65 WERE EXAMINED USING QUANTITATIVE REAL TIME POLYMERASE CHAIN REACTION AND WESTERN BLOTTING. THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) WERE ASSESSED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. THE BINDING BETWEEN MIR-34A-5P AND SIRT1 WAS CONFIRMED BY DUAL-LUCIFERASE REPORTER ASSAY. THE RESULTS SHOWED THAT CSE DOSE-DEPENDENTLY DECREASED CELL VIABILITY AND ELEVATED CELLULAR SENESCENCE, CHARACTERIZED BY INCREASED SA-BETA-GAL STAINING AND SENESCENCE-RELATED GENE EXPRESSIONS (P16, P21, AND P53). FURTHER, CSE DOSE-DEPENDENTLY INCREASED THE EXPRESSION OF MIR-34A-5P AND SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN BEAS-2B CELLS. PRETREATMENT WITH RES INHIBITED CSE-INDUCED CELLULAR SENESCENCE AND SECRETION OF SASP CYTOKINES (IL-1BETA, IL-6, IL-8, TNF-ALPHA) IN A DOSE-DEPENDENT MANNER. MOREOVER, RES REVERSED THE CSE-INDUCED DOWN-REGULATION OF SIRT1 AND UP-REGULATION OF MIR-34A-5P AND NF-KAPPAB P65. SIRT1 IS A TARGET OF MIR-34A-5P. OVEREXPRESSION OF MIR-34A-5P VIA TRANSFECTION WITH MIR-34A-5P MIMIC IN BEAS-2B CELLS ATTENUATED THE INHIBITORY EFFECT OF RES ON CELLULAR SENESCENCE, ACCOMPANIED BY REVERSING THE EXPRESSION OF SIRT1 AND NF-KAPPAB P65. IN CONCLUSION, RES ATTENUATED CSE-INDUCED CELLULAR SENESCENCE IN BEAS-2B CELLS BY REGULATING THE MIR-34A/SIRT1/NF-KAPPAB PATHWAY, WHICH MAY PROVIDE A NEW APPROACH FOR COPD TREATMENT.	2022	
                                                                                                                                                                                                                                                
20  1848  35 EFFECTS OF VENLAFAXINE ON THE EXPRESSION LEVEL AND METHYLATION STATUS OF GENES INVOLVED IN OXIDATIVE STRESS IN RATS EXPOSED TO A CHRONIC MILD STRESS. RECENT HUMAN AND ANIMAL STUDIES INDICATE THAT OXIDATIVE AND NITROSATIVE STRESS MAY PLAY A ROLE IN THE AETIOLOGY AND PATHOGENESIS OF DEPRESSION. THIS STUDY INVESTIGATES THE EFFECT OF CHRONIC ADMINISTRATION OF THE SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITOR, VENLAFAXINE, ON THE EXPRESSION AND METHYLATION STATUS OF SOD1, SOD2, GPX1, GPX4, CAT, NOS1 AND NOS2 IN THE BRAIN AND BLOOD OF RATS EXPOSED TO A CHRONIC MILD STRESS (CMS) MODEL OF DEPRESSION. SEPARATE GROUPS OF ANIMALS WERE EXPOSED TO CMS FOR 2 OR 7 WEEKS; THE SECOND GROUP RECEIVED SALINE OR VENLAFAXINE (10 MG/KG/D, IP) FOR 5 WEEKS. AFTER COMPLETION OF BOTH STRESS CONDITIONS AND DRUG ADMINISTRATION, THE MRNA AND PROTEIN EXPRESSION OF SELECTED GENES AND THE METHYLATION STATUS OF THEIR PROMOTERS WERE MEASURED IN PERIPHERAL MONONUCLEAR BLOOD CELLS (PBMCS) AND IN BRAIN STRUCTURES (HIPPOCAMPUS, AMYGDALA, HYPOTHALAMUS, MIDBRAIN, CORTEX, BASAL GANGLIA) WITH THE USE OF TAQMAN GENE EXPRESSION ASSAY, WESTERN BLOT AND METHYLATION-SENSITIVE HIGH-RESOLUTION MELTING TECHNIQUES. CMS CAUSED A DECREASE IN SUCROSE CONSUMPTION, AND THIS EFFECT WAS NORMALIZED BY FLUOXETINE. IN PBMCS, SOD1, SOD2 AND NOS2 MRNA EXPRESSION CHANGED ONLY AFTER VENLAFAXINE ADMINISTRATION. IN BRAIN, CAT, GPX1, GPX4 AND NOS1 GENE EXPRESSION CHANGED FOLLOWING CMS OR VENLAFAXINE EXPOSURE, MOST PROMINENTLY IN THE HIPPOCAMPUS, MIDBRAIN AND BASAL GANGLIA. CMS INCREASED THE METHYLATION OF THE GPX1 PROMOTER IN PBMCS, THE SECOND GPX4 PROMOTER IN MIDBRAIN AND BASAL GANGLIA, AND SOD1 AND SOD2 IN HIPPOCAMPUS. THE CMS ANIMALS TREATED WITH VENLAFAXINE DISPLAYED A SIGNIFICANTLY HIGHER CAT LEVEL IN MIDBRAIN AND CEREBRAL CORTEX. CMS CAUSED AN ELEVATION OF GPX4 IN THE HIPPOCAMPUS, WHICH WAS LOWERED IN CEREBRAL CORTEX BY VENLAFAXINE. THE RESULTS INDICATE THAT CMS AND VENLAFAXINE ADMINISTRATION AFFECT THE METHYLATION OF PROMOTERS OF GENES INVOLVED IN OXIDATIVE AND NITROSATIVE STRESS. THEY ALSO INDICATE THAT PERIPHERAL AND CENTRAL TISSUE DIFFER IN THEIR RESPONSE TO STRESS OR ANTIDEPRESSANT TREATMENTS. IT IS POSSIBLE THAT THAT APART FROM DNA METHYLATION, A CRUCIAL ROLE OF EXPRESSION LEVEL OF GENES MAY BE PLAYED BY OTHER FORMS OF EPIGENETIC REGULATION, SUCH AS HISTONE MODIFICATION OR MICRORNA INTERFERENCE. THESE FINDINGS PROVIDE STRONG EVIDENCE FOR THESIS THAT ANALYSIS OF THE LEVEL OF MRNA AND PROTEIN EXPRESSION AS WELL AS THE STATUS OF PROMOTER METHYLATION CAN HELP IN UNDERSTANDING THE PATHOMECHANISMS OF MENTAL DISEASES, INCLUDING DEPRESSION, AND THE MECHANISMS OF ACTION OF DRUGS EFFECTIVE IN THEIR THERAPY.	2020