1 2723 143 EXOSOMES: NOMENCLATURE, ISOLATION, AND BIOLOGICAL ROLES IN LIVER DISEASES. THE BIOGENESIS AND BIOLOGICAL ROLES OF EXTRACELLULAR VESICLES (EVS) IN THE PROGRESSION OF LIVER DISEASES HAVE ATTRACTED CONSIDERABLE ATTENTION IN RECENT YEARS. EVS ARE MEMBRANE-BOUND NANOSIZED VESICLES FOUND IN DIFFERENT TYPES OF BODY FLUIDS AND CONTAIN VARIOUS BIOACTIVE MATERIALS, INCLUDING PROTEINS, LIPIDS, NUCLEIC ACIDS, AND MITOCHONDRIAL DNA. BASED ON THEIR ORIGIN AND BIOGENESIS, EVS CAN BE CLASSIFIED AS APOPTOTIC BODIES, MICROVESICLES, AND EXOSOMES. AMONG THESE, EXOSOMES ARE THE SMALLEST EVS (30-150 NM IN DIAMETER), WHICH PLAY A SIGNIFICANT ROLE IN CELL-TO-CELL COMMUNICATION AND EPIGENETIC REGULATION. MOREOVER, EXOSOMAL CONTENT ANALYSIS CAN REVEAL THE FUNCTIONAL STATE OF THE PARENTAL CELL. THEREFORE, EXOSOMES CAN BE APPLIED TO VARIOUS PURPOSES, INCLUDING DISEASE DIAGNOSIS AND TREATMENT, DRUG DELIVERY, CELL-FREE VACCINES, AND REGENERATIVE MEDICINE. HOWEVER, EXOSOME-RELATED RESEARCH FACES TWO MAJOR LIMITATIONS: ISOLATION OF EXOSOMES WITH HIGH YIELD AND PURITY AND DISTINCTION OF EXOSOMES FROM OTHER EVS (ESPECIALLY MICROVESICLES). NO STANDARDIZED EXOSOME ISOLATION METHOD HAS BEEN ESTABLISHED TO DATE; HOWEVER, VARIOUS EXOSOME ISOLATION STRATEGIES HAVE BEEN PROPOSED TO INVESTIGATE THEIR BIOLOGICAL ROLES. EXOSOME-MEDIATED INTERCELLULAR COMMUNICATIONS ARE KNOWN TO BE INVOLVED IN ALCOHOLIC LIVER DISEASE AND NONALCOHOLIC FATTY LIVER DISEASE DEVELOPMENT. DAMAGED HEPATOCYTES OR NONPARENCHYMAL CELLS RELEASE LARGE NUMBERS OF EXOSOMES THAT PROMOTE THE PROGRESSION OF INFLAMMATION AND FIBROGENESIS THROUGH INTERACTIONS WITH NEIGHBORING CELLS. EXOSOMES ARE EXPECTED TO PROVIDE INSIGHT ON THE PROGRESSION OF LIVER DISEASE. HERE, WE REVIEW THE BIOGENESIS OF EXOSOMES, EXOSOME ISOLATION TECHNIQUES, AND BIOLOGICAL ROLES OF EXOSOMES IN ALCOHOLIC LIVER DISEASE AND NONALCOHOLIC FATTY LIVER DISEASE. 2023 2 1051 41 CLINICAL IMPLICATIONS OF EXOSOME-DERIVED NONCODING RNAS IN LIVER. EXOSOMES, ONE OF THREE MAIN TYPES OF EXTRACELLULAR VESICLES, ARE ~30-100 NM IN DIAMETER AND HAVE A LIPID BILAYER MEMBRANE. THEY ARE WIDELY DISTRIBUTED IN ALMOST ALL BODY FLUIDS. EXOSOMES HAVE THE POTENTIAL TO REGULATE UNKNOWN CELLULAR AND MOLECULAR MECHANISMS IN INTERCELLULAR COMMUNICATION, ORGAN HOMEOSTASIS, AND DISEASES. THEY ARE CRITICAL SIGNAL CARRIERS THAT TRANSFER NUCLEIC ACIDS, PROTEINS, LIPIDS, AND OTHER SUBSTANCES INTO RECIPIENT CELLS, PARTICIPATING IN CELLULAR SIGNAL TRANSDUCTION AND MATERIAL EXCHANGE. NCRNAS ARE NON-PROTEIN-CODING GENES THAT ACCOUNT FOR OVER 90% OF THE GENOME AND INCLUDE MICRORNAS (MIRNAS), LONG NCRNAS (LNCRNAS), AND CIRCULAR RNAS (CIRCRNAS). NCRNAS ARE CRUCIAL FOR PHYSIOLOGICAL AND PATHOLOGICAL ACTIVITIES IN THE LIVER BY PARTICIPATING IN GENE TRANSCRIPTION, POSTTRANSCRIPTIONAL EPIGENETIC REGULATION, AND CELLULAR PROCESSES THROUGH INTERACTING WITH DNA, RNA, OR PROTEINS. RECENT EVIDENCE FROM BOTH CLINICAL AND PRECLINICAL STUDIES INDICATES THAT EXOSOME-DERIVED NONCODING RNAS (NCRNAS) ARE HIGHLY INVOLVED IN THE PROGRESSION OF ACUTE AND CHRONIC LIVER DISEASES BY REGULATING HEPATIC LIPID METABOLISM, INNATE IMMUNITY, VIRAL INFECTION, FIBROSIS, AND CANCER. THEREFORE, EXOSOME-DERIVED NCRNAS HAVE PROMISING POTENTIAL AND CLINICAL IMPLICATIONS FOR THE EARLY DIAGNOSIS, TARGETED THERAPY, AND PROGNOSIS OF LIVER DISEASES. 2022 3 2722 39 EXOSOMES AS A NEW PAIN BIOMARKER OPPORTUNITY. EXOSOMES ARE EXTRACELLULAR MICROVESICLES IMPLICATED IN INTERCELLULAR COMMUNICATION WITH ABILITY TO TRANSFER CARGO MOLECULES, INCLUDING PROTEIN, LIPIDS, AND NUCLEIC ACIDS, AT BOTH CLOSE AND DISTANT TARGET SITES. IT HAS BEEN SHOWN THAT EXOSOMES ARE IMPLICATED IN PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES. IN RECENT YEARS, THE INTEREST ON EXOSOMES' ROLE IN MANY PAIN STATES HAS INCREASED. THEIR INVOLVEMENTS IN PAIN PROCESSES HAVE BEEN DEMONSTRATED BY STUDIES ON DIFFERENT CHRONIC PAIN DISEASES, BOTH INFLAMMATORY AND NEUROPATHIC, SUCH AS OSTEOARTHRITIS, RHEUMATOID ARTHRITIS, INFLAMMATORY BOWEL DISEASES, NEURODEGENERATIVE PATHOLOGIES, COMPLEX REGIONAL PAIN SYNDROME, AND PERIPHERAL NERVE INJURY. ANIMAL AND CLINICAL STUDIES INVESTIGATED EXOSOMES-BASED TREATMENTS, SHOWING THEIR ABILITY TO IMPROVE PAINFUL SYMPTOMS WITH FEWER SIDE EFFECTS, WITH POTENTIAL IMMUNOPROTECTIVE AND ANTI-INFLAMMATORY EFFECT. SPECIFIC MOLECULAR PATTERNS CHARACTERIZE EXOSOMES' CARGO ACCORDING TO THE CELLULAR ORIGIN, EPIGENETIC MODIFICATIONS, ENVIRONMENTAL STATE, AND STRESSOR FACTORS. THEREFORE, THE IDENTIFICATION OF SPECIFIC CARGO'S PROFILE ASSOCIATED TO PAIN STATES MAY LEAD TO RECOGNIZE SPECIFIC PATHOLOGICAL STATES AND TO CONSIDER THE USE OF EXOSOMES AS BIOMARKERS OF DISEASES. FURTHERMORE, EXOSOMES' ABILITY TO TRANSFER INFORMATION AND THEIR PRESENCE IN MANY ACCESSIBLE BIOLOGICAL FLUIDS SUGGEST A POTENTIAL USE AS NOVEL NON-INVASIVE THERAPEUTIC TOOLS IN PAIN FIELD. 2020 4 2721 46 EXOSOMAL NON CODING RNAS AS A NOVEL TARGET FOR DIABETES MELLITUS AND ITS COMPLICATIONS. DIABETES MELLITUS (DM) IS A FIRST-LINE PRIORITY AMONG THE PROBLEMS FACING MEDICAL SCIENCE AND PUBLIC HEALTH IN ALMOST ALL COUNTRIES OF THE WORLD. THE MAIN PROBLEM OF DM IS THE HIGH INCIDENCE OF DAMAGE TO THE CARDIOVASCULAR SYSTEM, WHICH IN TURN LEADS TO DISEASES SUCH AS MYOCARDIAL INFARCTION, STROKE, GANGRENE OF THE LOWER EXTREMITIES, BLINDNESS AND CHRONIC RENAL FAILURE. AS A RESULT, THE STUDY OF THE MOLECULAR GENETIC MECHANISMS OF THE PATHOGENESIS OF DM IS OF CRITICAL IMPORTANCE FOR THE DEVELOPMENT OF NEW DIAGNOSTIC AND THERAPEUTIC STRATEGIES. MOLECULAR GENETIC ASPECTS OF THE ETIOLOGY AND PATHOGENESIS OF DIABETES MELLITUS ARE INTENSIVELY STUDIED IN WELL-KNOWN LABORATORIES AROUND THE WORLD. ONE OF THE STRATEGIES IN THIS DIRECTION IS TO STUDY THE ROLE OF EXOSOMES IN THE PATHOGENESIS OF DM. EXOSOMES ARE MICROSCOPIC EXTRACELLULAR VESICLES WITH A DIAMETER OF 30-100 NM, RELEASED INTO THE INTERCELLULAR SPACE BY CELLS OF VARIOUS TISSUES AND ORGANS. THE CONTENT OF EXOSOMES DEPENDS ON THE CELL TYPE AND INCLUDES MRNA, NON-CODING RNAS, DNA, AND SO ON. NON-CODING RNAS, A GROUP OF RNAS WITH LIMITED TRANSCRIPTIONAL ACTIVITY, HAVE BEEN DISCOVERED TO PLAY A SIGNIFICANT ROLE IN REGULATING GENE EXPRESSION THROUGH EPIGENETIC AND POSTTRANSCRIPTIONAL MODULATION, SUCH AS SILENCING OF MESSENGER RNA. ONE OF THE PROBLEMS OF USAGE EXOSOMES IN DM IS THE IDENTIFICATION OF THE CELLULAR ORIGIN OF EXOSOMES AND THE STANDARDIZATION OF PROTOCOLS FOR MOLECULAR GENETIC STUDIES IN CLINICAL LABORATORIES. IN ADDITION, THE QUESTION OF THE TARGET ORIENTATION OF EXOSOMES AND THEIR TARGETED ACTIVITY REQUIRES ADDITIONAL STUDY. SOLVING THESE AND OTHER PROBLEMS WILL MAKE IT POSSIBLE TO USE EXOSOMES FOR THE DIAGNOSIS AND DELIVERY OF DRUGS DIRECTLY TO TARGET CELLS IN DM. THIS STUDY PRESENTS AN ANALYSIS OF LITERATURE DATA ON THE ROLE OF EXOSOMES AND NCRNAS IN THE DEVELOPMENT AND PROGRESSION OF DM, AS WELL AS THE PROSPECTS FOR THE USE OF EXOSOMES IN CLINICAL PRACTICE IN THIS DISEASE. 2023 5 2720 47 EXOSOMAL MIRNAS IN HEPATITIS B VIRUS RELATED LIVER DISEASE: A NEW HOPE FOR BIOMARKER. THE WORLD HEALTH ORGANISATION, IN ITS 2019 PROGRESS REPORT ON HIV, VIRAL HEPATITIS AND STDS INDICATES THAT 257 MILLION PEOPLE ARE AFFLICTED WITH CHRONIC HBV INFECTIONS, OF WHICH, 1 MILLION PATIENTS LOSE THEIR LIVES EVERY YEAR DUE TO HBV RELATED CHRONIC LIVER DISEASES INCLUDING SERIOUS COMPLICATIONS SUCH AS LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. THE COURSE OF HBV INFECTION AND ASSOCIATED LIVER INJURY DEPEND ON SEVERAL HOST FACTORS, GENETIC VARIABILITY OF THE VIRUS, AND THE HOST VIRAL INTERPLAY. THE CHALLENGE OF MEDICAL SCIENCE IS THE EARLY DIAGNOSIS/IDENTIFICATION OF THE POTENTIAL FOR DEVELOPMENT OF FATAL COMPLICATIONS LIKE LIVER CIRRHOSIS AND HCC SO THAT TIMELY MEDICAL INTERVENTION CAN IMPROVE THE CHANCES OF SURVIVAL. CURRENTLY, NEITHER THE VACCINATION REGIME NOR THE DIAGNOSTIC METHODS ARE COMPLETELY EFFECTIVE AS REFLECTED IN THE HIGH NUMBER OF ANNUAL DEATHS. IT IS EVIDENT FROM NUMEROUS PUBLICATIONS THAT MICRORNAS (MIRNAS) ARE THE CRITICAL REGULATORS OF GENE EXPRESSION AND VARIOUS CELLULAR PROCESSES LIKE PROLIFERATION, DEVELOPMENT, DIFFERENTIATION, APOPTOSIS AND TUMORIGENESIS. EXPRESSIONS OF THESE DIMINUTIVE RNAS ARE SIGNIFICANTLY AFFECTED IN CANCEROUS TISSUES AS A RESULT OF NUMEROUS GENOMIC AND EPIGENETIC MODIFICATIONS. EXOSOMES ARE MEMBRANE-DERIVED VESICLES (30-100 NM) SECRETED BY NORMAL AS WELL AS MALIGNANT CELLS, AND ARE PRESENT IN ALL BODY FLUIDS. THEY ARE RECOGNIZED AS CRITICAL MOLECULES IN INTERCELLULAR COMMUNICATION BETWEEN CELLS THROUGH HORIZONTAL TRANSFER OF INFORMATION VIA THEIR CARGO, WHICH INCLUDES SELECTIVE PROTEINS, MRNAS AND MIRNAS. EXOSOMAL MIRNAS ARE TRANSFERRED TO RECIPIENT CELLS WHERE THEY CAN REGULATE TARGET GENE EXPRESSION. THIS PROVIDES AN INSIGHT INTO THE ELEMENTARY BIOLOGY OF CANCER PROGRESSION AND THEREFORE THE DEVELOPMENT OF THERAPEUTIC APPROACHES. THIS CONCISE REVIEW OUTLINES VARIOUS ON-GOING RESEARCH ON MIRNA MEDIATED REGULATION OF HBV PATHOGENESIS WITH SPECIAL EMPHASIS ON ASSOCIATION OF EXOSOMAL MIRNA IN ADVANCED STAGE LIVER DISEASE LIKE HEPATOCELLULAR CARCINOMA. THIS REVIEW ALSO DISCUSSES THE POSSIBLE USE OF EXOSOMAL MIRNAS AS BIOMARKERS IN THE EARLY DETECTION OF HCC AND LIVER CIRRHOSIS. 2020 6 2775 24 EXTRACELLULAR VESICLES AND ASTHMA-MORE THAN JUST A CO-EXISTENCE. EXTRACELLULAR VESICLES (EVS) ARE MEMBRANOUS STRUCTURES, WHICH ARE SECRETED BY ALMOST EVERY CELL TYPE ANALYZED SO FAR. IN ADDITION TO THEIR IMPORTANCE FOR CELL-CELL COMMUNICATION UNDER PHYSIOLOGICAL CONDITIONS, EVS ARE ALSO RELEASED DURING PATHOGENESIS AND MECHANISTICALLY CONTRIBUTE TO THIS PROCESS. HERE WE SUMMARIZE THEIR FUNCTIONAL RELEVANCE IN ASTHMA, ONE OF THE MOST COMMON CHRONIC NON-COMMUNICABLE DISEASES. ASTHMA IS A COMPLEX PERSISTENT INFLAMMATORY DISORDER OF THE AIRWAYS CHARACTERIZED BY REVERSIBLE AIRFLOW OBSTRUCTION AND, FROM A LONG-TERM PERSPECTIVE, AIRWAY REMODELING. OVERALL, MECHANISTIC STUDIES SUMMARIZED HERE INDICATE THE IMPORTANCE OF DIFFERENT SUBTYPES OF EVS AND THEIR VARIABLE CARGOES IN THE FUNCTIONING OF THE PATHWAYS UNDERLYING ASTHMA, AND SHOW SOME INTERESTING POTENTIAL FOR THE DEVELOPMENT OF FUTURE THERAPEUTIC INTERVENTIONS. ASSOCIATION STUDIES IN TURN DEMONSTRATE A GOOD DIAGNOSTIC POTENTIAL OF EVS IN ASTHMA. 2021 7 1858 33 ELUCIDATING POTENTIAL PROFIBROTIC MECHANISMS OF EMERGING BIOMARKERS FOR EARLY PROGNOSIS OF HEPATIC FIBROSIS. HEPATIC FIBROSIS HAS BEEN ASSOCIATED WITH A SERIES OF PATHOPHYSIOLOGICAL PROCESSES CAUSING EXCESSIVE ACCUMULATION OF EXTRACELLULAR MATRIX PROTEINS. SEVERAL CELLULAR PROCESSES AND MOLECULAR MECHANISMS HAVE BEEN IMPLICATED IN THE DISEASED LIVER THAT AUGMENTS FIBROGENESIS, FIBROGENIC CYTOKINES AND ASSOCIATED LIVER COMPLICATIONS. LIVER BIOPSY REMAINS AN ESSENTIAL DIAGNOSTIC TOOL FOR HISTOLOGICAL EVALUATION OF HEPATIC FIBROSIS TO ESTABLISH A PROGNOSIS. IN ADDITION TO BEING INVASIVE, THIS METHODOLOGY PRESENTS WITH SEVERAL LIMITATIONS INCLUDING POOR COST-EFFECTIVENESS, PROLONGED HOSPITALIZATIONS, AND RISKS OF PERITONEAL BLEEDING, WHILE THE CLINICAL USE OF THIS METHOD DOES NOT REVEAL UNDERLYING PATHOGENIC MECHANISMS. SEVERAL ALTERNATE NONINVASIVE DIAGNOSTIC STRATEGIES HAVE BEEN DEVELOPED, TO DETERMINE THE EXTENT OF HEPATIC FIBROSIS, INCLUDING THE USE OF DIRECT AND INDIRECT BIOMARKERS. IMMEDIATE DIAGNOSIS OF HEPATIC FIBROSIS BY NONINVASIVE MEANS WOULD BE MORE PALATABLE THAN A BIOPSY AND COULD ASSIST CLINICIANS IN TAKING EARLY INTERVENTIONS TIMELY, AVOIDING FATAL COMPLICATIONS, AND IMPROVING PROGNOSIS. THEREFORE, WE SOUGHT TO REVIEW SOME COMMON BIOMARKERS OF LIVER FIBROSIS ALONG WITH SOME EMERGING CANDIDATES, INCLUDING THE OXIDATIVE STRESS-MEDIATED BIOMARKERS, EPIGENETIC AND GENETIC MARKERS, EXOSOMES, AND MIRNAS THAT NEEDS FURTHER EVALUATION AND WOULD HAVE BETTER SENSITIVITY AND SPECIFICITY. WE ALSO AIM TO ELUCIDATE THE POTENTIAL ROLE OF CARDIOTONIC STEROIDS (CTS) AND EVALUATE THE PRO-INFLAMMATORY AND PROFIBROTIC EFFECTS OF CTS IN EXACERBATING HEPATIC FIBROSIS. BY UNDERSTANDING THE UNDERLYING PATHOGENIC PROCESSES, THE EFFICACY OF THESE BIOMARKERS COULD ALLOW FOR EARLY DIAGNOSIS AND TREATMENT OF HEPATIC FIBROSIS IN CHRONIC LIVER DISEASES, ONCE VALIDATED. 2020 8 2691 27 EVOLUTION OF HEPATIC FIBROSIS RESEARCH. MOLECULAR ANALYSIS OF HEPATIC FIBROGENESIS HAS PROGRESSED WITH RESPECT TO BOTH FIBROSIS PROGRESSION AND REGRESSION BY USING CELL BIOLOGICAL, MOLECULAR BIOLOGICAL AND (EPI)GENETIC APPROACHES. RECENT RESEARCHES HAVE REVEALED SOURCES OF COLLAGEN-PRODUCING CELLS OTHER THAN HEPATIC STELLATE CELLS IN THE LIVER, AND THE INVOLVEMENT OF THE INNATE IMMUNE SYSTEM AND OXIDATIVE STRESS IN THE FIBROTIC PROCESS HAS ATTRACTED NEW ATTENTION. TOGETHER WITH THESE ADVANCEMENTS IN BASIC KNOWLEDGE ON THE CELLULAR AND MOLECULAR BIOLOGY OF HEPATIC FIBROSIS, CLINICAL RESEARCHES HAVE LINKED THE CLARIFICATION OF THE RELATIONSHIP BETWEEN PROGRESSION OF THE FIBROSIS STAGE AND THERAPEUTIC EFFICACY FOR CHRONIC VIRAL HEPATITIS AND NON-ALCOHOLIC STEATOHEPATITIS AND VALIDATION OF THE REGRESSION OF ADVANCED FIBROSIS, EVEN CIRRHOSIS, OF APPROPRIATE THERAPIES USING MODERN MEDICINES. FURTHERMORE, NON-INVASIVE ASSESSMENT OF LIVER FIBROSIS USING AN ULTRASOUND-BASED MODALITY HAS BECOME A FOCUS IN THE CLINICAL DIAGNOSIS OF LIVER FIBROSIS INSTEAD OF LIVER BIOPSY. TAKEN TOGETHER, LIVER FIBROSIS RESEARCH HAS BEEN EVOLVING BOTH BASICALLY AND CLINICALLY IN THE PAST THREE DECADES. 2011 9 2544 25 EPIGENETICS IN LIVER DISEASE: FROM BIOLOGY TO THERAPEUTICS. KNOWLEDGE OF THE FUNDAMENTAL EPIGENETIC MECHANISMS GOVERNING GENE EXPRESSION AND CELLULAR PHENOTYPE ARE SUFFICIENTLY ADVANCED THAT NOVEL INSIGHTS INTO THE EPIGENETIC CONTROL OF CHRONIC LIVER DISEASE ARE NOW EMERGING. HEPATOLOGISTS ARE IN THE PROCESS OF SHEDDING LIGHT ON THE ROLES PLAYED BY DNA METHYLATION, HISTONE/CHROMATIN MODIFICATIONS AND NON-CODING RNAS IN SPECIFIC LIVER PATHOLOGIES. ALONGSIDE THESE DISCOVERIES ARE ADVANCES IN THE TECHNOLOGIES FOR THE DETECTION AND QUANTIFICATION OF EPIGENETIC BIOMARKERS, EITHER DIRECTLY FROM PATIENT TISSUE OR FROM BODY FLUIDS. THE PREMISE FOR THIS REVIEW IS TO SURVEY THE RECENT ADVANCES IN THE FIELD OF LIVER EPIGENETICS AND TO EXPLORE THEIR POTENTIAL FOR TRANSLATION BY INDUSTRY AND CLINICAL HEPATOLOGISTS FOR THE DESIGN OF NOVEL THERAPEUTICS AND DIAGNOSTIC/PROGNOSTIC BIOMARKERS. IN PARTICULAR, WE PRESENT FINDINGS IN THE CONTEXT OF HEPATOCELLULAR CARCINOMA, FIBROSIS AND NON-ALCOHOLIC FATTY LIVER DISEASE, WHERE THERE IS URGENT UNMET NEED FOR NEW CLINICAL INTERVENTIONS AND BIOMARKERS. 2016 10 3964 33 LONG NONCODING RNAS IN LUNG CANCER. DESPITE GREAT PROGRESS IN RESEARCH AND TREATMENT OPTIONS, LUNG CANCER REMAINS THE LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE. ONCOGENIC DRIVER MUTATIONS IN PROTEIN-ENCODING GENES WERE DEFINED AND ALLOW FOR PERSONALIZED THERAPIES BASED ON GENETIC DIAGNOSES. NONETHELESS, DIAGNOSIS OF LUNG CANCER MOSTLY OCCURS AT LATE STAGES, AND CHRONIC TREATMENT IS FOLLOWED BY A FAST ONSET OF CHEMORESISTANCE. HENCE, THERE IS AN URGENT NEED FOR RELIABLE BIOMARKERS AND ALTERNATIVE TREATMENT OPTIONS. WITH THE ERA OF WHOLE GENOME AND TRANSCRIPTOME SEQUENCING TECHNOLOGIES, LONG NONCODING RNAS EMERGED AS A NOVEL CLASS OF VERSATILE, FUNCTIONAL RNA MOLECULES. ALTHOUGH FOR MOST OF THEM THE MECHANISM OF ACTION REMAINS TO BE DEFINED, ACCUMULATING EVIDENCE CONFIRMS THEIR INVOLVEMENT IN VARIOUS ASPECTS OF LUNG TUMORIGENESIS. THEY ARE FUNCTIONAL ON THE EPIGENETIC, TRANSCRIPTIONAL, AND POSTTRANSCRIPTIONAL LEVEL AND ARE REGULATORS OF PATHOPHYSIOLOGICAL KEY PATHWAYS INCLUDING CELL GROWTH, APOPTOSIS, AND METASTASIS. LONG NONCODING RNAS ARE GAINING INCREASING ATTENTION AS POTENTIAL BIOMARKERS AND A NOVEL CLASS OF DRUGGABLE MOLECULES. IT HAS BECOME CLEAR THAT WE ARE ONLY BEGINNING TO UNDERSTAND THE COMPLEXITY OF TUMORIGENIC PROCESSES. THE CLINICAL INTEGRATION OF LONG NONCODING RNAS IN TERMS OF PROGNOSTIC AND PREDICTIVE BIOMARKER SIGNATURES AND ADDITIONAL CANCER TARGETS COULD PROVIDE A CHANCE TO INCREASE THE THERAPEUTIC BENEFIT. HERE, WE REVIEW THE CURRENT KNOWLEDGE ABOUT THE EXPRESSION, REGULATION, BIOLOGICAL FUNCTION, AND CLINICAL RELEVANCE OF LONG NONCODING RNAS IN LUNG CANCER. 2016 11 6913 24 [VARIOUS PATHWAYS LEADING TO THE PROGRESSION OF CHRONIC LIVER DISEASES]. AS THE RESULT OF VARIOUS EFFECTS (VIRUSES, METABOLIC DISEASES, NUTRITIONAL FACTORS, TOXIC AGENTS, AUTOIMMUNE PROCESSES) ABNORMAL LIVER FUNCTION, LIVER STEATOSIS AND CONNECTIVE TISSUE REMODELING MAY DEVELOP. PROGRESSION OF THIS PROCESS IS COMPLEX INCLUDING VARIOUS PATHWAYS AND A NUMBER OF FACTORS. THE AUTHORS SUMMARIZE THE FACTORS INVOLVED IN THE PROGRESSION OF CHRONIC LIVER DISEASE. THEY DESCRIBE THE ROLE OF CELLS AND THE PRODUCED INFLAMMATORY MEDIATORS AND CYTOKINES, AS WELL AS THE RELATIONSHIP BETWEEN THE DISEASE AND THE INTESTINAL FLORA. THEY EMPHASIZE THE ROLE OF OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION AND CELL DEATH IN DISEASE PROGRESSION. INSULIN RESISTANCE AND MICRO-ELEMENTS (IRON, COPPER) IN RELATION TO LIVER DAMAGE ARE ALSO DISCUSSED, AND GENETIC AND EPIGENETIC ASPECTS UNDERLYING DISEASE PROGRESSION ARE SUMMARIZED. DISCOVERY OF NOVEL TREATMENT OPTIONS, ASSESSMENT OF THE EFFECTIVENESS OF TREATMENT, AS WELL AS THE SUCCESS AND PROPER TIMING OF LIVER TRANSPLANTATION MAY DEPEND ON A BETTER UNDERSTANDING OF THE PROCESS OF DISEASE PROGRESSION. 2016 12 3958 27 LONG NON-CODING RNAS IN BONE METASTASIS: PROGRESSES AND PERSPECTIVES AS POTENTIAL DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. IN A PRECISION MEDICINE PERSPECTIVE, AMONG THE BIOMARKERS POTENTIALLY USEFUL FOR EARLY DIAGNOSIS OF CANCERS, AS WELL AS TO DEFINE THEIR PROGNOSIS AND EVENTUALLY TO IDENTIFY NOVEL AND MORE EFFECTIVE THERAPEUTIC TARGETS, THERE ARE THE LONG NON-CODING RNAS (LNCRNAS). THE TERM LNCRNA IDENTIFIES A CLASS OF NON-CODING RNA MOLECULES INVOLVED IN THE REGULATION OF GENE EXPRESSION THAT INTERVENE AT THE TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC LEVEL. METASTASIS IS A NATURAL EVOLUTION OF SOME MALIGNANT TUMOURS, FREQUENTLY ENCOUNTERED IN PATIENTS WITH ADVANCED CANCERS. ONSET AND DEVELOPMENT OF METASTASIS REPRESENTS A DETRIMENTAL EVENT THAT WORSEN THE PATIENT'S PROGNOSIS BY PROFOUNDLY INFLUENCING THE QUALITY OF LIFE AND IS RESPONSIBLE FOR THE OMINOUS PROGRESSION OF THE DISEASE. DUE TO THE PECULIAR ENVIRONMENT AND THE BIOMECHANICAL PROPERTIES, BONE IS A PREFERENTIAL SITE FOR THE SECONDARY GROWTH OF BREAST, PROSTATE AND LUNG CANCERS. UNFORTUNATELY, ONLY PALLIATIVE AND PAIN THERAPIES ARE CURRENTLY AVAILABLE FOR PATIENTS WITH BONE METASTASES, WHILE NO EFFECTIVE AND DEFINITIVE TREATMENTS ARE AVAILABLE. THE UNDERSTANDING OF PATHOPHYSIOLOGICAL BASIS OF BONE METASTASIS FORMATION AND PROGRESSION, AS WELL AS THE IMPROVEMENT IN THE CLINICAL MANAGEMENT OF THE PATIENT, ARE CENTRAL BUT CHALLENGING TOPICS IN BASIC RESEARCH AND CLINICAL PRACTICE. THE IDENTIFICATION OF NEW MOLECULAR SPECIES THAT MAY HAVE A ROLE AS EARLY HALLMARKS OF THE METASTATIC PROCESS COULD OPEN THE DOOR TO THE DEFINITION OF NEW, AND MORE EFFECTIVE, THERAPEUTIC AND DIAGNOSTIC APPROACHES. NON-CODING RNAS SPECIES AND, PARTICULARLY, LNCRNAS ARE PROMISING COMPOUNDS IN THIS SETTING, AND THEIR STUDY MAY BRING TO THE IDENTIFICATION OF RELEVANT PROCESSES. IN THIS REVIEW, WE HIGHLIGHT THE ROLE OF LNCRNAS AS EMERGING MOLECULES IN MEDIATING THE FORMATION AND DEVELOPMENT OF BONE METASTASES, AS POSSIBLE BIOMARKERS FOR CANCER DIAGNOSIS AND PROGNOSIS, AND AS THERAPEUTIC TARGETS TO COUNTERACT CANCER SPREAD. 2023 13 5805 42 STRATEGIES TO PREVENT AND REVERSE LIVER FIBROSIS IN HUMANS AND LABORATORY ANIMALS. LIVER FIBROSIS RESULTS FROM CHRONIC DAMAGE TO THE LIVER IN CONJUNCTION WITH VARIOUS PATHWAYS AND IS MEDIATED BY A COMPLEX MICROENVIRONMENT. BASED ON CLINICAL OBSERVATIONS, IT IS NOW EVIDENT THAT FIBROSIS IS A DYNAMIC, BIDIRECTIONAL PROCESS WITH AN INHERENT CAPACITY FOR RECOVERY AND REMODELING. THE MAJOR MECHANISMS INVOLVED IN LIVER FIBROSIS INCLUDE THE REPETITIVE INJURY OF HEPATOCYTES, THE ACTIVATION OF THE INFLAMMATORY RESPONSE AFTER INJURY STIMULATION, AND THE ACTIVATION AND PROLIFERATION OF HEPATIC STELLATE CELLS (HSCS), WHICH REPRESENTS THE MAJOR EXTRACELLULAR MATRIX (ECM)-PRODUCING CELLS, STIMULATED BY HEPATOCYTE INJURY AND INFLAMMATION. THE MICROENVIRONMENT IN THE LIVER IS SYNERGISTICALLY REGULATED ABNORMAL ECM DEPOSITION, SCAR FORMATION, ANGIOGENESIS, AND FIBROGENESIS. MOREOVER, RECENT STUDIES HAVE CLARIFIED NOVEL MECHANISM IN FIBROSIS SUCH AS EPIGENETIC REGULATION OF HSCS, THE LEPTIN AND PPARGAMMA PATHWAYS, THE COAGULATION SYSTEM, AND EVEN AUTOPHAGY. UNCOVERING THE MECHANISMS OF LIVER FIBROGENESIS PROVIDES A BASIS TO DEVELOP POTENTIAL THERAPIES TO REVERSE AND TREAT THE FIBROTIC RESPONSE, THEREBY IMPROVING THE OUTCOMES OF PATIENTS WITH CHRONIC LIVER DISEASE. ALTHOUGH BOTH SCIENTIFIC AND CLINICAL CHALLENGES REMAIN, EMERGING STUDIES ATTEMPT TO REVEAL THE IDEAL ANTI-FIBROTIC DRUG THAT COULD BE EASILY DELIVERED TO THE LIVER WITH HIGH SPECIFICITY AND LOW TOXICITY. THIS REVIEW HIGHLIGHTS THE MECHANISMS, INCLUDING NOVEL PATHWAYS UNDERLYING FIBROGENESIS THAT MAY BE TRANSLATED INTO PREVENTIVE AND TREATMENT STRATEGIES, REVIEWS BOTH CURRENT AND NOVEL AGENTS THAT TARGET SPECIFIC PATHWAYS OR MULTIPLE TARGETS, AND DISCUSSES NOVEL DRUG DELIVERY SYSTEMS SUCH AS NANOTECHNOLOGY THAT CAN BE APPLIED IN THE TREATMENT OF LIVER FIBROSIS. IN ADDITION, WE ALSO DISCUSS SOME CURRENT TREATMENT STRATEGIES THAT ARE BEING APPLIED IN ANIMAL MODELS AND IN CLINICAL TRIALS. 2015 14 4045 34 MACROPHAGES IN THE AGING LIVER AND AGE-RELATED LIVER DISEASE. THE NUMBER OF INDIVIDUALS AGED 65 OR OLDER IS PROJECTED TO INCREASE GLOBALLY FROM 524 MILLION IN 2010 TO NEARLY 1. 5 BILLION IN 2050. AGED INDIVIDUALS ARE PARTICULARLY AT RISK FOR DEVELOPING CHRONIC ILLNESS, WHILE BEING LESS ABLE TO REGENERATE HEALTHY TISSUE AND TOLERATE WHOLE ORGAN TRANSPLANTATION PROCEDURES. IN THE LIVER, THESE AGE-RELATED DISEASES INCLUDE NON-ALCOHOLIC FATTY LIVER DISEASE, ALCOHOLIC LIVER DISEASE, HEPATITIS, FIBROSIS, AND CIRRHOSIS. HEPATIC MACROPHAGES, A POPULATION COMPRISED OF BOTH KUPFFER CELLS AND INFILTRATING MONOCYTE DERIVED MACROPHAGES, ARE IMPLICATED IN SEVERAL CHRONIC LIVER DISEASES AND ALSO PLAY IMPORTANT ROLES IN THE HOMEOSTATIC FUNCTIONS OF THE LIVER. THE EFFECTS OF AGING ON HEPATIC MACROPHAGE POPULATION DYNAMICS, POLARIZATION, AND FUNCTION ARE NOT WELL UNDERSTOOD. STUDIES PERFORMED ON MACROPHAGES DERIVED FROM OTHER AGED SOURCES, SUCH AS THE BONE MARROW, PERITONEAL CAVITY, LUNGS, AND BRAIN, DEMONSTRATE GENERAL REDUCTIONS IN AUTOPHAGY AND PHAGOCYTOSIS, DYSFUNCTION IN CYTOKINE SIGNALING, AND ALTERED MORPHOLOGY AND DISTRIBUTION, LIKELY MEDIATED BY EPIGENETIC CHANGES AND MITOCHONDRIAL DEFECTS, THAT MAY BE APPLICABLE TO HEPATIC MACROPHAGES. THIS REVIEW HIGHLIGHTS RECENT FINDINGS IN MACROPHAGE DEVELOPMENTAL BIOLOGY AND FUNCTION, PARTICULARLY IN THE LIVER, AND DISCUSSES THE ROLE OF MACROPHAGES IN VARIOUS AGE-RELATED LIVER DISEASES. A BETTER UNDERSTANDING OF THE BIOLOGY OF AGING THAT INFLUENCES HEPATIC MACROPHAGES AND THUS THE PROGRESSION OF CHRONIC LIVER DISEASE WILL BE CRUCIAL IN ORDER TO DEVELOP NEW INTERVENTIONS AND TREATMENTS FOR LIVER DISEASE IN AGING POPULATIONS. 2018 15 2283 29 EPIGENETIC REGULATION IN FIBROSIS PROGRESS. FIBROSIS, A COMMON PROCESS OF CHRONIC INFLAMMATORY DISEASES, IS DEFINED AS A REPAIR RESPONSE DISORDER WHEN ORGANS UNDERGO CONTINUOUS DAMAGE, ULTIMATELY LEADING TO SCAR FORMATION AND FUNCTIONAL FAILURE. AROUND THE WORLD, FIBROTIC DISEASES CAUSE HIGH MORTALITY, UNFORTUNATELY, WITH LIMITED TREATMENT MEANS IN CLINICAL PRACTICE. WITH THE DEVELOPMENT AND APPLICATION OF DEEP SEQUENCING TECHNOLOGY, COMPREHENSIVELY EXPLORING THE EPIGENETIC MECHANISM IN FIBROSIS HAS BEEN ALLOWED. EXTENSIVE REMODELING OF EPIGENETICS CONTROLLING VARIOUS CELLS PHENOTYPE AND MOLECULAR MECHANISMS INVOLVED IN FIBROGENESIS WAS SUBSEQUENTLY VERIFIED. IN THIS REVIEW, WE SUMMARIZE THE REGULATORY MECHANISMS OF DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNAS (NCRNAS) AND N6-METHYLADENOSINE (M6A) MODIFICATION IN ORGAN FIBROSIS, FOCUSING ON HEART, LIVER, LUNG AND KIDNEY. ADDITIONALLY, WE EMPHASIZE THE DIVERSITY OF EPIGENETICS IN THE CELLULAR AND MOLECULAR MECHANISMS RELATED TO FIBROSIS. FINALLY, THE POTENTIAL AND PROSPECT OF TARGETED THERAPY FOR FIBROSIS BASED ON EPIGENETIC IS DISCUSSED. 2021 16 6900 30 [THE DIAGNOSTIC IMPORTANCE OF CIRCULATING MICRORNA FOR NON-ALCOHOLIC FATTY LIVER DISEASE (REVIEW OF LITERATURE).]. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE LEADING CAUSES OF CHRONIC LIVER DISEASES IN THE WORLD. THE BIOPSY IS REQUIRED TO CONFIRM THE DIAGNOSIS BUT DUE TO ITS INVASIVENESS, THIS PROCEDURE IS NOT SUITABLE FOR THE MASSIVE SCREENING. THERE ARE LABORATORY CRITERIA OF PRIMARY MEDICAL EXAMINATION OF THE PATIENTS WHO ARE SUSPECTED TO HAVE NAFLD THAT ALLOW DIAGNOSING THE PATHOLOGICAL PROCESS, BUT THESE CRITERIA DO NOT COMPLY WITH CLINICIANS' REQUIREMENTS. AT THE SAME TIME, IT IS CRUCIAL TO IDENTIFY THE PATIENTS IN THE INITIAL STAGES OF NAFLD. RECENTLY, THE ATTENTION OF THE SCIENTISTS WAS CONCENTRATED ON THE RESEARCH OF THE MECHANISM OF NAFLD DEVELOPMENT AND NEW DIAGNOSTIC APPROACHES. ACCUMULATING RESULTS OF THIS RESEARCH SHOW THAT NAFLD DEVELOPMENT IS REGULATED WITH EPIGENETIC FACTORS, INCLUDING MICRORNAS FAMILY (MICRORNA, MIR), THAT MAY HAVE HIGH DIAGNOSTIC AND PROGNOSTIC VALUE. IN THIS REVIEW, DATA EXTRACTED FROM PUBMED ARE USED TO DISCUSS THE POTENTIAL ROLE OF MICRORNA IN THE LIVER LIPID METABOLISM AND FATTY LIVER DISEASE. THE POSSIBILITIES OF MICRO RNA (MIR-16, MIR-21, MIR-34A, MIR-103, MIR-122, MIR-145, MIR-192, AND OTHERS) USE AS PROSPECTIVE BIOMARKERS FOR LOW-INVASIVE NAFLD DIAGNOSTIC, EVALUATION OF STEATOSIS ACTIVITY AND FIBROSIS SCORE AND STAGES, AND PROGNOSTIC MARKERS OF THE DISEASE ARE REVIEWED. THIS RESEARCH DISCUSSES THE ANALYTICAL CHARACTERISTICS, BENEFITS AND POSSIBLE LIMITATIONS OF THEIR USE IN THE CLINICAL PRACTICE. THE PRELIMINARY DATA ALLOW CLAIMING THAT SOME MICRORNAS ARE EXTREMELY PERSPECTIVE LOW-INVASIVE DIAGNOSTIC INSTRUMENT AND FURTHER RESEARCH IS REQUIRED TO INVESTIGATE THE IMPACT OF CERTAIN MICRORNAS IN THE PATHOGENETIC MECHANISM OF NAFLD DEVELOPMENT. 2019 17 4369 31 MIRNAS AND NAFLD: FROM PATHOPHYSIOLOGY TO THERAPY. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ASSOCIATED WITH A THOROUGH REPROGRAMMING OF HEPATIC METABOLISM. EPIGENETIC MECHANISMS, IN PARTICULAR THOSE ASSOCIATED WITH DEREGULATION OF THE EXPRESSIONS AND ACTIVITIES OF MICRORNAS (MIRNAS), PLAY A MAJOR ROLE IN METABOLIC DISORDERS ASSOCIATED WITH NAFLD AND THEIR PROGRESSION TOWARDS MORE SEVERE STAGES OF THE DISEASE. IN THIS REVIEW, WE DISCUSS THE RECENT PROGRESS ADDRESSING THE ROLE OF THE MANY FACETS OF COMPLEX MIRNA REGULATORY NETWORKS IN THE DEVELOPMENT AND PROGRESSION OF NAFLD. THE BASIC CONCEPTS AND MECHANISMS OF MIRNA-MEDIATED GENE REGULATION AS WELL AS THE VARIOUS SETBACKS ENCOUNTERED IN BASIC AND TRANSLATIONAL RESEARCH IN THIS FIELD ARE DEBATED. MIRNAS IDENTIFIED SO FAR, WHOSE EXPRESSIONS/ACTIVITIES ARE DEREGULATED IN NAFLD, AND WHICH CONTRIBUTE TO THE OUTCOMES OF THIS PATHOLOGY ARE FURTHER REVIEWED. FINALLY, THE POTENTIAL THERAPEUTIC USAGES IN A SHORT TO MEDIUM TERM OF MIRNA-BASED STRATEGIES IN NAFLD, IN PARTICULAR TO IDENTIFY NON-INVASIVE BIOMARKERS, OR TO DESIGN PHARMACOLOGICAL ANALOGUES/INHIBITORS HAVING A BROAD RANGE OF ACTIONS ON HEPATIC METABOLISM, ARE HIGHLIGHTED. 2019 18 2232 35 EPIGENETIC MODIFICATIONS OF MIRNAS IN OSTEOARTHRITIS: A SYSTEMATIC REVIEW ON THEIR METHYLATION LEVELS AND EFFECTS ON CHONDROCYTES, EXTRACELLULAR MATRIX AND JOINT INFLAMMATION. OSTEOARTHRITIS (OA) IS A JOINT DISORDER CHARACTERIZED BY PROGRESSIVE DEGENERATION OF CARTILAGE EXTRACELLULAR MATRIX (ECM), CHONDROCYTE HYPERTROPHY AND APOPTOSIS AND INFLAMMATION. THE CURRENT TREATMENTS MAINLY CONCERN PAIN CONTROL AND REDUCTION OF INFLAMMATION, BUT NO THERAPEUTIC STRATEGY HAS BEEN IDENTIFIED AS A DISEASE-MODIFYING TREATMENT. THEREFORE, IDENTIFYING SPECIFIC BIOMARKERS USEFUL TO PREVENT, TREAT OR DISTINGUISH THE STAGES OF OA DISEASE HAS BECOME AN IMMEDIATE NEED OF CLINICAL PRACTICE. THE ROLE OF MICRORNAS (MIRNAS) IN OA HAS BEEN INVESTIGATED IN THE LAST DECADE, AND INCREASING EVIDENCE HAS EMERGED THAT THE INFLUENCE OF THE ENVIRONMENT ON GENE EXPRESSION THROUGH EPIGENETIC PROCESSES CONTRIBUTES TO THE DEVELOPMENT, PROGRESSION AND AGGRESSIVENESS OF OA, IN PARTICULAR ACTING ON THE MICROENVIRONMENT MODULATIONS. THE EFFECTS OF EPIGENETIC REGULATION, PARTICULARLY DIFFERENT MIRNA METHYLATION DURING OA DISEASE, WERE HIGHLIGHTED IN THE PRESENT SYSTEMATIC REVIEW. THE EVIDENCE ARISING FROM THIS STUDY OF THE LITERATURE CONDUCTED IN THREE DATABASES (PUBMED, SCOPUS, WEB OF SCIENCE) SUGGESTED THAT MIRNA METHYLATION STATE ALREADY STRONGLY IMPACTS OA PROGRESSION, DRIVING CHONDROCYTES AND SYNOVIOCYTE PROLIFERATION, APOPTOSIS, INFLAMMATION AND ECM DEPOSITION. HOWEVER, THE POSSIBILITY OF UNDERSTANDING THE MECHANISM BY WHICH DIFFERENT EPIGENETIC MODIFICATIONS OF MIRNA OR PRE-MIRNA SEQUENCES DRIVE THE AGGRESSIVENESS OF OA COULD BE THE NEW FOCUS OF FUTURE INVESTIGATIONS. 2023 19 2954 34 GENETIC AND EPIGENETIC FACTORS DETERMINING NAFLD RISK. BACKGROUND: HEPATIC STEATOSIS IS A COMMON CHRONIC LIVER DISEASE THAT CAN PROGRESS INTO MORE SEVERE STAGES OF NAFLD OR PROMOTE THE DEVELOPMENT OF LIFE-THREATENING SECONDARY DISEASES FOR SOME OF THOSE AFFECTED. THESE INCLUDE THE LIVER ITSELF (NONALCOHOLIC STEATOHEPATITIS OR NASH; FIBROSIS AND CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA) OR OTHER ORGANS SUCH AS THE VESSELS AND THE HEART (CARDIOVASCULAR DISEASE) OR THE ISLETS OF LANGERHANS (TYPE 2 DIABETES). IN ADDITION TO ELEVATED CALORIC INTAKE AND A SEDENTARY LIFESTYLE, GENETIC AND EPIGENETIC PREDISPOSITION CONTRIBUTE TO THE DEVELOPMENT OF NAFLD AND THE SECONDARY DISEASES. SCOPE OF REVIEW: WE PRESENT DATA FROM GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND FUNCTIONAL STUDIES IN RODENTS WHICH DESCRIBE POLYMORPHISMS IDENTIFIED IN GENES RELEVANT FOR THE DISEASE AS WELL AS CHANGES CAUSED BY ALTERED DNA METHYLATION AND GENE REGULATION VIA SPECIFIC MIRNAS. THE REVIEW ALSO PROVIDES INFORMATION ON THE CURRENT STATUS OF THE USE OF GENETIC AND EPIGENETIC FACTORS AS RISK MARKERS. MAJOR CONCLUSION: WITH OUR OVERVIEW WE PROVIDE AN INSIGHT INTO THE GENETIC AND EPIGENETIC LANDSCAPE OF NAFLD AND ARGUE ABOUT THE APPLICABILITY OF CURRENTLY DEFINED RISK SCORES FOR RISK STRATIFICATION AND CONCLUDE THAT FURTHER EFFORTS ARE NEEDED TO MAKE THE SCORES MORE USABLE AND MEANINGFUL. 2021 20 3022 37 GENETICS AND EPIGENETICS PURPOSE IN NONALCOHOLIC FATTY LIVER DISEASE. INTRODUCTION: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) COMPRISES A BROAD SPECTRUM OF DISEASES, WHICH CAN PROGRESS FROM BENIGN STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NAFLD IS THE MOST COMMON CHRONIC LIVER DISEASE IN DEVELOPED COUNTRIES, AFFECTING APPROXIMATELY 25% OF THE GENERAL POPULATION. INSULIN RESISTANCE, ADIPOSE TISSUE DYSFUNCTION, MITOCHONDRIAL AND ENDOPLASMIC RETICULUM STRESS, CHRONIC INFLAMMATION, GENETIC AND EPIGENETIC FACTORS ARE NAFLD TRIGGERS THAT CONTROL THE DISEASE SUSCEPTIBILITY AND PROGRESSION. AREAS COVERED: IN RECENT YEARS A LARGE NUMBER OF INVESTIGATIONS HAVE BEEN CARRIED OUT TO ELUCIDATE GENETIC AND EPIGENETIC FACTORS IN THE DISEASE PATHOGENESIS, AS WELL AS THE SEARCH FOR DIAGNOSTIC MARKERS AND THERAPEUTIC TARGETS. THIS PAPER OBJECTIVE IS TO REPORT THE MOST STUDIED GENETIC AND EPIGENETIC VARIANTS AROUND NAFLD. EXPERT OPINION: NAFLD LEAD TO VARIOUS COMORBIDITIES, WHICH HAVE A CONSIDERABLE IMPACT ON THE PATIENT WELLNESS AND LIFE QUALITY, AS WELL AS ON THE COSTS THEY GENERATE FOR THE COUNTRY'S HEALTH SERVICES. IT IS ESSENTIAL TO CONTINUE WITH MOLECULAR RESEARCH, SINCE IT COULD BE USED AS A CLINICAL TOOL FOR PROGNOSIS AND DISEASE SEVERITY. SPECIFICALLY, IN THE FIELD OF HEPATOLOGY, PLASMA MIRNAS COULD PROVIDE A NOVEL TOOL IN LIVER DISEASES DIAGNOSIS AND MONITORING, REPRESENTING AN ALTERNATIVE TO INVASIVE DIAGNOSTIC PROCEDURES. 2020