1 5891 123 SYSTEMS BIOLOGY IN CHRONIC HEART FAILURE-IDENTIFICATION OF POTENTIAL MIRNA REGULATORS. HEART FAILURE (HF) IS A COMPLEX DISEASE ENTITY WITH HIGH CLINICAL IMPACT, POORLY UNDERSTOOD PATHOPHYSIOLOGY AND SCANTLY KNOWN MIRNA-MEDIATED EPIGENETIC REGULATION. WE HAVE ANALYSED MIRNA PATTERNS IN PATIENTS WITH CHRONIC HF (CHF) AND A SEX- AND AGE-MATCHED REFERENCE GROUP AND PURSUED AN IN SILICO SYSTEM BIOLOGY ANALYSIS TO DISCERN PATHWAYS INVOLVED IN CHF PATHOPHYSIOLOGY. TWENTY-EIGHT MIRNAS WERE IDENTIFIED IN CHF THAT WERE UP-REGULATED IN THE REFERENCE GROUP, AND EIGHT OF THEM WERE VALIDATED BY RT-QPCR. IN SILICO ANALYSIS OF PREDICTED TARGETS BY STRING PROTEIN-PROTEIN INTERACTION NETWORKS REVEALED EIGHT CLUSTER NETWORKS (INVOLVING SEVEN OF THE IDENTIFIED MIRNAS) ENRICHED IN PATHWAYS RELATED TO CELL CYCLE, RAS, CHEMOKINE, PI3K-AKT AND TGF-BETA SIGNALING. BY ROC CURVE ANALYSIS, COMBINED PROBABILITIES OF THESE SEVEN MIRNAS (LET-7A-5P, MIR-107, MIR-125A-5P, MIR-139-5P, MIR-150-5P, MIR-30B-5P AND MIR-342-3P; CLUSTERS 1-4 [C:1-4]), DISCRIMINATED BETWEEN HF WITH PRESERVED EJECTION FRACTION (HFPEF) AND HF WITH REDUCED EJECTION FRACTION (HFREF), AND ISCHAEMIC AND NON-ISCHAEMIC AETIOLOGY. A COMBINATION OF MIR-107, MIR-139-5P AND MIR-150-5P, INVOLVED IN CLUSTERS 5 AND 7 (C:5+7), DISCRIMINATED HFPEF FROM HFREF. PATHWAY ENRICHMENT ANALYSIS OF MIRNAS PRESENT IN C:1-4 (LET-7A-5P, MIR-125A-5P, MIR-30B-5P AND MIR-342-3P) REVEALED PATHWAYS RELATED TO HF PATHOGENESIS. IN CONCLUSION, WE HAVE IDENTIFIED A DIFFERENTIAL SIGNATURE OF DOWN-REGULATED MIRNAS IN THE PLASMA OF HF PATIENTS AND PROPOSE NOVEL CELLULAR MECHANISMS INVOLVED IN CHF PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2 2331  37 EPIGENETIC REGULATION OF INFLAMMATION BY MICRORNAS IN POST-INFECTIOUS BRONCHIOLITIS OBLITERANS. OBJECTIVES: POST-INFECTIOUS BRONCHIOLITIS OBLITERANS (PIBO) IS A RARE, CHRONIC DISEASE INITIATED BY SEVERE INFECTION AND FOLLOWED BY PERPETUATING INFLAMMATION AND OBLITERATION OF THE SMALL AIRWAYS. MICRORNAS (MIRNAS) HAVE BEEN PROPOSED TO PLAY A CENTRAL ROLE AS EPIGENETIC REGULATORS, WHICH CONTROL RESOLUTION AND PREVENT THE UNCONTROLLED PROGRESS OF INFLAMMATION. THE AIM OF THIS STUDY WAS TO DEFINE BIOMARKERS ON THE LEVEL OF POST-TRANSCRIPTIONAL GENE REGULATION IN ORDER TO CHARACTERISE PIBO. METHODS: A TOTAL OF 39 PATIENTS WITH WELL-DEFINED PIBO AND 31 CONTROLS FROM TWO CENTRES, BARCELONA, SPAIN, AND FRANKFURT, GERMANY, WERE ANALYSED BY NEXT-GENERATION SEQUENCING (NGS). THE EVALUATION OF THE BIOLOGICAL TARGETS OF THE MIRNAS WAS PERFORMED BY PATHWAY ENRICHMENT ANALYSIS AND PROTEIN-PROTEIN INTERACTION NETWORK ANALYSIS RESPECTIVELY. RESULTS: PATIENTS WITH PIBO HAD SIGNIFICANTLY LOWER LUNG FUNCTION VALUES AND INCREASED AIRWAY INFLAMMATION IN INDUCED SPUTUM AS INDICATED BY TOTAL CELL COUNTS, NEUTROPHILS, IL-1BETA, IL-6, IL-8 AND TGF-BETA COMPARED TO CONTROLS.NEXT-GENERATION SEQUENCING ANALYSIS REVEALED A TOTAL OF 22 DYSREGULATED MIRNAS, WHICH PASSED SIGNIFICANCE THRESHOLD FOR PADJ </= 0.001 WITH 17 BEING UPREGULATED AND 5 BEING DOWNREGULATED. OF THESE DYSREGULATED MIRNAS, MIR-335-5P, MIR-186-5P, MIR-30B-5P AND MIR-30C-5P WERE FURTHER VALIDATED USING QRT-PCR. INTERESTINGLY, THESE MIRNAS ARE FUNCTIONALLY IMPLICATED IN CYTOKINE-CYTOKINE RECEPTOR INTERACTION, TGF-BETA SIGNALLING AND FOXO SIGNALLING PATHWAY AND SIGNIFICANTLY CORRELATED WITH LUNG FUNCTION VALUES (FEV1). CONCLUSION: OUR RESULTS DEMONSTRATE AN ABERRANT MIRNA EXPRESSION PROFILE IN PIBO, WHICH IMPACTS PATHWAYS RESPONSIBLE FOR THE REGULATION OF INFLAMMATION AND FIBROSIS. THE DEFINED MIRNAS ARE USEFUL BIOMARKERS AND SHOULD BE ASSESSED AS POTENTIAL TARGET IN THE FIELD OF MIRNA THERAPEUTICS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
3   50  35 A DEEP LEARNING MODEL FOR EARLY RISK PREDICTION OF HEART FAILURE WITH PRESERVED EJECTION FRACTION BY DNA METHYLATION PROFILES COMBINED WITH CLINICAL FEATURES. BACKGROUND: HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF), AFFECTED COLLECTIVELY BY GENETIC AND ENVIRONMENTAL FACTORS, IS THE COMMON SUBTYPE OF CHRONIC HEART FAILURE. ALTHOUGH THE AVAILABLE RISK ASSESSMENT METHODS FOR HFPEF HAVE ACHIEVED SOME PROGRESS, THEY WERE BASED ON CLINICAL OR GENETIC FEATURES ALONE. HERE, WE HAVE DEVELOPED A DEEP LEARNING FRAMEWORK, HFMERISK, USING BOTH 5 CLINICAL FEATURES AND 25 DNA METHYLATION LOCI TO PREDICT THE EARLY RISK OF HFPEF IN THE FRAMINGHAM HEART STUDY COHORT. RESULTS: THE FRAMEWORK INCORPORATES LEAST ABSOLUTE SHRINKAGE AND SELECTION OPERATOR AND EXTREME GRADIENT BOOSTING-BASED FEATURE SELECTION, AS WELL AS A FACTORIZATION-MACHINE BASED NEURAL NETWORK-BASED RECOMMENDER SYSTEM. MODEL DISCRIMINATION AND CALIBRATION WERE ASSESSED USING THE AUC AND HOSMER-LEMESHOW TEST. HFMERISK, INCLUDING 25 CPGS AND 5 CLINICAL FEATURES, HAVE ACHIEVED THE AUC OF 0.90 (95% CONFIDENCE INTERVAL 0.88-0.92) AND HOSMER-LEMESHOW STATISTIC WAS 6.17 (P = 0.632), WHICH OUTPERFORMED MODELS WITH CLINICAL CHARACTERISTICS OR DNA METHYLATION LEVELS ALONE, PUBLISHED CHRONIC HEART FAILURE RISK PREDICTION MODELS AND OTHER BENCHMARK MACHINE LEARNING MODELS. OUT OF THEM, THE DNA METHYLATION LEVELS OF TWO CPGS WERE SIGNIFICANTLY CORRELATED WITH THE PAIRED TRANSCRIPTOME LEVELS (R < -0.3, P < 0.05). BESIDES, DNA METHYLATION LOCUS IN HFMERISK WERE ASSOCIATED WITH INTERCELLULAR SIGNALING AND INTERACTION, AMINO ACID METABOLISM, TRANSPORT AND ACTIVATION AND THE CLINICAL VARIABLES WERE ALL RELATED WITH THE MECHANISM OF OCCURRENCE OF HFPEF. TOGETHER, THESE FINDINGS GIVE NEW EVIDENCE INTO THE HFMERISK MODEL. CONCLUSION: OUR STUDY PROPOSES AN EARLY RISK ASSESSMENT FRAMEWORK FOR HFPEF INTEGRATING BOTH CLINICAL AND EPIGENETIC FEATURES, PROVIDING A PROMISING PATH FOR CLINICAL DECISION MAKING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
4 2537  29 EPIGENETICS IN HEART FAILURE PHENOTYPES. CHRONIC HEART FAILURE (HF) IS A LEADING CLINICAL AND PUBLIC PROBLEM POSING A HIGHER RISK OF MORBIDITY AND MORTALITY IN DIFFERENT POPULATIONS. HF APPEARS TO BE IN BOTH PHENOTYPIC FORMS: HF WITH REDUCED LEFT VENTRICULAR EJECTION FRACTION (HFREF) AND HF WITH PRESERVED LEFT VENTRICULAR EJECTION FRACTION (HFPEF). ALTHOUGH BOTH HF PHENOTYPES CAN BE DISTINGUISHED THROUGH CLINICAL FEATURES, CO-MORBIDITY STATUS, PREDICTION SCORE, AND TREATMENT, THE CLINICAL OUTCOMES IN PATIENTS WITH HFREF AND HFPEF ARE SIMILAR. IN THIS CONTEXT, INVESTIGATION OF VARIOUS MOLECULAR AND CELLULAR MECHANISMS LEADING TO THE DEVELOPMENT AND PROGRESSION OF BOTH HF PHENOTYPES IS VERY IMPORTANT. THERE IS EMERGING EVIDENCE THAT EPIGENETIC REGULATION MAY HAVE A CLUE IN THE PATHOGENESIS OF HF. THIS REVIEW REPRESENTS CURRENT AVAILABLE EVIDENCE REGARDING THE IMPLICATION OF EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF DIFFERENT HF PHENOTYPES AND PERSPECTIVES OF EPIGENETIC-BASED THERAPIES OF HF.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5  353  31 ALTERED LEVELS OF IMMUNE-REGULATORY MICRORNAS IN PLASMA SAMPLES OF PATIENTS WITH LUPUS NEPHRITIS. INTRODUCTION: LUPUS NEPHRITIS (LN) IS A MAJOR CAUSE OF MORTALITY AND MORBIDITY IN THE PATIENTS WITH LUPUS, A CHRONIC AUTOIMMUNE DISEASE. THE ROLE OF GENETIC AND EPIGENETIC FACTORS IS EMPHASIZED IN THE PATHOGENESIS OF LN. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE LEVELS OF IMMUNE-REGULATORY MICRORNAS (E.G., MIR-31, MIR-125A, MIR-142-3P, MIR-146A, AND MIR-155) IN PLASMA SAMPLES OF PATIENTS WITH LN. METHODS: IN THIS STUDY, 26 PATIENTS WITH LN AND 26 HEALTHY INDIVIDUALS WERE INCLUDED. THE PLASMA LEVELS OF THE MICRORNAS WERE EVALUATED BY A QUANTITATIVE REAL-TIME PCR. MOREOVER, THE CORRELATION OF CIRCULATING PLASMA MICRORNAS WITH DISEASE ACTIVITY AND PATHOLOGICAL FINDINGS ALONG WITH THEIR ABILITY TO DISTINGUISH PATIENTS WITH LN WERE ASSESSED. RESULTS: PLASMA LEVELS OF MIR-125A (P = 0.048), MIR-146A (P = 0.005), AND MIR-155 (P< 0.001) WERE SIGNIFICANTLY HIGHER IN COMPARISON BETWEEN THE CASES AND CONTROLS. THE PLASMA LEVEL OF MIR-146A SIGNIFICANTLY CORRELATED WITH THE LEVEL OF ANTI-DOUBLE STRAND-DNA ANTIBODY AND PROTEINURIA. MOREOVER, THERE WAS A SIGNIFICANT CORRELATION BETWEEN MIR-142-3P LEVELS AND DISEASE CHRONICITY AND ACTIVITY INDEX (P <0.05). THE MULTIVARIATE ROC CURVE ANALYSIS INDICATED THE PLASMA CIRCULATING MIR-125A, MIR-142-3P, MIR-146, AND MIR-155 TOGETHER COULD DISCRIMINATE MOST OF THE PATIENTS WITH LN FROM CONTROLS WITH AREA AN UNDER CURVE (AUC) OF 0.89 [95% CI, 0.80-0.98, P<0.001], 88% SENSITIVITY, AND 78% SPECIFICITY. CONCLUSION: BASED ON THE FINDINGS OF THE PRESENT STUDY, THE STUDIED MICRORNAS MAY BE INVOLVED IN THE PATHOGENESIS AND DEVELOPMENT OF LN AND HAVE THE POTENTIAL TO BE USED AS DIAGNOSTIC AND THERAPEUTIC MARKERS IN LN.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6 5437  38 REMOTE HIND-LIMB ISCHEMIA MECHANISM OF PRESERVED EJECTION FRACTION DURING HEART FAILURE. DURING ACUTE HEART FAILURE (HF), REMOTE ISCHEMIC CONDITIONING (RIC) HAS PROVEN TO BE BENEFICIAL; HOWEVER, IT IS CURRENTLY UNCLEAR WHETHER IT ALSO EXTENDS BENEFITS FROM CHRONIC CONGESTIVE, CARDIOPULMONARY HEART FAILURE (CHF). PREVIOUS STUDIES FROM OUR LABORATORY HAVE SHOWN THREE PHASES DESCRIBING CHF VIZ. (1) HF WITH PRESERVED EJECTION FRACTION (HFPEF), (2) HF WITH REDUCED EF (HFREF), AND (3) HF WITH REVERSED EF. ALTHOUGH RECIPROCAL ORGAN INTERACTION, ABLATION OF SYMPATHETIC, AND CALCIUM SIGNALING GENES ARE ASSOCIATED WITH HFPEF TO HFREF, THE MECHANISM IS UNCLEAR. THE HFREF ENSUES, IN PART, DUE TO REDUCED ANGIOGENESIS, CORONARY RESERVE, AND LEAKAGE OF ENDOCARDIAL ENDOTHELIAL (EE) AND FINALLY BREAKDOWN OF THE BLOOD-HEART BARRIER (BHB) INTEGRITY. IN FACT, OUR HYPOTHESIS STATES THAT A CHANGE IN PHENOTYPE FROM COMPENSATORY HFPEF TO DECOMPENSATORY HFREF IS DETERMINED BY A POTENTIAL DECREASE IN REGENERATIVE, PROANGIOGENIC FACTORS ALONG WITH A CONCOMITANT INCREASE IN EPIGENETIC MEMORY, INFLAMMATION THAT COMBINEDLY CAUSES OXIDATIVE, AND PROTEOLYTIC STRESS RESPONSE. TO TEST THIS HYPOTHESIS, WE CREATED CHF BY AORTA-VENA-CAVA (AV) FISTULA IN A GROUP OF MICE THAT WERE SUBSEQUENTLY TREATED WITH THAT OF HIND-LIMB RIC. HFPEF VS. HFREF TRANSITION WAS DETERMINED BY SERIAL/LONGITUDINAL ECHO MEASUREMENTS. RESULTS REVEALED AN INCREASE IN SKELETAL MUSCLE MUSCLIN CONTENTS, BONE-MARROW (CD71), AND SYMPATHETIC ACTIVATION (BETA2-AR) BY RIC. WE ALSO OBSERVED A DECREASE IN VASCULAR DENSITY AND ATTENUATION OF EE-BHB FUNCTION DUE TO A CORRESPONDING INCREASE IN THE ACTIVITY OF MMP-2, VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), CASPASE, AND CALPAIN. THIS DECREASE WAS SUCCESSFULLY MITIGATED BY RIC-RELEASED SKELETAL MUSCLE EXOSOMES THAT CONTAIN MUSCLIN, THE MYOKINE ALONG WITH BONE MARROW, AND SYMPATHETIC ACTIVATION. IN SHORT, BASED ON PROTEOME (OMICS) ANALYSIS, APPROXIMATELY 20 PROTEINS THAT APPEAR TO BE INVOLVED IN SIGNALING PATHWAYS RESPONSIBLE FOR THE SYNTHESIS, CONTRACTION, AND RELAXATION OF CARDIAC MUSCLE WERE FOUND TO BE THE DOMINANT FEATURES. THUS, OUR RESULTS SUPPORT THAT THE CHF PHENOTYPE CAUSES DYSFUNCTION OF CARDIAC METABOLISM, ITS CONTRACTION, AND RELAXATION. INTERESTINGLY, RIC WAS ABLE TO MITIGATE MANY OF THE DELETERIOUS CHANGES, AS REVEALED BY OUR MULTI-OMICS FINDINGS.	2021	
                                                                                                                                                                                                                                                     
7 3504  35 IDENTIFICATION OF POTENTIALLY FUNCTIONAL CIRCRNAS AND PREDICTION OF CIRCRNA-MIRNA-MRNA REGULATORY NETWORK IN PERIODONTITIS: BRIDGING THE GAP BETWEEN BIOINFORMATICS AND CLINICAL NEEDS. BACKGROUND AND OBJECTIVE: PERIODONTITIS IS A MULTIFACTORIAL CHRONIC INFLAMMATORY DISEASE THAT CAN LEAD TO THE IRREVERSIBLE DESTRUCTION OF DENTAL SUPPORT TISSUES. AS AN EPIGENETIC FACTOR, THE EXPRESSION OF CIRCRNA IS TISSUE-DEPENDENT AND DISEASE-DEPENDENT. THIS STUDY AIMED TO IDENTIFY NOVEL PERIODONTITIS-ASSOCIATED CIRCRNAS AND PREDICT RELEVANT CIRCRNA-PERIODONTITIS REGULATORY NETWORK BY USING RECENTLY DEVELOPED BIOINFORMATIC TOOLS AND INTEGRATING SEQUENCING PROFILING WITH CLINICAL INFORMATION FOR GETTING A BETTER AND MORE THOROUGH IMAGE OF PERIODONTITIS PATHOGENESIS, FROM GENE TO CLINIC. MATERIAL AND METHODS: HIGH-THROUGHPUT SEQUENCING AND RT-QPCR WERE CONDUCTED TO IDENTIFY DIFFERENTIALLY EXPRESSED CIRCRNAS IN GINGIVAL TISSUES FROM PERIODONTITIS PATIENTS. THE RELATIONSHIP BETWEEN UPREGULATED CIRCRNAS EXPRESSION AND PROBING DEPTH (PD) WAS PERFORMED USING SPEARMAN'S CORRELATION ANALYSIS. BIOINFORMATIC ANALYSES INCLUDING GO ANALYSIS, CIRCRNA-DISEASE ASSOCIATION PREDICTION, AND CIRCRNA-MIRNA-MRNA NETWORK PREDICTION WERE PERFORMED TO CLARIFY POTENTIAL REGULATORY FUNCTIONS OF IDENTIFIED CIRCRNAS IN PERIODONTITIS. A RECEIVER-OPERATING CHARACTERISTIC (ROC) CURVE WAS ESTABLISHED TO ASSESS THE DIAGNOSTIC SIGNIFICANCE OF IDENTIFIED CIRCRNAS. RESULTS: HIGH-THROUGHPUT SEQUENCING IDENTIFIED 70 DIFFERENTIALLY EXPRESSED CIRCRNAS (68 UPREGULATED AND 2 DOWNREGULATED CIRCRNAS) IN HUMAN PERIODONTITIS (FOLD CHANGE >2.0 AND P < .05). THE TOP FIVE UPREGULATED CIRCRNAS WERE VALIDATED BY RT-QPCR THAT HAD STRONG ASSOCIATIONS WITH MULTIPLE HUMAN DISEASES, INCLUDING PERIODONTITIS. THE UPREGULATION OF CIRCRNAS WERE POSITIVELY CORRELATED WITH PD (R = .40-.69, P < .05, MODERATE). A CIRCRNA-MIRNA-MRNA NETWORK WITH THE TOP FIVE UPREGULATED CIRCRNAS, DIFFERENTIALLY EXPRESSED MRNAS, AND OVERLAPPED PREDICTED MIRNAS INDICATED POTENTIAL ROLES OF CIRCRNAS IN IMMUNE RESPONSE, CELL APOPTOSIS, MIGRATION, ADHESION, AND REACTION TO OXIDATIVE STRESS. THE ROC CURVE SHOWED THAT CIRCRNAS HAD POTENTIAL VALUE IN PERIODONTITIS DIAGNOSIS (AUC = 0.7321-0.8667, P < .05). CONCLUSION: CIRCRNA-DISEASE ASSOCIATIONS WERE PREDICTED BY ONLINE BIOINFORMATIC TOOLS. POSITIVE CORRELATION BETWEEN UPREGULATED CIRCRNAS, CIRCPTP4A2, CHR22:23101560-23135351+, CIRCARHGEF28, CIRCBARD1 AND CIRCRASA2, AND PD SUGGESTED FUNCTION OF CIRCRNAS IN PERIODONTITIS. NETWORK PREDICTION FURTHER FOCUSED ON DOWNSTREAM TARGETS REGULATED BY CIRCRNAS DURING PERIODONTITIS PATHOGENESIS.	2022	

8 4350  30 MIR-181A-5P IS A POTENTIAL CANDIDATE EPIGENETIC BIOMARKER IN MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS) CHARACTERIZED BY DEMYELINATION AND AXONAL DEGENERATION. ABNORMAL EXPRESSION OF MICRORNAS (MIRNAS) PLAYS AN IMPORTANT ROLE IN MS PATHOLOGY. IN THIS COHORT STUDY, DIFFERENTIAL EXPRESSION OF THE FOUR MIRNAS (HSA-MIR-155-5P, HSA-MIR-9-5P, HSA-MIR-181A-5P, AND HSA-MIR-125B-5P) WAS INVESTIGATED IN 69 INDIVIDUALS, INCLUDING 39 MS PATIENTS (RELAPSING-REMITTING MS (RRMS), N = 27; SECONDARY PROGRESSIVE MS (SPMS), N = 12) AND 30 HEALTHY CONTROLS. IN SILICO ANALYSES REVEALED POSSIBLE GENES AND PATHWAYS SPECIFIC TO MIRNAS. PERIPHERAL BLOOD MIRNA EXPRESSIONS WERE DETECTED BY QUANTITATIVE REAL-TIME PCR (QPCR). HSA-MIR-181A-5P WAS DOWNREGULATED AND ASSOCIATED WITH INCREASED MS RISK (P = 0.012). THE OTHER THREE MIRNAS WERE UPREGULATED AND NOT ASSOCIATED WITH MS (P < 0.05). THE AREA UNDER THE CURVE (AUC) IS 0.779. IN SILICO ANALYSES SHOWED THAT HSA-MIR-181A-5P MAY PARTICIPATE IN MS PATHOLOGY BY TARGETING MAP2K1, CREB1, ATXN1, AND ATXN3 GENES IN INFLAMMATION AND NEURODEGENERATION PATHWAYS. THE CIRCULATORY HSA-MIR-181A-5P CAN REGULATE TARGET GENES, REVERSING THE MECHANISMS INVOLVED IN MS PATHOLOGIES SUCH AS PROTEIN UPTAKE AND PROCESSING, CELL PROLIFERATION AND SURVIVAL, INFLAMMATION, AND NEURODEGENERATION. THUS, THIS MIRNA COULD BE USED AS AN EPIGENOMIC-GUIDED DIAGNOSTIC TOOL AND FOR THERAPEUTIC PURPOSE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9 4287  33 MICRORNA EXPRESSION PROFILING IN BEHCET'S DISEASE. BACKGROUND: BEHCET'S DISEASE (BD) IS A CHRONIC INFLAMMATORY MULTISYSTEM DISEASE CHARACTERIZED BY ORAL AND GENITAL ULCERS, UVEITIS, AND SKIN LESIONS. MICRORNAS (MIRNAS) ARE KEY REGULATORS OF IMMUNE RESPONSES. DIFFERENTIAL EXPRESSION OF MIRNAS HAS BEEN REPORTED IN SEVERAL INFLAMMATORY AUTOIMMUNE DISEASES; HOWEVER, THEIR ROLE IN BD IS NOT FULLY ELUCIDATED. WE AIMED TO IDENTIFY MIRNA EXPRESSION SIGNATURES ASSOCIATED WITH BD AND TO INVESTIGATE THEIR POTENTIAL IMPLICATION IN THE DISEASE PATHOGENESIS. METHODS: MIRNA MICROARRAY ANALYSIS WAS PERFORMED IN BLOOD CELLS OF BD PATIENTS AND HEALTHY CONTROLS. MIRNA EXPRESSION PROFILES WERE ANALYZED USING AFFYMETRIX ARRAYS WITH A COMPREHENSIVE COVERAGE OF MIRNA SEQUENCES. PATHWAY ANALYSES WERE PERFORMED, AND THE GLOBAL MIRNA PROFILING WAS COMBINED WITH TRANSCRIPTOMA DATA IN BD. DEREGULATION OF SELECTED MIRNAS WAS VALIDATED BY REAL-TIME PCR. RESULTS: WE IDENTIFIED SPECIFIC MIRNA SIGNATURES ASSOCIATED WITH BD PATIENTS WITH ACTIVE DISEASE. THESE MIRNAS TARGET PATHWAYS RELEVANT IN BD, SUCH AS TNF, IFN GAMMA, AND VEGF-VEGFR SIGNALING CASCADES. NETWORK ANALYSIS REVEALED SEVERAL MIRNAS REGULATING HIGHLY CONNECTED GENES WITHIN THE BD TRANSCRIPTOMA. CONCLUSIONS: THE COMBINED ANALYSIS OF DEREGULATED MIRNAS AND BD TRANSCRIPTOME SHEDS LIGHT ON SOME EPIGENETIC ASPECTS OF BD IDENTIFYING SPECIFIC MIRNAS, WHICH MAY REPRESENT PROMISING CANDIDATES AS BIOMARKERS AND/OR FOR THE DESIGN OF NOVEL THERAPEUTIC STRATEGIES IN BD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10 5888  29 SYSTEMIC TRANSCRIPTIONAL ALTERATIONS OF INNATE AND ADAPTIVE IMMUNE SIGNALING PATHWAYS IN ATHEROSCLEROSIS, ISCHEMIA STROKE, AND MYOCARDIAL INFARCTION. BACKGROUND: TRANSCRIPTIONAL PROFILES ARE AVAILABLE FOR A VARIETY OF CARDIOVASCULAR-RELATED DISEASES. THE GOAL OF THIS STUDY WAS TO COMPARE BLOOD TRANSCRIPTIONAL PROFILES OF THE TOLL-LIKE RECEPTOR (TLR), T-CELL RECEPTOR (TCR), AND B-CELL RECEPTOR (BCR) SIGNALING PATHWAYS IN ASYMPTOMATIC ATHEROSCLEROSIS, ACUTE ISCHEMIC STROKE, AND MYOCARDIAL INFARCTION PATIENTS TO IDENTIFY COMMON MECHANISMS OF IMMUNE REGULATION AND THEIR ASSOCIATION WITH EPIGENETIC REGULATION. METHODS AND RESULTS: PERIPHERAL BLOOD GENE EXPRESSION PROFILES FROM HUMAN ATHEROSCLEROSIS-RELATED DISEASES AND HEALTHY CONTROLS WERE DOWNLOADED FROM GENE EXPRESSION OMNIBUS (GEO). GENES IN THE TLR, TCR, AND BCR PATHWAYS WERE RETRIEVED FROM THE NCBI BIOSYSTEMS DATABASE. SIGNIFICANCE OF GENE ENRICHMENT AND CONCORDANCE OF EXPRESSION CHANGES IN EACH PATHWAY WAS COMPARED BETWEEN STUDIES. GENE EXPRESSION WAS SIGNIFICANTLY CORRELATED ACROSS THE THREE DISEASE CONDITIONS (P<10(-15)) AND THE PROPORTION OF SIGNIFICANT GENES WAS HIGH (30~60%, P<0.001). HUB GENES IDENTIFIED BY WEIGHTED GENE CO-EXPRESSION NETWORK ANALYSIS (WGCNA) IN THE TCR/BCR SUB-NETWORK, INCLUDING CD81 AND TCR-CD3ZETA, WERE SIGNIFICANTLY DOWN-REGULATED AND HIGHLY CORRELATED WITH DNA (CYTOSINE-5-)-METHYLTRANSFERASE 1 (DNMT1). CONCLUSION: COMMON BIOLOGICALLY RELEVANT NETWORKS ASSOCIATED WITH IMMUNE REGULATION IN STROKE, ATHEROSCLEROSIS, AND MYOCARDIAL INFARCTION WERE DISCOVERED. GIVEN THE HIGH CORRELATION OF DNMT1 WITH THESE IMMUNE SIGNALING PATHWAYS, EPIGENETIC REGULATION MAY CONTRIBUTE TO THE COORDINATION OF INNATE AND ADAPTIVE IMMUNE RESPONSE IN ALL CVD DISEASE STATES. DOWN-REGULATION OF THE TCR-BCR AXIS IN THE ADAPTIVE IMMUNE SYSTEM OFFERS CRITICAL INFORMATION FOR THE INVESTIGATION OF THE FUNCTIONAL MECHANISMS UNDERLYING CHRONIC INFLAMMATION-INDUCED IMMUNE SUPPRESSION IN CARDIOVASCULAR DISEASE AND STROKE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 1587  23 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12 1131  30 COMPREHENSIVE CIRCULAR RNA EXPRESSION PROFILING WITH ASSOCIATED CERNA NETWORK REVEALS THEIR THERAPEUTIC POTENTIAL IN CHOLESTEATOMA. CHOLESTEATOMA IS A CHRONIC DISEASE THAT PATHOLOGICALLY DISPLAYS A BENIGN TUMOR WITH EXCESSIVE SQUAMOUS EPITHELIAL CELL PROLIFERATION IN THE MIDDLE EAR. CLINICALLY, HOWEVER, IT CAN MANIFEST MALIGNANT BEHAVIOR BY DESTROYING ADJACENT TISSUES AND ORGANS. ALTHOUGH PREVIOUS STUDIES HAVE DEMONSTRATED THAT THE PATHOGENESIS OF CHOLESTEATOMA IS CORRELATED WITH EPIGENETIC DYSREGULATION, THE EXACT MECHANISM REMAINS UNCLEAR. CIRCULAR RNAS (CIRCRNAS) HAVE BEEN REVEALED AS BEING ABUNDANTLY EXPRESSED IN VARIOUS ORGANISMS AND HAVE BEEN FOUND TO CONTRIBUTE TO THE REGULATION OF MANY DISEASES. TO DATE, NO REPORTS HAVE ELUCIDATED THEIR EXPRESSION PROFILES AND FUNCTIONS IN CHOLESTEATOMA. IN THE PRESENT STUDY, THE CIRCRNA EXPRESSION PROFILE IN CHOLESTEATOMA WAS EXPLORED FOR THE FIRST TIME BY USING MICROARRAY ANALYSIS. WE OBTAINED A TOTAL OF 355 SIGNIFICANTLY DIFFERENTIALLY EXPRESSED CIRCRNAS IN CHOLESTEATOMA, AMONG WHICH 101 WERE IDENTIFIED TO BE UPREGULATED AND 254 DOWNREGULATED. BY CONSTRUCTING CIRCRNA?LNCRNA?MIRNA?MRNA COMPETING ENDOGENOUS RNA (CERNA) NETWORK, IT WAS DISCOVERED THAT CIRCRNAS MAY FUNCTION AS CERNAS AND CONTRIBUTE TO THE FORMATION OF CHOLESTEATOMA. THESE RESULTS PROVIDE NOVEL INSIGHT INTO THE PATHOGENESIS OF CHOLESTEATOMA AND SUGGEST CIRCRNAS AS POTENTIAL PROMISING THERAPEUTIC TARGETS FOR CHOLESTEATOMA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13  782  29 CELL-FREE MICRORNA-148A IS ASSOCIATED WITH RENAL ALLOGRAFT DYSFUNCTION: IMPLICATION FOR BIOMARKER DISCOVERY. BACKGROUND: CHRONIC ALLOGRAFT DYSFUNCTION (CAD), THE FOREMOST CAUSE OF RENAL GRAFT LOSS WORLDWIDE, IS A SERIOUS CHALLENGE FOR MOST OF THE RECIPIENTS. AS THE EPIGENETIC ERA IS EMERGING, EPIGENETIC BIOMARKERS ESPECIALLY MICRORNAS (MIRNAS) MAY REFLECT THE CURRENT STAGE OF THE DISEASE AND PATIENT'S THERAPY RESPONSE. THE CURRENT STUDY INVESTIGATED THE POTENTIAL SIGNIFICANCE OF CIRCULATING MIRNA-148A IN PREDICTING THE RENAL GRAFT FUNCTION. DESIGN AND METHODS: CIRCULATING MIRNAS WERE ISOLATED FROM 53 PLASMA SAMPLES OF RECIPIENTS WITH HISTOLOGICALLY VALIDATED INTERSTITIAL FIBROSIS AND TUBULAR ATROPHY (IFTA, N = 26), AND RECIPIENTS WITH STABLE GRAFT FUNCTION (SGF, N = 27), AND ALSO HEALTHY INDIVIDUALS ( N = 15). THE LEVEL OF MIRNA-148A WAS EVALUATED BY THE QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) AND CORRELATED WITH CLINICAL AND HISTOLOGICAL PARAMETERS. RESULTS: SIGNIFICANTLY, MIRNA-148A DECREASED IN IFTA COMPARED WITH SGF SUBJECTS (P < 0.001). MIRNA-148A LEVELS INDICATED A SIGNIFICANT ASSOCIATION WITH SERUM CREATININE LEVELS ( R = 0.451, P = 0.021) AND GLOMERULAR FILTRATION RATE ( R = -0.520, P = 0.006). MIRNA-148A EXPRESSION LEVELS COULD DISCRIMINATE IFTA CASES FROM SGF INDIVIDUALS WITH AN AREA UNDER THE CURVE OF 0.89 ( P < 0.001), 97% SENSITIVITY, AND 72% SPECIFICITY. A NUMBER OF PREDICTED TARGETS THAT MIGHT BE INVOLVED IN CAD BY MIRNA-148A WERE PREDICTED. CONCLUSION: PLASMA CELL-FREE MIRNA-148A CORRELATED WITH RENAL FUNCTION AND HISTOLOGICAL GRADES; THEREFORE, IT MAY BE FURTHER INVESTIGATED AS A NOVEL NONINVASIVE MOLECULAR MARKER OF THE PROGRESSION TO IFTA IN RENAL TRANSPLANT RECIPIENTS; MOREOVER, THE EMERGING BIOMARKER MAY BECOME A THERAPEUTIC TARGET IN THE FUTURE CLINIC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14 1718  28 DYSREGULATED LONG NON-CODING RNAS IN THE TEMPORAL LOBE EPILEPSY MOUSE MODEL. PURPOSE: TO PERFORM COMPREHENSIVE PROFILING OF LONG NON-CODING RNAS (LNCRNAS) IN TEMPORAL LOBE EPILEPSY. METHODS: WE PERFORMED EXTENSIVE PROFILING OF LNCRNAS AND MRNAS IN THE MOUSE PILOCARPINE MODEL IN SPECIFIC BRAIN REGIONS, THE HIPPOCAMPUS AND CORTEX, AND COMPARED THE RESULTS TO THOSE OF THE CONTROL MOUSE. DIFFERENTIALLY EXPRESSED LNCRNAS AND MRNAS WERE IDENTIFIED WITH A MICROARRAY ANALYSIS (ARRAYSTAR MOUSE LNCRNA EXPRESSION MICROARRAY V3.0). THEN, GENE ONTOLOGY (GO) AND PATHWAY ANALYSIS WERE PERFORMED TO INVESTIGATE THE POTENTIAL ROLES OF THE DIFFERENTIALLY EXPRESSED MRNAS IN THE PILOCARPINE MODEL. PROTEIN-PROTEIN INTERACTIONS TRANSCRIBED BY DYSREGULATED MRNAS WITH/WITHOUT CO-DYSREGULATED LNCRNAS WERE ANALYZED USING STRING V10 (HTTP://STRING-DB.ORG/). RESULTS: A TOTAL OF 22 AND 83 LNCRNAS WERE UP- AND DOWN-REGULATED (>/=2.0-FOLD, ALL P < .05), RESPECTIVELY, IN THE HIPPOCAMPUS OF THE EPILEPSY MODEL, WHILE 46 AND 659 LNCRNAS WERE UP- AND DOWN-REGULATED, RESPECTIVELY, IN THE CORTEX OF THE EPILEPSY MODEL. GO AND PATHWAY ANALYSIS REVEALED THAT THE DYSREGULATED MRNAS WERE CLOSELY ASSOCIATED WITH A PROCESS ALREADY KNOWN TO BE INVOLVED IN EPILEPTOGENESIS: ACUTE INFLAMMATION, CALCIUM ION REGULATION, EXTRACELLULAR MATRIX REMODELING, AND NEURONAL DIFFERENTIATION. AMONG THE LNCRNAS, WE IDENTIFIED 10 LNCRNAS COMMONLY DYSREGULATED WITH CORRESPONDING MRNAS IN THE CORTEX. THE STRING ANALYSIS SHOWED THAT THE DYSREGULATED MRNAS WERE INTERCONNECTED AROUND TWO CENTERS: THE MTOR PATHWAY-RELATED GENES AND REST PATHWAY-RELATED GENES. CONCLUSION: LNCRNAS WERE DYSREGULATED IN THE PILOCARPINE MOUSE MODEL ACCORDING TO THE BRAIN REGIONS OF THE HIPPOCAMPUS AND CORTEX. THE DYSREGULATED LNCRNAS WITH CO-DYSREGULATED MRNAS MIGHT BE POSSIBLE THERAPEUTIC TARGETS FOR THE EPIGENETIC REGULATION OF CHRONIC EPILEPSY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  413  32 ANALYSIS OF MIRNAS PROFILES IN SERUM OF PATIENTS WITH STEATOSIS AND STEATOHEPATITIS. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS EMERGING AS ONE OF THE MOST COMMON CHRONIC LIVER DISEASES WORLDWIDE, AFFECTING 25% OF THE WORLD POPULATION. IN RECENT YEARS, THERE HAS BEEN INCREASING EVIDENCE FOR THE INVOLVEMENT OF MICRORNAS IN THE EPIGENETIC REGULATION OF GENES TAKING PART IN THE DEVELOPMENT OF STEATOSIS AND STEATOHEPATITIS-TWO MAIN STAGES OF NAFLD PATHOGENESIS. IN THE PRESENT STUDY, MIRNA PROFILES WERE STUDIED IN GROUPS OF PATIENTS WITH STEATOSIS AND STEATOHEPATITIS TO COMPARE THE CHARACTERISTICS OF RNA-DEPENDENT EPIGENETIC REGULATION OF THE STAGES OF NAFLD DEVELOPMENT. ACCORDING TO THE RESULTS OF MIRNA SCREENING, 23 MIRNAS WERE DIFFERENTIALLY EXPRESSED SERUM IN A GROUP OF PATIENTS WITH STEATOHEPATITIS AND 2 IN A GROUP OF PATIENTS WITH STEATOSIS. MIR-195-5P AND MIR-16-5P ARE COMMON DIFFERENTIALLY EXPRESSED MIRNAS FOR BOTH STEATOSIS AND STEATOHEPATITIS. WE ANALYZED THE OBTAINED RESULTS: THE SEARCH FOR TARGET GENES FOR THE DIFFERENTIALLY EXPRESSED MIRNAS IN OUR STUDY AND THE SUBSEQUENT GENE SET ENRICHMENT ANALYSIS PERFORMED ON KEGG AND REACTOME DATABASES REVEALED WHICH METABOLIC PATHWAYS UNDERGO CHANGES IN RNA-DEPENDENT EPIGENETIC REGULATION IN STEATOSIS AND STEATOHEPATITIS. NEW FINDINGS WITHIN THE FRAMEWORK OF THIS STUDY ARE THE DYSREGULATION OF NEUROHUMORAL PATHWAYS IN THE PATHOGENESIS OF NAFLD AS AN OBJECT OF CHANGES IN RNA-DEPENDENT EPIGENETIC REGULATION. THE MIRNAS DIFFERENTIALLY EXPRESSED IN OUR STUDY WERE FOUND TO TARGET 7% OF GENES IN THE CLASSIC PATHOGENESIS OF NAFLD IN THE GROUP OF PATIENTS WITH STEATOSIS AND 50% IN THE GROUP OF PATIENTS WITH STEATOHEPATITIS. THE EFFECTS OF THESE MICRORNAS ON GENES FOR THE PATHOGENESIS OF NAFLD WERE ANALYZED IN DETAIL. MIR-374A-5P, MIR-1-3P AND MIR-23A-3P DO NOT TARGET GENES DIRECTLY INVOLVED IN THE PATHOGENESIS OF NAFLD. THE DIFFERENTIALLY EXPRESSED MIRNAS FOUND IN THIS STUDY TARGET GENES LARGELY RESPONSIBLE FOR MITOCHONDRIAL FUNCTION. THE ROLE OF MIR-423-5P, MIR-143-5P AND MIR-200C-3 IN REGULATING APOPTOTIC PROCESSES IN THE LIVER AND HEPATOCARCINOGENESIS IS OF INTEREST FOR FUTURE EXPERIMENTAL STUDIES. THESE MIR-374A, MIR-143, MIR-1, MIR-23A, AND MIR-423 HAVE POTENTIAL FOR STEATOHEPATITIS DIAGNOSIS AND ARE POORLY STUDIED IN THE CONTEXT OF NAFLD. THUS, THIS WORK OPENS UP PROSPECTS FOR FURTHER STUDIES OF MICRORNAS AS DIAGNOSTIC AND THERAPEUTIC BIOMARKERS FOR NAFLD.	2021	
                                                                                                                                                                               
16 4286  28 MICRORNA EXPRESSION ANALYSIS IN HIGH FAT DIET-INDUCED NAFLD-NASH-HCC PROGRESSION: STUDY ON C57BL/6J MICE. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON MALIGNANT TUMOR OF THE LIVER. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A FREQUENT CHRONIC LIVER DISORDER IN DEVELOPED COUNTRIES. NAFLD CAN PROGRESS THROUGH THE MORE SEVERE NON ALCOHOLIC STEATOHEPATITIS (NASH), CIRRHOSIS AND, LASTLY, HCC. GENETIC AND EPIGENETIC ALTERATIONS OF CODING GENES AS WELL AS DEREGULATION OF MICRORNAS (MIRNAS) ACTIVITY PLAY A ROLE IN HCC DEVELOPMENT. IN THIS STUDY, THE C57BL/6J MOUSE MODEL WAS LONG TERM HIGH-FAT (HF) OR LOW-FAT (LF) DIET FED, IN ORDER TO ANALYZE MOLECULAR MECHANISMS RESPONSIBLE FOR THE HEPATIC DAMAGE PROGRESSION. METHODS: MICE WERE HF OR LF DIET FED FOR DIFFERENT TIME POINTS, THEN PLASMA AND HEPATIC TISSUES WERE COLLECTED. HISTOLOGICAL AND CLINICAL CHEMISTRY ASSAYS WERE PERFORMED TO ASSESS THE PROGRESSION OF LIVER DISEASE. MICRORNAS' DIFFERENTIAL EXPRESSION WAS EVALUATED ON POOLED RNAS FROM TISSUES, AND SOME MIRNAS SHOWING DYSREGULATION WERE FURTHER ANALYZED AT THE INDIVIDUAL LEVEL. RESULTS: CHOLESTEROL, LOW AND HIGH DENSITY LIPOPROTEINS, TRIGLYCERIDES AND ALANINE AMINOTRANSFERASE INCREASE WAS DETECTED IN HF MICE. GROSS ANATOMICAL EXAMINATION REVEALED HEPATOMEGALY IN HF LIVERS, AND HISTOLOGICAL ANALYSIS HIGHLIGHTED DIFFERENT DEGREES AND LEVELS OF STEATOSIS, INFLAMMATORY INFILTRATE AND FIBROSIS IN HF AND LF ANIMALS, DEMONSTRATING THE PROGRESSION FROM NAFLD THROUGH NASH. MACROSCOPIC NODULES, SHOWING TYPICAL NEOPLASTIC FEATURES, WERE OBSERVED IN 20% OF HF DIET FED MICE. FIFTEEN MIRNAS DIFFERENTIALLY EXPRESSED IN HF WITH RESPECT TO LF HEPATIC TISSUES DURING THE PROGRESSION OF LIVER DAMAGE, AND IN TUMORS WITH RESPECT TO HF NON TUMOR LIVER SPECIMENS WERE IDENTIFIED. AMONG THEM, MIR-340-5P, MIR-484, MIR-574-3P, MIR-720, WHOSE EXPRESSION WAS NEVER DESCRIBED IN NAFLD, NASH AND HCC TISSUES, AND MIR-125A-5P AND MIR-182, WHICH SHOWED EARLY AND SIGNIFICANT DYSREGULATION IN THE SEQUENTIAL HEPATIC DAMAGE PROCESS. CONCLUSIONS: IN THIS STUDY, FIFTEEN MICRORNAS WHICH WERE MODULATED IN HEPATIC TISSUES AND IN TUMORS DURING THE TRANSITION NAFLD-NASH-HCC ARE REPORTED. BESIDES SOME ALREADY DESCRIBED, NEW AND EARLY DYSREGULATED MIRNAS WERE IDENTIFIED. FUNCTIONAL ANALYSES ARE NEEDED TO VALIDATE THE RESULTS HERE OBTAINED, AND TO BETTER DEFINE THE ROLE OF THESE MOLECULES IN THE PROGRESSION OF THE HEPATIC DISEASE.	2016	
                                                                                                                                                                                        
17 2749  20 EXPRESSION AND POLYMORPHISM OF MICRO-RNA ACCORDING TO BODY MASS INDEX AND BREAST CANCER PRESENTATION IN TUNISIAN PATIENTS. MICRO-RNAS (MIRS) CONSTITUTE A CLASS OF SMALL NONCODING RNAS IMPLICATED IN THE REGULATION OF GENE EXPRESSION BY BINDING TO TARGET MRNAS. A MIR CAN TARGET SEVERAL MRNAS, BEING INVOLVED IN DIFFERENT BIOLOGIC PROCESSES AND PATHOLOGIES. THIS PLEIOTROPIC FUNCTION MIGHT EXPLAIN THE LINK BETWEEN DISEASES CO-OCCURRENCE. EPIGENETIC ORIGIN OF THE LINK BETWEEN OBESITY AND BREAST CANCER (BC) IS INVESTIGATED IN A COHORT OF TUNISIAN PATIENTS, FOCUSING ON POLYMORPHISM AT GERMLINE LEVEL (MIR-146A) AND ON EXPRESSION IN MAMMARY TUMORS (MIR-21, MIR-146A, AND MIR-34A), ACCORDING TO BODY MASS INDEX (BMI) AND CLINICO-PATHOLOGIC FEATURES. THE MEASURE OF MIR EXPRESSION IN 60 MAMMARY TUMORS WAS REALIZED USING QUANTITATIVE RT-PCR. STUDY OF RS 2910164 IN MIR-146A WAS PERFORMED BY PCR AND DIRECT SEQUENCING USING BLOOD DNA OF 83 AFFECTED WOMEN AND 50 UNRELATED SUBJECTS FROM GREAT TUNIS. MIR-21, MIR-146A, AND MIR-34A HAVE BEEN QUANTIFIED IN BREAST TUMOR ACCORDING TO BMI. MIR-21 IS SIGNIFICANTLY MORE EXPRESSED IN TUMORS OF OBESE WOMEN COMPARATIVELY TO NONOBESE PATIENTS. ON THE CONTRARY, MIR-34A IS DECREASED IN TUMORS OF OBESE WOMEN. MOREOVER, IN OBESE BC PATIENTS, A SIGNIFICANT INCREASE IN BOTH MIR-21 AND MIR-146A EXPRESSION IS REVEALED IN CASES WITH LYMPH NODE METASTASIS. THE POLYMORPHISM AT RS 2910164 (MIR-146A) LOCUS WAS NOT SHOWN AS A RISK FACTOR FOR BC. HOWEVER THE MUTANT CC GENOTYPE WAS REVEALED TO BE ASSOCIATED WITH A RISK FOR BAD OUTCOME OF THE DISEASE. CHRONIC INFLAMMATION IN OBESE WOMEN WOULD BE LINKED TO AGGRESSIVE BREAST TUMORS VIA INDUCTION OF ONCOMIRS OVEREXPRESSION AND DECREASE OF TUMOR SUPPRESSOR MIRS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18 5638  35 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19 1909  32 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH CHRONIC MUSCULOSKELETAL PAIN IN OLDER ADULTS: AN EXPLORATORY STUDY. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED CPGS/REGIONS AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH UNDERLYING CHRONIC MUSCULOSKELETAL PAIN IN OLDER INDIVIDUALS. WE RECRUITED COGNITIVELY HEALTHY OLDER ADULTS WITH (N = 20) AND WITHOUT (N = 9) SELF-REPORTED MUSCULOSKELETAL PAIN AND COLLECTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 31,739 HYPERMETHYLATED CPG AND 10,811 HYPOMETHYLATED CPG PROBES (PS </= 0.05). ALL CPG PROBES WERE CLUSTERED INTO 5966 REGIONS, AMONG WHICH 600 REGIONS WERE DIFFERENTIALLY METHYLATED AT P </= 0.05 LEVEL, INCLUDING 294 HYPERMETHYLATED REGIONS AND 306 HYPOMETHYLATED REGIONS (DIFFERENTIALLY METHYLATED REGIONS). INGENUITY PATHWAY ENRICHMENT ANALYSIS REVEALED THAT THE PAIN-RELATED DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED ACROSS MULTIPLE PATHWAYS. THE TOP 10 CANONICAL PATHWAYS WERE LINKED TO CELLULAR SIGNALING PROCESSES RELATED TO IMMUNE RESPONSES (I.E. ANTIGEN PRESENTATION, PROGRAMED CELL DEATH 1 RECEPTOR/PD-1 LIGAND 1, INTERLEUKIN-4, OX40 SIGNALING, T CELL EXHAUSTION, AND APOPTOSIS) AND GAMMA-AMINOBUTYRIC ACID RECEPTOR SIGNALING. FURTHER, WEIGHTED GENE CORRELATION NETWORK ANALYSIS REVEALED A COMETHYLATION NETWORK MODULE IN THE PAIN GROUP THAT WAS NOT PRESERVED IN THE CONTROL GROUP, WHERE THE HUB GENE WAS THE CYCLIC ADENOSINE MONOPHOSPHATE-DEPENDENT TRANSCRIPTION FACTOR ATF-2. OUR PRELIMINARY FINDINGS PROVIDE NEW EPIGENETIC INSIGHTS INTO THE ROLE OF ABERRANT IMMUNE SIGNALING IN MUSCULOSKELETAL PAIN IN OLDER ADULTS WHILE FURTHER SUPPORTING INVOLVEMENT OF DYSFUNCTIONAL GABAERGIC SIGNALING MECHANISMS IN CHRONIC PAIN. OUR FINDINGS NEED TO BE URGENTLY REPLICATED IN LARGER COHORTS AS THEY MAY SERVE AS A BASIS FOR DEVELOPING AND TARGETING FUTURE INTERVENTIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20 2909  29 GENE EXPRESSION PROFILING IN FIBROMYALGIA INDICATES AN AUTOIMMUNE ORIGIN OF THE DISEASE AND OPENS NEW AVENUES FOR TARGETED THERAPY. FIBROMYALGIA IS A CHRONIC DISORDER CHARACTERIZED BY WIDESPREAD PAIN AND BY SEVERAL NON-PAIN SYMPTOMS. AUTOIMMUNITY, SMALL FIBER NEUROPATHY AND NEUROINFLAMMATION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF THE DISEASE. WE HAVE INVESTIGATED THE GENE EXPRESSION PROFILE IN PERIPHERAL BLOOD MONONUCLEAR CELLS OBTAINED FROM TEN PATIENTS AND TEN HEALTHY SUBJECTS. OF THE 545,500 TRANSCRIPTS ANALYZED, 1673 RESULTED MODULATED IN FIBROMYALGIC PATIENTS. THE MAJORITY OF THESE GENES ARE INVOLVED IN BIOLOGICAL PROCESSES AND PATHWAYS LINKED TO THE CLINICAL MANIFESTATIONS OF THE DISEASE. MOREOVER, GENES INVOLVED IN IMMUNOLOGICAL PATHWAYS CONNECTED TO INTERLEUKIN-17 AND TO TYPE I INTERFERON SIGNATURES WERE ALSO MODULATED, SUGGESTING THAT AUTOIMMUNITY PLAYS A ROLE IN THE DISEASE. WE THEN AIMED AT IDENTIFYING DIFFERENTIALLY EXPRESSED LONG NON-CODING RNAS (LNCRNAS) FUNCTIONALLY CONNECTED TO MODULATED GENES BOTH DIRECTLY AND VIA MICRORNA TARGETING. ONLY TWO LNCRNAS OF THE 298 FOUND MODULATED IN PATIENTS, WERE ABLE TO TARGET THE MOST HIGHLY CONNECTED GENES IN THE FIBROMYALGIA INTERACTOME, SUGGESTING THEIR INVOLVEMENT IN CRUCIAL GENE REGULATION. OUR GENE EXPRESSION DATA WERE CONFIRMED BY REAL TIME PCR, BY AUTOANTIBODY TESTING, DETECTION OF SOLUBLE MEDIATORS AND TH-17 POLARIZATION IN A VALIDATION COHORT OF 50 PATIENTS. OUR RESULTS INDICATE THAT GENETIC AND EPIGENETIC MECHANISMS AS WELL AS AUTOIMMUNITY PLAY A PIVOTAL ROLE IN THE PATHOGENESIS OF FIBROMYALGIA.	2020