1  5518 118 RISK FACTORS AND FUTURE DIRECTIONS FOR PREVENTING AND DIAGNOSING EXERTIONAL RHABDOMYOLYSIS. EXERTIONAL RHABDOMYOLYSIS MAY OCCUR WHEN AN INDIVIDUAL IS SUBJECTED TO STRENUOUS PHYSICAL EXERCISE. IT IS OCCASIONALLY ASSOCIATED WITH MYOGLOBINURIA (I.E. "COLA-COLORED" URINE) ALONGSIDE MUSCLE PAIN AND WEAKNESS. THE PATHOPHYSIOLOGY OF EXERTIONAL RHABDOMYOLYSIS INVOLVES STRIATED MUSCLE DAMAGE AND THE RELEASE OF CELLULAR COMPONENTS INTO EXTRACELLULAR FLUID AND BLOODSTREAM. THIS CAN CAUSE ACUTE RENAL FAILURE, ELECTROLYTE ABNORMALITIES, ARRHYTHMIAS AND POTENTIALLY DEATH. EXERTIONAL RHABDOMYOLYSIS IS OBSERVED IN HIGH-PERFORMANCE ATHLETES WHO ARE SUBJECTED TO INTENSE, REPETITIVE AND/OR PROLONGED EXERCISE BUT IS ALSO OBSERVED IN UNTRAINED INDIVIDUALS AND HIGHLY TRAINED OR ELITE GROUPS OF MILITARY PERSONNEL. SEVERAL RISK FACTORS HAVE BEEN REPORTED TO INCREASE THE LIKELIHOOD OF THE CONDITION IN ATHLETES, INCLUDING: VIRAL INFECTION, DRUG AND ALCOHOL ABUSE, EXERCISE IN INTENSELY HOT AND HUMID ENVIRONMENTS, GENETIC POLYMORPHISMS (E.G. SICKLE CELL TRAIT AND MCARDLE DISEASE) AND EPIGENETIC MODIFICATIONS. THIS ARTICLE REVIEWS SEVERAL OF THESE RISK FACTORS AND PROPOSES SCREENING PROTOCOLS TO IDENTIFY INDIVIDUAL SUSCEPTIBILITY TO EXERTIONAL RHABDOMYOLYSIS AS WELL AS THE RELEVANCE OF PROTEOMICS FOR THE EVALUATION OF POTENTIAL BIOMARKERS OF MUSCLE DAMAGE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  5542  18 ROLE OF DNA METHYLATION ON HUMAN CTSG IN DERMATOMYOSITIC MYOIDEUM. DERMATOMYOSITIS (DM) IS A MULTIFACTORIAL CHRONIC AUTOIMMUNE DISORDER WITH CHARACTERISTIC SKIN AND MUSCLE PATHOLOGICAL CHANGES AND INVOLVEMENT OF OTHER ORGAN SYSTEMS. CATHEPSIN G (CTSG) CONTRIBUTES TO THE RISK OF DEVELOPING DM, WHICH IS LIKELY TO BE ASSOCIATED WITH INFLAMMATORY CYTOKINES. DIFFERENTIAL DNA METHYLATION ON CTSG HAS BEEN DETERMINED TO BE IMPLICATED IN DM IN VIVO. HOWEVER, THE UNDERLYING MECHANISM OF THIS EPIGENETIC REGULATION ON CTST IN DM IS POORLY EXPLORED. IN THIS STUDY, WE INVESTIGATED DNA METHYLATION SIGNATURE ON CTSG AT SINGLE-NUCLEOTIDE RESOLUTION IN QUADRICEPS FEMORIS OF SIX DM PATIENTS AND PARACANCEROUS MUSCLES OF THREE PATIENTS WITH RHABDOMYOSARCOMA ON INNER THIGH USING PYROSEQUENCING AND OBSERVED THAT THE OVERALL DNA METHYLATION LEVEL OF CTSG WAS INCREASED IN DM COMPARED WITH CONTROL, IN WHICH CPG LOCI AT THIRD AND FOURTH EXONS BUT NOT PROMOTER CONTRIBUTED TO THE SIGNIFICANT HYPERMETHYLATION. FURTHERMORE, WE OBSERVED THAT TRANSCRIPTION AND DNA METHYLATION OF CTSG WERE BOTH DECLINED IN DNMT3A KNOCKDOWN COMPARED WITH DNMT1 AND DNMT3B KNOCKDOWN IN HUMAN SKELETAL MUSCLE SJCRH30 AND A-204 CELL LINES EXPOSED TO TUMOR NECROSIS FACTOR-ALPHA. FURTHERMORE, BORTEZOMIB (NF-KAPPAB INHIBITOR) AND BREVILIN A (JAK/STAT INHIBITOR) WERE EMPLOYED TO TREAT SJCRH30 AND A-204 CELLS, RESPECTIVELY, AND WE OBSERVED THAT CTSG WAS HYPOMETHYLATED AND SILENCED AFTER BORTEZOMIB TREATMENT COMPARED WITH UNTREATMENT AND BREVILIN A. FINALLY, CHROMATIN IMMUNOPRECIPITATION-QUANTITATIVE POLYMERASE CHAIN REACTION INDICATED THAT DNMT3A COULD BIND TO THE CODING REGIONS OF CTSG AND THE INTERACTION WAS DEPENDENT ON NF-KAPPAB ACTIVITY. TAKEN TOGETHER, OUR RESULTS DETERMINED A NOVEL REGULATORY MECHANISM OF DNA METHYLATION ON CTSG IN DM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3  2904  15 GENE BODY METHYLATION FACILITATES THE TRANSCRIPTION OF CTSG VIA ANTISENSE LNCRNA AL136018.1 IN DERMATOMYOSITIC MYOIDEUM. DERMATOMYOSITIS (DM) IS CHARACTERIZED AS A CHRONIC AUTOIMMUNE DISORDER WITH MULTIPLE ORGAN INVOLVEMENT. OUR PREVIOUS STUDY HAS REVEALED THAT CATHEPSIN G (CTSG) HIGHLY EXPRESSED IN DERMATOMYOSITIC IN VIVO IS REGULATED BY DNMT3A THROUGH DNA METHYLATION OF 5'-C-PHOSPHATE-G-3' LOCI AT EXONS AND INTRONS. HOWEVER, THE MECHANISM OF GENE BODY METHYLATION ON REGULATING CTSG TRANSCRIPTION REMAINS UNKNOWN. IN THIS STUDY, WE STUDIED QUADRICEPS FEMORIS TISSUES OF SIX DM PATIENTS, AND OBSERVED THAT ANTISENSE LONG NONCODING RNA AL136018.1 CONTIGUOUS TO CTSG WAS HIGHLY EXPRESSED IN SKELETAL MUSCLE TISSUES OF DM AND POSITIVELY CORRELATED WITH THE TRANSCRIPTION LEVEL AND DNA METHYLATION LEVEL IN GENE BODY OF CTSG IN VIVO. MOREOVER, WE OBSERVED THAT THE LONGER TRANSCRIPT OF AL136018.1 (AL136018.1-201) COULD BIND TO THIRD AND FOURTH EXONS AND THIRD INTRON OF CTSG VIA THE 3'-END. FINALLY, AL136018.1-201 COULD RECRUIT DNMT3A TOWARDS GENE BODY VIA 5'-TERMINAL FOR ADDING DNA METHYLATION AND FACILITATING TRANSCRIPTION OF CTSG. TAKEN TOGETHER, OUR DATA UNCOVERED A NOVEL EPIGENETIC MECHANISM BEHIND THE GENE BODY METHYLATION FOR TRANSCRIPTIONAL REGULATION OF CTSG IN DM.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4  5686  20 SICKLE CELL DISEASE: CLINICAL PRESENTATION AND MANAGEMENT OF A GLOBAL HEALTH CHALLENGE. SICKLE CELL DISEASE IS AN AUTOSOMAL RECESSIVE, MULTISYSTEM DISORDER, CHARACTERISED BY CHRONIC HAEMOLYTIC ANAEMIA, PAINFUL EPISODES OF VASO-OCCLUSION, PROGRESSIVE ORGAN FAILURE AND A REDUCED LIFE EXPECTANCY. SICKLE CELL DISEASE IS THE MOST COMMON MONOGENETIC DISEASE, WITH MILLIONS AFFECTED WORLDWIDE. IN WELL-RESOURCED COUNTRIES, COMPREHENSIVE CARE PROGRAMS HAVE INCREASED LIFE EXPECTANCY OF SICKLE CELL DISEASE PATIENTS, WITH ALMOST ALL INFANTS SURVIVING INTO ADULTHOOD. THERAPEUTIC OPTIONS FOR SICKLE CELL DISEASE PATIENTS ARE HOWEVER, STILL SCARCE. PREDICTORS OF SICKLE CELL DISEASE SEVERITY AND A BETTER UNDERSTANDING OF PATHOPHYSIOLOGY AND (EPI)GENETIC MODIFIERS ARE WARRANTED AND COULD LEAD TO MORE PRECISE MANAGEMENT AND TREATMENT. THIS REVIEW PROVIDES AN EXTENSIVE SUMMARY OF THE PATHOPHYSIOLOGY AND MANAGEMENT OF SICKLE CELL DISEASE AND ENCOMPASSES THE CHARACTERISTICS, COMPLICATIONS AND CURRENT AND FUTURE TREATMENT OPTIONS OF THE DISEASE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  6149  21 THE EXPRESSION PROFILE OF MIR-23B IS NOT ALTERED IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHIES. IDIOPATHIC INFLAMMATORY MYOPATHIES (IIM) BELONG TO A GROUP OF AUTOIMMUNE DISORDERS, PRIMARILY CHARACTERIZED BY CHRONIC INFLAMMATION OF HUMAN SKELETAL MUSCLE TISSUE. THE ETIOLOGY OF THESE DISEASES IS UNKNOWN, HOWEVER, GENETIC PREDISPOSITION PLAYS A SIGNIFICANT ROLE IN DISEASE ONSET. BESIDE THE KNOWN GENETIC RISK LOCATED IN THE MHC COMPLEX, THE EPIGENETIC MODIFICATIONS INCLUDING CHANGES IN MIRNAS EXPRESSION PROFILES HAVE BEEN RECENTLY IMPLICATED RECENTLY IN MANY AUTOIMMUNE DISEASES. MICRO RNA MOLECULES ARE INVOLVED IN MANY PHYSIOLOGICAL PROCESSES, INCLUDING THE REGULATION OF THE IMMUNE RESPONSE. IN OUR STUDY WE HAVE FOCUSED ON THE MIR-23B, AS IT REPRESENTS A NOVEL PROMISING AUTOIMMUNITY REGULATOR MOLECULE. DOWNREGULATION OF MIR-23B WAS RECENTLY DESCRIBED IN PATIENTS WITH RHEUMATOID ARTHRITIS AND SYSTEMIC LUPUS ERYTHEMATOSUS. WE HAVE MEASURED THE EXPRESSION MIR-23B PERIPHERAL BLOOD MONONUCLEAR CELLS OF PATIENTS WITH DERMATOMYOSITIS AND POLYMYOSITIS. NO MEANINGFUL DIFFERENCE WAS FOUND IN COMPARISON WITH HEALTHY CONTROLS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6  1297  16 DECREASED MRNA EXPRESSION LEVELS OF DNA METHYLTRANSFERASES TYPE 1 AND 3A IN SYSTEMIC LUPUS ERYTHEMATOSUS. OBJECTIVES: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC RELAPSING AUTOIMMUNE DISEASE CHARACTERIZED BY THE PRESENCE OF AUTOANTIBODIES DIRECTED AGAINST NUCLEAR ANTIGENS AND BY CHRONIC INFLAMMATION. ALTHOUGH THE ETIOLOGY OF SLE REMAINS UNCLEAR, THE INFLUENCE OF ENVIRONMENT FACTORS, WHICH IS LARGELY REFLECTED BY THE EPIGENETIC MECHANISMS, WITH DNA METHYLATION CHANGES IN PARTICULAR, IS GENERALLY CONSIDERED AS MAIN PLAYERS IN THE PATHOGENESIS OF SLE. WE STUDIED DNA METHYLTRANSFERASES' (DNMTS) TYPE 1, 3A AND 3B TRANSCRIPT LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM PATIENTS DIAGNOSED WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND FROM THE HEALTHY CONTROL SUBJECTS. FURTHERMORE, THE ASSOCIATION OF DNMT1, DNMT3A, AND DNMT3B MRNA LEVELS WITH GENDER, AGE, AND MAJOR CLINICAL MANIFESTATIONS WAS ANALYZED. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE ISOLATED FROM 32 SLE PATIENTS AND 40 HEALTHY CONTROLS. REVERSE TRANSCRIPTION AND REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION (RT-QPCR) ANALYSES WERE USED TO DETERMINE DNMT1, DNMT3A, AND DNMT3B MRNA EXPRESSION LEVELS. RESULTS: SIGNIFICANTLY LOWER DNMT1 (P = 0.015543) AND DNMT3A (P = 0.003652) TRANSCRIPT LEVELS IN SLE PATIENTS WERE OBSERVED COMPARED WITH HEALTHY CONTROLS. NEVERTHELESS, THE DNMT3B MRNA EXPRESSION LEVELS WERE MARKEDLY LOWER COMPARED WITH DNMT1 AND DNMT3A, BOTH IN PBMCS FROM AFFECTED PATIENTS AND THOSE FROM CONTROL SUBJECTS. FURTHERMORE, THE DNMT1 TRANSCRIPT LEVELS WERE POSITIVELY CORRELATED WITH SLE DISEASE ACTIVITY INDEX (SLEDAI) (R (S) = 0.4087, P = 0.020224), WHILE THE DNMT3A TRANSCRIPT LEVELS WERE NEGATIVELY CORRELATED WITH PATIENTS AGE (R (S) = -0.3765, P = 0.03369). CONCLUSIONS: OUR ANALYSES CONFIRMED THE IMPORTANCE OF EPIGENETIC ALTERATIONS IN SLE ETIOLOGY. MOREOVER, OUR RESULTS SUGGEST THAT THE PRESENCE OF SOME CLINICAL MANIFESTATIONS, SUCH AS PHOTOTOSENSITIVITY AND ARTHRITIS, MIGHT BE ASSOCIATED WITH THE DYSREGULATION OF DNA METHYLTRANSFERASES' MRNA EXPRESSION LEVELS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                          
7  1215  24 CPG PROMOTER METHYLATION STATUS IS NOT A PROGNOSTIC INDICATOR OF GENE EXPRESSION IN BERYLLIUM CHALLENGE. INDIVIDUALS EXPOSED TO BERYLLIUM (BE) MAY DEVELOP BE SENSITIZATION (BES) AND PROGRESS TO CHRONIC BERYLLIUM DISEASE (CBD). RECENT STUDIES WITH OTHER METAL ANTIGENS SUGGEST EPIGENETIC MECHANISMS MAY BE INVOLVED IN INFLAMMATORY DISEASE PROCESSES, INCLUDING GRANULOMATOUS LUNG DISORDERS AND THAT A NUMBER OF METAL CATIONS ALTER GENE METHYLATION. THE OBJECTIVE OF THIS STUDY WAS TO DETERMINE IF BE CAN EXERT AN EPIGENETIC EFFECT ON GENE EXPRESSION BY ALTERING METHYLATION IN THE PROMOTER REGION OF SPECIFIC GENES KNOWN TO BE INVOLVED IN BE ANTIGEN-MEDIATED GENE EXPRESSION. TO INVESTIGATE THIS OBJECTIVE, THREE MACROPHAGE TUMOR MOUSE CELL LINES KNOWN TO DIFFERENTIALLY PRODUCE TUMOR NECROSIS FACTOR (TNF)-ALPHA, BUT NOT INTERFERON (IFN)-GAMMA, IN RESPONSE TO BE ANTIGEN WERE CULTURED WITH BE OR CONTROLS. FOLLOWING CHALLENGES, ELISA WERE PERFORMED TO QUANTIFY INDUCED TNFALPHA AND IFNGAMMA EXPRESSION. BISULFATE-CONVERTED DNA WAS EVALUATED BY PYROSEQUENCING TO QUANTIFY CPG METHYLATION WITHIN THE PROMOTERS OF TNFALPHA AND IFNGAMMA. BE-CHALLENGED H36.12J CELLS EXPRESSED HIGHER LEVELS OF TNFALPHA COMPARED TO EITHER H36.12E CELLS OR P388D.1 CELLS. HOWEVER, THERE WERE NO VARIATIONS IN TNFALPHA PROMOTER CPG METHYLATION LEVELS BETWEEN CELL LINES AT THE SIX CPG SITES TESTED. H36.12J CELL TNFALPHA EXPRESSION WAS SHOWN TO BE METAL-SPECIFIC BY THE INDUCTION OF SIGNIFICANTLY MORE TNFALPHA WHEN EXPOSED TO BE THAN WHEN EXPOSED TO ALUMINUM SULFATE, OR NICKEL (II) CHLORIDE, BUT NOT WHEN EXPOSED TO COBALT (II) CHLORIDE. HOWEVER, H36.12J CELL METHYLATION LEVELS AT THE SIX CPG SITES EXAMINED IN THE TNFALPHA PROMOTER DID NOT CORRELATE WITH CYTOKINE EXPRESSION DIFFERENCES. NONETHELESS, ALL THREE CELL LINES HAD SIGNIFICANTLY MORE PROMOTER METHYLATION AT THE SIX CPG SITES INVESTIGATED WITHIN THE IFNGAMMA PROMOTER (A GENE THAT IS NOT EXPRESSED) WHEN COMPARED TO THE SIX CPG SITES INVESTIGATED IN THE TNFALPHA PROMOTER, REGARDLESS OF TREATMENT CONDITION (P < 1.17 X 10(-9)). THESE FINDINGS SUGGEST THAT, IN THIS CELL SYSTEM, PROMOTER HYPO-METHYLATION MAY BE NECESSARY TO ALLOW EXPRESSION OF METAL-INDUCED TNFALPHA AND THAT PROMOTER HYPER-METHYLATION IN THE IFNGAMMA PROMOTER MAY INTERFERE WITH EXPRESSION. ALSO, AT THE DOZEN CPG SITES INVESTIGATED IN THE PROMOTER REGIONS OF BOTH GENES, BERYLLIUM HAD NO IMPACT ON PROMOTER METHYLATION STATUS, DESPITE ITS ABILITY TO INDUCE PRO-INFLAMMATORY CYTOKINE EXPRESSION.	2016	

8  2797  23 FCER1G GENE HYPOMETHYLATION IN PATIENTS WITH RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE THAT, WHEN IMPROPERLY TREATED, LEADS TO DISABILITY IN PATIENTS. VARIOUS FACTORS THAT MAY CAUSE THE DEVELOPMENT AND ACTIVITY OF RA ARE BEING CONSIDERED. EPIGENETIC FACTORS ARE ALSO RECEIVING INCREASING ATTENTION. IN OUR STUDY, WE ANALYZED THE ASSOCIATION BETWEEN FCER1G GENE METHYLATION AND RA ACTIVITY. WE CONDUCTED OUR STUDY IN 50 RA PATIENTS AND 24 CONTROLS. THE PATIENTS WERE DIVIDED INTO TWO GROUPS IN TERMS OF HIGH DISEASE ACTIVITY AND REMISSION. QUANTITATIVE REAL-TIME METHYLATION-SPECIFIC PCR WAS USED TO ANALYZE THE METHYLATION STATUS OF THE INVESTIGATED GENES. WE OBSERVED THAT RA PATIENTS HAVE LOWER LEVELS OF METHYLATION OF THE FCER1G GENE COMPARED TO CONTROLS, BUT WE DID NOT FIND ANY DIFFERENCE IN THE METHYLATION STATUS OF THIS GENE BETWEEN PATIENTS WITH HIGH DISEASE ACTIVITY AND REMISSION. THE RESULTS OF THIS STUDY SUGGEST THAT FCER1G GENE METHYLATION MAY BE A NEW POTENTIAL EPIGENETIC MARKER OF RA THAT IS INDEPENDENT OF DISEASE ACTIVITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9  5856  25 SUBSTRATE UTILISATION OF CULTURED SKELETAL MUSCLE CELLS IN PATIENTS WITH CFS. CHRONIC FATIGUE SYNDROME (CFS) PATIENTS OFTEN SUFFER FROM SEVERE MUSCLE PAIN AND AN INABILITY TO EXERCISE DUE TO MUSCLE FATIGUE. IT HAS PREVIOUSLY BEEN SHOWN THAT CFS SKELETAL MUSCLE CELLS HAVE LOWER LEVELS OF ATP AND HAVE AMP-ACTIVATED PROTEIN KINASE DYSFUNCTION. THIS STUDY OUTLINES EXPERIMENTS LOOKING AT THE UTILISATION OF DIFFERENT SUBSTRATES BY SKELETAL MUSCLE CELLS FROM CFS PATIENTS (N = 9) AND HEALTHY CONTROLS (N = 11) USING EXTRACELLULAR FLUX ANALYSIS. RESULTS SHOW THAT CFS SKELETAL MUSCLE CELLS ARE UNABLE TO UTILISE GLUCOSE TO THE SAME EXTENT AS HEALTHY CONTROL CELLS. CFS SKELETAL MUSCLE CELLS WERE SHOWN TO OXIDISE GALACTOSE AND FATTY ACIDS NORMALLY, INDICATING THAT THE BIOENERGETIC DYSFUNCTION LIES UPSTREAM OF THE TCA CYCLE. THE DYSFUNCTION IN GLUCOSE OXIDATION IS SIMILAR TO WHAT HAS PREVIOUSLY BEEN SHOWN IN BLOOD CELLS FROM CFS PATIENTS. THE CONSISTENCY OF CELLULAR BIOENERGETIC DYSFUNCTION IN DIFFERENT CELL TYPES SUPPORTS THE HYPOTHESIS THAT CFS IS A SYSTEMIC DISEASE. THE RETENTION OF BIOENERGETIC DEFECTS IN CULTURED CELLS INDICATES THAT THERE IS A GENETIC OR EPIGENETIC COMPONENT TO THE DISEASE. THIS IS THE FIRST STUDY TO USE CELLS DERIVED FROM SKELETAL MUSCLE BIOPSIES IN CFS PATIENTS AND HEALTHY CONTROLS TO LOOK AT CELLULAR BIOENERGETIC FUNCTION IN WHOLE CELLS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10  2031  15 EPIGENETIC CHANGES IN LYMPHOCYTES OF SOLVENT-EXPOSED INDIVIDUALS. AIM: WE INVESTIGATED GLOBAL DNA METHYLATION ALTERATIONS IN LYMPHOCYTES OF SOLVENT WORKERS AND CHRONIC TOXIC ENCEPHALOPATHY (CTE) PATIENTS AND EXPLORED POTENTIAL GENE-ENVIRONMENT INTERACTIONS FOR GST. POPULATION & METHODS: A CROSS-SECTIONAL STUDY WAS SET UP IN 41 REFERENTS, 128 SOLVENT WORKERS AND 23 CTE PATIENTS. RESULTS: WE FOUND A GLOBAL DNA HYPERMETHYLATION IN THE SOLVENT-EXPOSED POPULATION COMPARED WITH THE REFERENTS (P = 0.001, R = -0.544). GLOBAL DNA METHYLATION WAS NEGATIVELY ASSOCIATED WITH EXPOSURE. FURTHERMORE, GSTP1 GENOTYPIC POLYMORPHISM WAS FOUND TO BE SIGNIFICANTLY ASSOCIATED (P = 0.033) WITH GLOBAL DNA HYPOMETHYLATION, WHICH INDICATES A POTENTIAL ROLE FOR GENE-ENVIRONMENT INTERACTION IN THE ETIOLOGY OF SOLVENT-INDUCED NEUROBEHAVIORAL DISORDERS. CONCLUSION: THIS STUDY INDICATES THAT SOLVENT-INDUCED DNA METHYLATION ALTERATIONS HAVE AN IMPACT ON NEUROTOXICITY AND DEVELOPMENT OF CTE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  1969  18 EPIGENETIC ALTERATIONS AND AN INCREASED FREQUENCY OF MICRONUCLEI IN WOMEN WITH FIBROMYALGIA. FIBROMYALGIA (FM), CHARACTERIZED BY CHRONIC WIDESPREAD PAIN, FATIGUE, AND COGNITIVE/MOOD DISTURBANCES, LEADS TO REDUCED WORKPLACE PRODUCTIVITY AND INCREASED HEALTHCARE EXPENSES. TO DETERMINE IF ACQUIRED EPIGENETIC/GENETIC CHANGES ARE ASSOCIATED WITH FM, WE COMPARED THE FREQUENCY OF SPONTANEOUSLY OCCURRING MICRONUCLEI (MN) AND GENOME-WIDE METHYLATION PATTERNS IN WOMEN WITH FM (N = 10) TO THOSE SEEN IN COMPARABLY AGED HEALTHY CONTROLS (N = 42 (MN); N = 8 (METHYLATION)). THE MEAN (SD) MN FREQUENCY OF WOMEN WITH FM (51.4 (21.9)) WAS SIGNIFICANTLY HIGHER THAN THAT OF CONTROLS (15.8 (8.5)) (CHI (2) = 45.552; DF = 1; P = 1.49 X 10(-11)). SIGNIFICANT DIFFERENCES (N = 69 SITES) IN METHYLATION PATTERNS WERE OBSERVED BETWEEN CASES AND CONTROLS CONSIDERING A 5% FALSE DISCOVERY RATE. THE MAJORITY OF DIFFERENTIALLY METHYLATED (DM) SITES (91%) WERE ATTRIBUTABLE TO INCREASED VALUES IN THE WOMEN WITH FM. THE DM SITES INCLUDED SIGNIFICANT BIOLOGICAL CLUSTERS INVOLVED IN NEURON DIFFERENTIATION/NERVOUS SYSTEM DEVELOPMENT, SKELETAL/ORGAN SYSTEM DEVELOPMENT, AND CHROMATIN COMPACTION. GENES ASSOCIATED WITH DM SITES WHOSE FUNCTION HAS PARTICULAR RELEVANCE TO FM INCLUDED BDNF, NAT15, HDAC4, PRKCA, RTN1, AND PRKG1. RESULTS SUPPORT THE NEED FOR FUTURE RESEARCH TO FURTHER EXAMINE THE POTENTIAL ROLE OF EPIGENETIC AND ACQUIRED CHROMOSOMAL ALTERATIONS AS A POSSIBLE BIOLOGICAL MECHANISM UNDERLYING FM.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12   143  15 ABERRANT DNA METHYLATION OF TWO TUMOR SUPPRESSOR GENES, P14(ARF) AND P15(INK4B), AFTER CHRONIC OCCUPATIONAL EXPOSURE TO LOW LEVEL OF BENZENE. BACKGROUND: EXPOSURE TO BENZENE WOULD BE ASSOCIATED WITH MANY DISEASES INCLUDING LEUKEMIA. EPIGENETIC ALTERATIONS SEEM TO BE AMONG THE MAIN MECHANISMS INVOLVED. OBJECTIVE: TO DETERMINE IF CHRONIC OCCUPATIONAL EXPOSURE TO LOW LEVEL OF BENZENE WOULD BE ASSOCIATED WITH DNA METHYLATION. METHODS: GLOBAL DNA METHYLATION AND PROMOTER-SPECIFIC METHYLATION OF THE TWO TUMOR SUPPRESSOR GENES, P14(ARF) AND P15(INK4B), WERE ASSESSED EMPLOYING METHYLATION-SPECIFIC PCR USING THE DNA EXTRACTED FROM 40 PETROCHEMICAL WORKERS EXPOSED TO AMBIENT BENZENE LEVELS OF <1 PPM, AND 31 OFFICE WORKERS NOT EXPOSED TO BENZENE OR ITS DERIVATIVES. RESULTS: WHILE AN INCREASE IN GLOBAL DNA METHYLATION OF 5% IN P14(ARF) (P=0.501) AND 28% IN P15(INK4B) (P=0.02) GENES WAS OBSERVED IN THE EXPOSED GROUP, NO HYPERMETHYLATION IN EITHER OF THE STUDIED GENES WAS OBSERVED IN THE UNEXPOSED GROUP. NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN THE FREQUENCY OF ABERRANT METHYLATION AND EITHER OF AGE, WORK EXPERIENCE, AND SMOKING HABIT IN THE EXPOSED GROUP. CONCLUSION: CHRONIC OCCUPATIONAL EXPOSURE TO LOWER THAN THE PERMISSIBLE EXPOSURE LIMIT OF BENZENE MAY STILL RESULT IN DNA METHYLATION OF TUMOR SUPPRESSOR GENES THAT MAY ULTIMATELY LEAD TO DEVELOPMENT OF CANCER.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13  3057  27 GENOME-WIDE DNA METHYLATION ANALYSIS IN ANKYLOSING SPONDYLITIS IDENTIFIES HLA-B*27 DEPENDENT AND INDEPENDENT DNA METHYLATION CHANGES IN WHOLE BLOOD. BACKGROUND AND OBJECTIVE: ANKYLOSING SPONDYLITIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY INFLAMMATION OF THE SACROILIAC JOINTS AND THE SPINE THAT CAN LEAD TO SIGNIFICANT PAIN, IMMOBILITY, AND DISABILITY. THE ETIOLOGY AND PATHOGENESIS OF ANKYLOSING SPONDYLITIS ARE INCOMPLETELY UNDERSTOOD, THOUGH MOST PATIENTS CARRY THE HLA-B*27 ALLELE. THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE DNA METHYLATION CHANGES IN ANKYLOSING SPONDYLITIS WITH THE GOAL OF REVEALING NOVEL MECHANISTIC INSIGHTS INTO THIS DISEASE. METHODS: GENOME-WIDE DNA METHYLATION ANALYSIS WAS PERFORMED IN WHOLE BLOOD DNA SAMPLES USING THE INFINIUM METHYLATIONEPIC ARRAY IN PATIENTS WITH ANKYLOSING SPONDYLITIS COMPARED TO AGE, SEX, AND RACE MATCHED PATIENTS WITH OSTEOARTHRITIS AS A NON-INFLAMMATORY DISEASE CONTROL. WE STUDIED 24 PATIENTS WITH ANKYLOSING SPONDYLITIS, INCLUDING 12 PATIENTS WHO CARRY HLA-B*27 AND 12 PATIENTS WHO ARE HLA-B*27 NEGATIVE. DNA METHYLATION ANALYSIS WAS PERFORMED WITH ADJUSTMENT FOR BLOOD CELL COMPOSITION IN EACH SAMPLE. RESULTS: WE IDENTIFIED A TOTAL OF 67 DIFFERENTIALLY METHYLATED SITES BETWEEN ANKYLOSING SPONDYLITIS PATIENTS AND OSTEOARTHRITIS CONTROLS. HYPERMETHYLATED GENES FOUND INCLUDED GTPASE-RELATED GENES, WHILE HYPOMETHYLATED GENES INCLUDED HCP5, WHICH ENCODES A LNCRNA WITHIN THE MHC REGION, PREVIOUSLY ASSOCIATED WITH GENETIC RISK FOR PSORIASIS AND TOXIC EPIDERMAL NECROLYSIS. CARRYING HLA-B*27 WAS ASSOCIATED WITH ROBUST HYPOMETHYLATION OF HCP5, TUBULIN FOLDING COFACTOR A (TBCA) AND PHOSPHOLIPASE D FAMILY MEMBER 6 (PLD6) IN ANKYLOSING SPONDYLITIS PATIENTS. HYPOMETHYLATION WITHIN HCP5 INVOLVES A CPG SITE THAT CONTAINS A SINGLE NUCLEOTIDE POLYMORPHISM IN LINKAGE DISEQUILIBRIUM WITH HLA-B*27 AND THAT CONTROLS DNA METHYLATION AT THIS LOCUS IN AN ALLELE-SPECIFIC MANNER. CONCLUSIONS: A GENOME-WIDE DNA METHYLATION ANALYSIS IN ANKYLOSING SPONDYLITIS IDENTIFIED DNA METHYLATION PATTERNS THAT COULD PROVIDE POTENTIAL NOVEL INSIGHTS INTO THIS DISEASE. OUR FINDINGS SUGGEST THAT HLA-B*27 MIGHT PLAY A ROLE IN ANKYLOSING SPONDYLITIS IN PART THROUGH INDUCING EPIGENETIC DYSREGULATION.	2019	
                                                                                                                                                                                                                                                                
14  1603  29 DNA METHYLATION STUDIES IN SALIVA OF PATIENTS WITH SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A RELATIVELY COMMON SYSTEMIC AUTOIMMUNE DISEASE OF UNKNOWN AETIOLOGY, ALTHOUGH GENETIC, HORMONAL, IMMUNOLOGIC, AND ENVIRONMENTAL FACTORS ARE THOUGHT TO BE INVOLVED IN DISEASE PATHOGENESIS. IT IS ALSO TERMED "AUTOIMMUNE EPITHELITIS", AND AFFLICTS MAINLY THE EPITHELIAL STRUCTURES OF SALIVARY AND LACHRYMAL GLANDS, THROUGH PERIEPITHELIAL LYMPHOCYTIC INFILTRATION RESPONSIBLE FOR THE OCCURRENCE OF DRYNESS SYMPTOMS. SJOGREN'S SYNDROME (SS) IS ALSO CHARACTERISED BY B CELL HYPERACTIVITY AS REFLECTED BY THE PRESENCE OF HYPERGAMMAGLOBULINEMIA AND THE PRODUCTION OF AUTOANTIBODIES, WHICH SEEMS TO BE ASSOCIATED WITH THE PRESENCE OF ECTOPIC GERMINAL CENTRES WITHIN THE INFLAMED MINOR SALIVARY GLANDS. CHRONIC ANTIGENIC STIMULATION MAY LEAD TO EXPANSION OF B CELL AUTOREACTIVE CLONES WITH RHEUMATOID FACTOR ACTIVITY, AND ADDITIONAL MOLECULAR EVENTS MEDIATE MALIGNANT TRANSFORMATION INTO NON-HODGKIN'S LYMPHOMAS OF B CELL ORIGIN. THEREFORE, THE INTERACTION BETWEEN THE IMMUNE CELLS OF THE INFLAMMATORY INFILTRATE AND THE SALIVARY EPITHELIUM SEEMS TO HAVE AN IMPORTANT CONTRIBUTION IN DISEASE PROCESS. RECENT HISTOPATHOLOGIC AND MOLECULAR STUDIES HAVE SHOWN THAT DNA METHYLATION LEVELS OF SS PATIENTS COMPARED TO HEALTHY INDIVIDUALS DIFFER IN EPITHELIAL CELLS OF SALIVARY GLANDS AND PERIPHERAL BLOOD MONONUCLEAR CELLS. IN THE PRESENT STUDY, WE INTEND TO ANALYSE THE EPIGENETIC MODIFICATIONS OF DNA IN THE SALIVA OF SS PATIENTS COMPARED TO HEALTHY CONTROLS. MORE SPECIFICALLY, SALIVARY DNA METHYLATION LEVELS OF SELECTED GENETIC LOCI PREVIOUSLY FOUND TO DIFFER IN OTHER TISSUES, WILL BE COMPARED BETWEEN SS PATIENTS AND HEALTHY CONTROLS. THE STUDY INCLUDES SALIVA COLLECTION FROM SS PATIENTS AND HEALTHY INDIVIDUALS, EXTRACTION OF GENOMIC DNA AND METHYLATION ASSESSMENT. THE EPIGENETIC PROFILE OF EACH GENETIC LOCUS WILL BE CORRELATED WITH SS PATIENTS' CLINICAL CHARACTERISTICS AND THE POSSIBILITY OF GENETIC LOCI WITH DIFFERENTIAL DIFFERENCES IN METHYLATION TO BE USED AS POTENTIAL DIAGNOSTIC BIOMARKERS WILL BE EXPLORED. THE CURRENT STUDY IS ANTICIPATED TO REVEAL POTENTIAL BIOMARKERS FOR DIAGNOSTIC AND THERAPEUTIC PURPOSES, OFFERING THE ADVANTAGE TO UTILISE THE EASILY COLLECTED AND HANDLED SALIVA AS THE MAIN BIOLOGIC MATERIAL.	2021	
                                                                                                                                                                                       
15  5517  32 RISK FACTOR ASSESSMENT OF RHEUMATOID ARTHRITIS IN NORTH KERALA. OBJECTIVE: RHEUMATOID ARTHRITIS (RA) IS A MULTIFACTORIAL DISEASE; IT LEADS TO DISABLING AND PAINFUL CHRONIC INFLAMMATORY ARTHRITIS. ITS ONSET MAY BE DELAYED OR EVEN PREVENTED BY MODIFYING THE RISK FACTORS INVOLVED. MANY GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS ARE IMPLICATED IN THE PATHOGENESIS OF RA. THE OBJECTIVES OF THIS CASE-CONTROL STUDY WERE TO ASSESS VARIOUS RISK FACTORS IN OUR POPULATION AND TO COMPARE THE SAME WITH AGE- AND SEX-MATCHED CONTROLS. METHODS: WE STUDIED 118 CASES WITH RA DIAGNOSED USING THE EULAR CRITERIA. IN TOTAL, 581 AGE- AND SEX-MATCHED CONTROLS WERE SELECTED. EACH INDIVIDUAL WAS ADMINISTERED A SEPARATE QUESTIONNAIRE REGARDING THEIR RISK FACTORS (KNOWN RISK FACTORS WERE STUDIED). THE IMPLICATED DIETARY FACTORS WERE INCORPORATED IN A FOOD FREQUENCY QUESTIONNAIRE (FFQ) AND ADMINISTERED TO BOTH CASES AND CONTROLS. COMPARISON WAS MADE BETWEEN THOSE WHO CONSUME AN ITEM AT A PARTICULAR FREQUENCY, WHO CONSUME LESS, AND WHO CONSUME NOTHING AT ALL. AMONG THOSE WHO CONSUME, EACH GROUP WAS RE-COMPARED. STATISTICAL ANALYSIS WAS CONDUCTED USING STATISTICAL PACKAGE FOR SOCIAL SCIENCES (IBM CORP.; ARMONK, NY, USA). RESULTS: THERE WAS SIGNIFICANT RELATIONSHIP FOR FAMILY HISTORY, PERIODONTITIS, HISTORY OF CHIKUNGUNYA, AND SUN EXPOSURE (P<0.05). ASSOCIATION WITH VARIOUS FOOD ITEMS WAS STUDIED USING THE FFQ, BUT THE RELATIONSHIP WAS INCONSISTENT, PROBABLY DUE TO CONSUMPTION OF MODIFIED DIET BY THE PERSONS WITH RA. ALSO, A MAJORITY OF CASES WERE FEMALES AND NONSMOKERS FOR ASSESSING AN ASSOCIATION WITH SMOKING HABITS. CONCLUSION: IN OUR POPULATION, PREVIOUS INFECTIONS (E.G., CHIKUNGUNYA AND POOR ORAL HYGIENE WITH PERIODONTITIS) WERE THE PROMINENTLY OBSERVED RISK FACTORS. ALSO, SMOKING WAS LESS COMMON AMONG WOMEN, AND PROBABLY CONTRIBUTED LESS, AS MAJORITY OF CASES WERE FEMALES. FOR DIETARY PATTERN ASSOCIATION, A PROSPECTIVE COHORT STUDY MAY BE NEEDED.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16  5700  23 SINGLE NUCLEOTIDE POLYMORPHISM IN DNMT3B PROMOTER AND THE RISK FOR IDIOPATHIC THROMBOCYTOPENIC PURPURA IN CHINESE POPULATION. OBJECTIVE: EPIGENETIC CHANGES IN GENE EXPRESSION, INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS, MIGHT CONTRIBUTE TO AUTOIMMUNITY. DNA METHYLATION IS MEDIATED BY A FAMILY OF DNA METHYLTRANSFERASES. POLYMORPHISMS OF THE DNA METHYLTRANSFERASE 3B (DNMT3B) GENE MAY INFLUENCE DNMT3B ACTIVITY ON DNA METHYLATION, THEREBY MODULATING THE SUSCEPTIBILITY TO SOME DISEASES. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE ASSOCIATION BETWEEN THE SINGLE NUCLEOTIDE POLYMORPHISM (SNP) IN PROMOTER OF THE DNMT3B GENE AND THE RISK FOR DEVELOPMENT OF IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP). METHODS: IN THIS HOSPITAL-BASED CASE-CONTROL STUDY, THE DNMT3B SNP WAS GENOTYPED IN 201 PATIENTS WITH ITP AND 136 HEALTHY CONTROLS BY POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM. RESULTS: THE C/C GENOTYPE WAS NOT DETECTED IN BOTH THE PATIENTS WITH ITP AND THE CONTROLS. IN THE CONTROLS, THE FREQUENCIES OF T/T AND C/T GENOTYPES AND T AND C ALLELES WERE 97.8%, 2.2%, 98.9%, AND 1.1%, RESPECTIVELY. THERE WAS NO SIGNIFICANT DIFFERENCE IN GENOTYPE AND ALLELE DISTRIBUTION BETWEEN THE PATIENTS WITH ITP AND THE CONTROLS (P = 0.745 AND 0.747, RESPECTIVELY). NO SIGNIFICANT DIFFERENCE WAS OBSERVED IN GENOTYPE AND ALLELE DISTRIBUTION BETWEEN THE TWO GROUPS WHEN STRATIFIED BY THE AGE. THE SIMILAR RESULTS WERE SHOWN AMONG THE FOUR GROUPS OF PATIENTS WITH ITP: ACUTE CHILDHOOD, CHRONIC CHILDHOOD, ACUTE ADULT, AND CHRONIC ADULT. CONCLUSION: THIS POLYMORPHISM WAS DISTRIBUTED SIMILARLY BETWEEN THE PATIENTS WITH ITP AND THE CONTROLS. IT DEMONSTRATED THAT IT MAY NOT BE USED AS A STRATIFICATION MARKER TO PREDICT THE SUSCEPTIBILITY TO ITP, AT LEAST IN THE POPULATION OF NORTH CHINA.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17  1937  23 EOMES IS ESSENTIAL FOR ANTITUMOR ACTIVITY OF CD8(+) T CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA. GENOME-WIDE ASSOCIATION STUDIES IDENTIFIED A SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) AFFECTING THE TRANSCRIPTION FACTOR EOMESODERMIN (EOMES) ASSOCIATED WITH A SIGNIFICANTLY INCREASED RISK TO DEVELOP CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). EPIGENETIC ANALYSES, RNA SEQUENCING, AND FLOW CYTOMETRY REVEALED THAT EOMES IS NOT EXPRESSED IN CLL CELLS, BUT IN CD8(+) T CELLS FOR WHICH EOMES IS A KNOWN MASTER REGULATOR. WE THUS HYPOTHESIZED THAT THE INCREASED CLL RISK ASSOCIATED WITH THE EOMES SNP MIGHT BE EXPLAINED BY ITS NEGATIVE IMPACT ON CD8(+) T-CELL-MEDIATED IMMUNE CONTROL OF CLL. FLOW CYTOMETRY ANALYSES REVEALED A HIGHER EOMES EXPRESSION IN CD8(+) T CELLS OF CLL PATIENTS COMPARED TO HEALTHY INDIVIDUALS, AND AN ACCUMULATION OF PD-1(+) EOMES(+) CD8(+) T CELLS IN LYMPH NODES RATHER THAN BLOOD OR BONE MARROW IN CLL. THIS WAS IN LINE WITH AN OBSERVED EXPANSION OF EOMES(+) CD8(+) T CELLS IN THE SPLEEN OF LEUKEMIC EMICRO-TCL1 MICE. AS EOMES EXPRESSION WAS HIGHEST IN CD8(+) T CELLS THAT EXPRESS INHIBITORY RECEPTORS, AN INVOLVEMENT OF EOMES IN T-CELL EXHAUSTION AND DYSFUNCTION SEEMS LIKELY. INTERESTINGLY, EOMES-DEFICIENCY IN CD8(+) T CELLS RESULTED IN THEIR IMPAIRED EXPANSION ASSOCIATED WITH DECREASED CLL CONTROL IN MICE. OVERALL, THESE OBSERVATIONS SUGGEST THAT EOMES IS ESSENTIAL FOR CD8(+) T-CELL EXPANSION AND/OR MAINTENANCE, AND THEREFORE INVOLVED IN ADAPTIVE IMMUNE CONTROL OF CLL.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18  3047  16 GENOME-WIDE ANALYSIS OF DNA METHYLATION IN ENDOMETRIOSIS USING ILLUMINA HUMAN METHYLATION 450 K BEADCHIPS. ENDOMETRIOSIS IS A COMMON CHRONIC GYNECOLOGIC DISORDER CHARACTERIZED BY THE PRESENCE AND GROWTH OF ENDOMETRIAL-LIKE TISSUE OUTSIDE OF THE UTERINE CAVITY. ALTHOUGH THE EXACT ETIOLOGY REMAINS UNCLEAR, EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, ARE THOUGHT TO CONTRIBUTE TO THE PATHOGENESIS OF ENDOMETRIOSIS. HERE, WE USED THE ILLUMINA HUMAN METHYLATION 450 K BEADCHIP ARRAY TO ANALYZE THE GENOME-WIDE DNA METHYLATION PROFILES OF SIX ENDOMETRIOTIC LESIONS AND SIX EUTOPIC ENDOMETRIA FROM PATIENTS WITH OVARIAN ENDOMETRIOSIS AND SIX ENDOMETRIA OF WOMEN WITHOUT ENDOMETRIOSIS. COMPARED WITH THE EUTOPIC ENDOMETRIA OF WOMEN WITH ENDOMETRIOSIS, 12,159 DIFFERENTIALLY METHYLATED CPG SITES AND 375 DIFFERENTIALLY METHYLATED PROMOTER REGIONS WERE IDENTIFIED IN ENDOMETRIOTIC LESIONS. GO ANALYSES SHOWED THAT THESE PUTATIVE DIFFERENTIALLY METHYLATED GENES WERE PRIMARILY ASSOCIATED WITH IMMUNE RESPONSE, INFLAMMATORY RESPONSE, RESPONSE TO STEROID HORMONE STIMULUS, CELL ADHESION, NEGATIVE REGULATION OF APOPTOSIS, AND ACTIVATION OF THE MAPK ACTIVITY. IN ADDITION, THE EXPRESSION LEVELS OF DNMT1, DNMT3A, DNMT3B, AND MBD2 IN ENDOMETRIOTIC LESIONS AND EUTOPIC ENDOMETRIA WERE SIGNIFICANTLY DECREASED COMPARED WITH CONTROL ENDOMETRIA. OUR FINDINGS SUGGEST THAT ABERRANT DNA METHYLATION STATUS IN ENDOMETRIOTIC LESIONS MAY PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS AND PROGRESSION OF ENDOMETRIOSIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  3442  27 HYPERMETHYLATION IN THE PROMOTER OF THE MTHFR GENE IS ASSOCIATED WITH DIABETIC COMPLICATIONS AND BIOCHEMICAL INDICATORS. BACKGROUND: DNA METHYLATION IS AN EPIGENETIC MECHANISM FOR REGULATING THE TRANSCRIPTION OF MANY GENES AND HAS BEEN LINKED TO THE DEVELOPMENT OF VARIOUS DISEASES. A PROMISING GENE TO INVESTIGATE IS METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR), SINCE THE ENZYME METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) PROMOTES METHYL RADICAL SYNTHESIS IN THE HOMOCYSTEINE CYCLE AND CAN PROVIDE METHYL GROUPS FOR DNA METHYLATION. IN ADDITION, SEVERAL STUDIES HAVE CORRELATED GENE POLYMORPHISMS OF THIS ENZYME WITH A GREATER RISK OF DIABETES, BUT LITTLE IS KNOWN REGARDING THE RELATIONSHIP BETWEEN EPIGENETIC CHANGES IN THIS GENE AND DIABETES AND ITS COMPLICATIONS. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE RELATIONSHIP BETWEEN METHYLATION PROFILE IN THE MTHFR GENE PROMOTER AND BIOCHEMICAL, INFLAMMATORY AND OXIDATIVE STRESS MARKERS IN INDIVIDUALS WITH TYPE 2 DIABETES (T2DM) WHO HAVE BEEN DIAGNOSED FOR 5-10 YEARS WITH OR WITHOUT DIABETIC RETINOPATHY (DR) AND NEPHROPATHY (DN). METHODS: SPECIFIC PCR FOR METHYLATION (MSP) WAS USED TO ANALYZE MTHFR METHYLATION PROFILE IN LEUCOCYTES DNA. BIOCHEMICAL MARKERS (GLYCEMIA, GLYCATED HEMOGLOBIN, TOTAL CHOLESTEROL, LDL, HDL, TRIGLYCERIDES, SERUM CREATININE), INFLAMMATORY MARKERS (C-REACTIVE PROTEIN AND ALPHA-1 ACID GLYCOPROTEIN) AND OXIDATIVE STRESS (TOTAL ANTIOXIDANT AND MALONALDEHYDE) WERE DETERMINED IN PERIPHERIC BLOOD SAMPLES AND MICROALBUMINURIA IN 24 H URINE SAMPLES. THE X(2) AND MANN-WHITNEY STATISTICAL TESTS WERE PERFORMED AND P < 0.05 WERE CONSIDERED SIGNIFICANT. RESULTS: THE HYPERMETHYLATED PROFILE WAS MOST FREQUENTLY OBSERVED IN INDIVIDUALS WITH RETINOPATHY (P < 0.01) AND WAS ASSOCIATED WITH HIGHER TOTAL CHOLESTEROL AND LDL LEVELS (P = 0.0046, 0.0267, RESPECTIVELY). INDIVIDUALS WITH DN AND HYPERMETHYLATED PROFILES HAD HIGHER LEVELS OF ALPHA-1 ACID GLYCOPROTEIN (P = 0.0080) AND TOTAL ANTIOXIDANT CAPACITY (P = 0.0169) COMPARED TO SUBJECTS WITHOUT COMPLICATIONS. CONCLUSIONS: HYPERMETHYLATION IN THE PROMOTER OF THE MTHFR GENE IS ASSOCIATED WITH THE OCCURRENCE OF DR AND WITH BIOCHEMICAL, INFLAMMATORY AND OXIDATIVE STRESS PARAMETERS IN THE CONTEXT OF CHRONIC COMPLICATIONS.	2017	
                                                                                                                                                                                                                                                             
20  6242  19 THE MATRICELLULAR PROTEIN SPARC DECREASES IN THE LACRIMAL GLAND AT ADULTHOOD AND DURING INFLAMMATION. PURPOSE: SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE (SPARC) IS A MATRICELLULAR GLYCOPROTEIN ABUNDANTLY EXPRESSED IN BASEMENT MEMBRANES AND CAPSULES SURROUNDING A VARIETY OF ORGANS AND TISSUES. IT MEDIATES EXTRACELLULAR MATRIX ORGANIZATION AND HAS BEEN IMPLICATED IN CELL CONTRACTION. HERE, WE EVALUATED THE EXPRESSION OF SPARC IN THE MURINE LACRIMAL GLAND AT ADULTHOOD AND DURING INFLAMMATION. METHODS: LACRIMAL GLANDS OF YOUNG MICE (4-6 WEEKS OLD) AND ADULT MICE (32-40 WEEKS OLD) WERE USED FOR EXTRACTION OF DNA, RNA, AND PROTEIN. THE PRESENCE OF SPARC WAS ASSESSED BY QUANTITATIVE PCR, ELISA, AND IMMUNOFLUORESCENCE MICROSCOPY. 5-METHYLCYTOSINE AND DNA METHYLATION WERE EVALUATED USING ELISA AND BISULFITE GENOMIC SEQUENCING, RESPECTIVELY. THE EFFECTS OF CYTOKINES AND INFLAMMATION IN SPARC EXPRESSION WERE EVALUATED IN VITRO AND IN THE NON-OBESE DIABETIC (NOD) MOUSE MODEL OF SJOGREN'S SYNDROME. RESULTS: THE MRNA AND PROTEIN LEVELS OF SPARC WERE DOWNREGULATED IN LACRIMAL GLANDS OF MATURE ADULT MICE PRESENTING AGE-RELATED HISTOLOGICAL ALTERATIONS SUCH AS INCREASED DEPOSITION OF LIPOFUSCIN AND LIPIDS. EPIGENETIC ANALYSES INDICATED THAT GLANDS IN ADULT MICE CONTAIN HIGHER LEVELS OF GLOBAL DNA METHYLATION AND SHOW INCREASED HYPERMETHYLATION OF SPECIFIC CPG SITES WITHIN THE SPARC GENE PROMOTER. ANALYSIS OF SMOOTH MUSCLE ACTIN (SMA)-GREEN FLUORESCENT PROTEIN (GFP) TRANSGENIC MICE REVEALED THAT SPARC LOCALIZES PRIMARILY TO MYOEPITHELIAL CELLS WITHIN THE GLAND. TREATMENT OF MYOEPITHELIAL CELLS WITH IL-1BETA OR TNF-ALPHA AND THE DEVELOPMENT OF INFLAMMATION IN THE NOD MICE LED TO DECREASED TRANSCRIPTION OF SPARC. CONCLUSIONS: SPARC IS A NOVEL MATRICELLULAR GLYCOPROTEIN EXPRESSED BY MYOEPITHELIAL CELLS IN THE LACRIMAL GLAND. LOSS OF SPARC DURING ADULTHOOD AND CHRONIC INFLAMMATION MIGHT HAVE DETRIMENTAL CONSEQUENCES ON MYOEPITHELIAL CELL CONTRACTION AND THE SECRETION OF TEAR FLUID.	2022