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 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 4 4379 36 MITOCHONDRIAL DYSFUNCTION AND AGING: INSIGHTS FROM THE ANALYSIS OF EXTRACELLULAR VESICLES. THE PROGRESSIVE DECLINE OF CELL FUNCTION AND INTEGRITY, MANIFESTING CLINICALLY AS INCREASED VULNERABILITY TO ADVERSE OUTCOMES AND DEATH, IS CORE TO BIOLOGICAL AGING. MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ALTERED INTERCELLULAR COMMUNICATION (INCLUDING CHRONIC LOW-GRADE INFLAMMATION), GENOMIC INSTABILITY, TELOMERE ATTRITION, LOSS OF PROTEOSTASIS, ALTERED NUTRIENT SENSING, EPIGENETIC ALTERATIONS, AND STEM CELL EXHAUSTION HAVE BEEN PROPOSED AS HALLMARKS OF AGING. THESE "AGING PILLARS" ARE NOT MUTUALLY EXCLUSIVE, MAKING THE MATTER INTRICATE AND LEAVING NUMEROUS UNANSWERED QUESTIONS. THE CHARACTERIZATION OF CIRCULATING EXTRACELLULAR VESICLES (EVS) HAS RECENTLY ALLOWED SPECIFIC SECRETORY PHENOTYPES ASSOCIATED WITH AGING TO BE IDENTIFIED. AS SUCH, EVS MAY SERVE AS NOVEL BIOMARKERS FOR CAPTURING THE COMPLEXITY OF AGING. BESIDES THE MITOCHONDRIAL(-)LYSOSOMAL AXIS, EV TRAFFICKING HAS BEEN PROPOSED AS AN ADDITIONAL LAYER IN MITOCHONDRIAL QUALITY CONTROL. INDEED, DISRUPTION OF THE MITOCHONDRIAL(-)LYSOSOMAL AXIS COUPLED WITH ABNORMAL EV SECRETION MAY PLAY A ROLE IN THE PATHOGENESIS OF AGING AND SEVERAL DISEASE CONDITIONS. HERE, WE DISCUSS (1) THE MECHANISMS OF EV GENERATION; (2) THE RELATIONSHIP BETWEEN THE MITOCHONDRIAL(-)LYSOSOMAL AXIS AND EV TRAFFICKING IN THE SETTING OF MITOCHONDRIAL QUALITY CONTROL; AND (3) THE PROSPECT OF USING EVS AS AGING BIOMARKERS AND AS DELIVERY SYSTEMS FOR THERAPEUTICS AGAINST AGE-RELATED CONDITIONS. 2019 5 4326 37 MICRORNAS IN THE PATHOGENESIS OF NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), OR, MORE ACCURATELY, METABOLIC ASSOCIATED FATTY LIVER DISEASE, ACCOUNTS FOR A LARGE PROPORTION OF CHRONIC LIVER DISORDERS WORLDWIDE AND IS CLOSELY ASSOCIATED WITH OTHER CONDITIONS SUCH AS CARDIOVASCULAR DISEASE, OBESITY, AND TYPE 2 DIABETES MELLITUS. NAFLD RANGES FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH) AND CAN PROGRESS TO CIRRHOSIS AND, EVENTUALLY, ALSO HEPATOCELLULAR CARCINOMA. THE MORBIDITY AND MORTALITY ASSOCIATED WITH NAFLD ARE INCREASING RAPIDLY YEAR ON YEAR. CONSEQUENTLY, THERE IS AN URGENT NEED TO UNDERSTAND THE ETIOLOGY AND PATHOGENESIS OF NAFLD AND IDENTIFY EFFECTIVE THERAPEUTIC TARGETS. MICRORNAS (MIRNAS), IMPORTANT EPIGENETIC FACTORS, HAVE RECENTLY BEEN PROPOSED TO PARTICIPATE IN NAFLD PATHOGENESIS. HERE, WE REVIEW THE ROLES OF MIRNAS IN LIPID METABOLISM, INFLAMMATION, APOPTOSIS, FIBROSIS, HEPATIC STELLATE CELL ACTIVATION, INSULIN RESISTANCE, AND OXIDATIVE STRESS, KEY FACTORS THAT CONTRIBUTE TO THE OCCURRENCE AND PROGRESSION OF NAFLD. ADDITIONALLY, WE SUMMARIZE THE ROLE OF MIRNA-ENRICHED EXTRACELLULAR VESICLES IN NAFLD. THESE MIRNAS MAY COMPRISE SUITABLE THERAPEUTIC TARGETS FOR THE TREATMENT OF THIS CONDITION. 2021 6 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 7 4720 32 NONCODING RNAS AS ADDITIONAL MEDIATORS OF EPIGENETIC REGULATION IN NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS EMERGED AS THE MOST COMMON CAUSE OF CHRONIC LIVER DISORDER WORLDWIDE. IT REPRESENTS A SPECTRUM THAT INCLUDES A CONTINUUM OF DIFFERENT CLINICAL ENTITIES RANGING FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, WHICH CAN EVOLVE TO CIRRHOSIS AND IN SOME CASES TO HEPATOCELLULAR CARCINOMA, ULTIMATELY LEADING TO LIVER FAILURE. THE PATHOGENESIS OF NAFLD AND THE MECHANISMS UNDERLYING ITS PROGRESSION TO MORE PATHOLOGICAL STAGES ARE NOT COMPLETELY UNDERSTOOD. BESIDES GENETIC FACTORS, EVIDENCE INDICATES THAT EPIGENETIC MECHANISMS OCCURRING IN RESPONSE TO ENVIRONMENTAL STIMULI ALSO CONTRIBUTE TO THE DISEASE RISK. NONCODING RNAS (NCRNAS), INCLUDING MICRORNAS, LONG NONCODING RNAS, AND CIRCULAR RNAS, ARE ONE OF THE EPIGENETIC FACTORS THAT PLAY KEY REGULATORY ROLES IN THE DEVELOPMENT OF NAFLD. AS THE FIELD OF NCRNAS IS RAPIDLY EVOLVING, THE PRESENT REVIEW AIMS TO EXPLORE THE CURRENT STATE OF KNOWLEDGE ON THE ROLES OF THESE RNA SPECIES IN THE PATHOGENESIS OF NAFLD, HIGHLIGHT RELEVANT MECHANISMS BY WHICH SOME NCRNAS CAN MODULATE REGULATORY NETWORKS IMPLICATED IN NAFLD, AND DISCUSS KEY CHALLENGES AND FUTURE DIRECTIONS FACING CURRENT RESEARCH IN THE HOPES OF DEVELOPING NCRNAS AS NEXT-GENERATION NON-INVASIVE DIAGNOSTICS AND THERAPIES IN NAFLD AND SUBSEQUENT PROGRESSION TO HEPATOCELLULAR CARCINOMA. 2022 8 1021 30 CIRCULAR RNA AS AN EPIGENETIC REGULATOR IN CHRONIC LIVER DISEASES. CIRCULAR RNA (CIRCRNA) IS A TYPE OF NON-CODING RNA CHARACTERIZED BY A COVALENTLY CLOSED CONTINUOUS LOOP. CIRCRNA IS GENERATED BY PRE-MRNA THROUGH BACK-SPLICING AND IS PROBABLY CLEARED UP BY EXTRACELLULAR VESICLES. CIRCRNAS PLAY A PIVOTAL ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION AT TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL LEVELS. RECENTLY, CIRCRNAS HAVE BEEN DEMONSTRATED TO BE INVOLVED IN THE REGULATION OF LIVER HOMEOSTASIS AND DISEASES. HOWEVER, THE EPIGENETIC ROLE AND UNDERLYING MECHANISMS OF CIRCRNAS IN CHRONIC LIVER DISEASES REMAIN UNCLEAR. THIS REVIEW DISCUSSED THE ROLE OF CIRCRNAS IN NON-NEOPLASTIC CHRONIC LIVER DISEASES, INCLUDING ALCOHOLIC LIVER DISEASE (ALD), METABOLIC-ASSOCIATED FATTY LIVER DISEASE (MAFLD), VIRAL HEPATITIS, LIVER INJURY AND REGENERATION, LIVER CIRRHOSIS, AND AUTOIMMUNE LIVER DISEASE. THE REVIEW ALSO HIGHLIGHTED THAT FURTHER EFFORTS ARE URGENTLY NEEDED TO DEVELOP CIRCRNAS AS NOVEL DIAGNOSTICS AND THERAPEUTICS FOR CHRONIC LIVER DISEASES. 2021 9 4722 27 NONCODING RNAS IN NONALCOHOLIC FATTY LIVER DISEASE: POTENTIAL DIAGNOSIS AND PROGNOSIS BIOMARKERS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS CURRENTLY THE MOST COMMON CHRONIC LIVER DISEASE WORLDWIDE IN PART DUE TO THE CONCOMITANT OBESITY PANDEMIC AND INSULIN RESISTANCE (IR). IT IS INCREASINGLY BECOMING EVIDENT THAT NAFLD IS A DISEASE AFFECTING NUMEROUS EXTRAHEPATIC VITAL ORGANS AND REGULATORY PATHWAYS. THE MOLECULAR MECHANISMS UNDERLYING THE NONALCOHOLIC STEATOSIS FORMATION ARE POORLY UNDERSTOOD, AND LITTLE INFORMATION IS AVAILABLE ON THE PATHWAYS THAT ARE RESPONSIBLE FOR THE PROGRESSIVE HEPATOCELLULAR DAMAGE THAT FOLLOWS LIPID ACCUMULATION. RECENTLY, MUCH RESEARCH HAS FOCUSED ON THE IDENTIFICATION OF THE EPIGENETIC MODIFICATIONS THAT CONTRIBUTE TO NAFLD PATHOGENESIS. NONCODING RNAS (NCRNAS) ARE ONE OF SUCH EPIGENETIC FACTORS THAT COULD BE IMPLICATED IN THE NAFLD DEVELOPMENT AND PROGRESSION. IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE GENETIC AND EPIGENETIC FACTORS POTENTIALLY UNDERLYING THE DISEASE. PARTICULAR EMPHASIS WILL BE PUT ON THE CONTRIBUTION OF MICRORNAS (MIRNAS), LONG NONCODING RNAS (LNCRNAS), AND CIRCULAR RNAS (CIRCRNAS) TO THE PATHOPHYSIOLOGY OF NAFLD AS WELL AS THEIR POTENTIAL USE AS THERAPEUTIC TARGETS OR AS MARKERS FOR THE PREDICTION AND THE PROGRESSION OF THE DISEASE. 2020 10 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 11 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 12 4282 36 MICRORNA AND EXOSOME: KEY PLAYERS IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS KNOWN AS ONE OF IMPORTANT AUTOIMMUNE DISORDERS WHICH CAN LEAD TO JOINT PAIN AND DAMAGE THROUGHOUT BODY. GIVEN THAT INTERNAL (IE, GENETIC AND EPIGENETIC ALTERATIONS) AND EXTERNAL FACTORS (IE, LIFESTYLE CHANGES, AGE, HORMONES, SMOKING, STRESS, AND OBESITY) INVOLVED IN RA PATHOGENESIS. INCREASING EVIDENCE INDICATED THAT CELLULAR AND MOLECULAR ALTERATIONS PLAY CRITICAL ROLES IN THE INITIATION AND PROGRESSION OF RA. AMONG VARIOUS TARGETS AND MOLECULAR SIGNALING PATHWAYS, MICRORNAS (MIRNAS) AND THEIR REGULATORY NETWORKS HAVE KEY ROLES IN THE RA PATHOGENESIS. IT HAS BEEN SHOWED THAT DEREGULATION OF MANY MIRNAS INVOLVED IN DIFFERENT STAGES OF RA. HENCE, IDENTIFICATION OF MIRNAS AND THEIR SIGNALING PATHWAYS IN RA, COULD CONTRIBUTE TO NEW KNOWLEDGE WHICH HELP TO BETTER TREATMENT OF PATIENTS WITH RA. BESIDES MIRNAS, EXOSOMES HAVE BEEN EMERGED AS KEY MESSENGERS IN RA PATHOGENESIS. EXSOSOMES ARE NANOCARRIERS WHICH COULD BE RELEASED FROM VARIOUS CELLS AND LEAD TO CHANGING OF BEHAVIORS RECIPIENT CELLS VIA TARGETING THEIR CARGOS (EG, PROTEINS, MESSENGER RNAS, MIRNAS, LONG NONCODING RNAS, DNAS). HERE, WE SUMMARIZED SEVERAL MIRNAS INVOLVED IN RA PATHOGENESIS. MOREOVER, WE HIGHLIGHTED THE ROLES OF EXOSOMES IN RA PATHOGENESIS. 2019 13 5672 36 SHARED AND DIVERGENT EPIGENETIC MECHANISMS IN CACHEXIA AND SARCOPENIA. SIGNIFICANT LOSS OF MUSCLE MASS MAY OCCUR IN CACHEXIA AND SARCOPENIA, WHICH ARE MAJOR CAUSES OF MORTALITY AND DISABILITY. CACHEXIA REPRESENTS A COMPLEX MULTI-ORGAN SYNDROME ASSOCIATED WITH CANCER AND CHRONIC DISEASES. IT IS OFTEN CHARACTERIZED BY BODY WEIGHT LOSS, INFLAMMATION, AND MUSCLE AND ADIPOSE WASTING. PROGRESSIVE MUSCLE LOSS IS ALSO A HALLMARK OF HEALTHY AGING, WHICH IS EMERGING WORLDWIDE AS A MAIN DEMOGRAPHIC TREND. A GREAT CHALLENGE FOR THE HEALTH CARE SYSTEMS IS THE AGE-RELATED DECLINE IN FUNCTIONALITY WHICH THREATENS THE INDEPENDENCE AND QUALITY OF LIFE OF ELDERLY PEOPLE. THIS BIOLOGICAL DECLINE CAN ALSO BE ASSOCIATED WITH FUNCTIONAL MUSCLE LOSS, KNOWN AS SARCOPENIA. PREVIOUS STUDIES HAVE SHOWN THAT MICRORNAS (MIRNAS) PLAY PIVOTAL ROLES IN THE DEVELOPMENT AND PROGRESSION OF MUSCLE WASTING IN BOTH CACHEXIA AND SARCOPENIA. THESE SMALL NON-CODING RNAS, OFTEN CARRIED IN EXTRACELLULAR VESICLES, INHIBIT TRANSLATION BY TARGETING MESSENGER RNAS, THEREFORE REPRESENTING POTENT EPIGENETIC MODULATORS. THE MOLECULAR MECHANISMS BEHIND CACHEXIA AND SARCOPENIA, INCLUDING THE EXPRESSION OF SPECIFIC MIRNAS, SHARE COMMON AND DISTINCTIVE TRENDS. THE AIM OF THE PRESENT REVIEW IS TO COMPILE RECENT EVIDENCE ABOUT SHARED AND DIVERGENT EPIGENETIC MECHANISMS, PARTICULARLY FOCUSING ON MIRNAS, BETWEEN CACHEXIA AND SARCOPENIA TO UNDERSTAND A FACET IN THE UNDERLYING MUSCLE WASTING ASSOCIATED WITH THESE MORBIDITIES AND DISCLOSE POTENTIAL THERAPEUTIC INTERVENTIONS. 2022 14 3640 29 INCREASED EXTRACELLULAR MATRIX PROTEIN PRODUCTION IN CHRONIC DIABETIC COMPLICATIONS: IMPLICATIONS OF NON-CODING RNAS. MANAGEMENT OF CHRONIC DIABETIC COMPLICATIONS REMAINS A MAJOR MEDICAL CHALLENGE WORLDWIDE. ONE OF THE CHARACTERISTIC FEATURES OF ALL CHRONIC DIABETIC COMPLICATIONS IS AUGMENTED PRODUCTION OF EXTRACELLULAR MATRIX (ECM) PROTEINS. SUCH ECM PROTEINS ARE DEPOSITED IN ALL TISSUES AFFECTED BY CHRONIC COMPLICATIONS, ULTIMATELY CAUSING ORGAN DAMAGE AND DYSFUNCTION. A CONTRIBUTING FACTOR TO THIS PATHOGENETIC PROCESS IS GLUCOSE-INDUCED ENDOTHELIAL DAMAGE, WHICH INVOLVES PHENOTYPIC TRANSFORMATION OF ENDOTHELIAL CELLS (ECS). THIS PHENOTYPIC TRANSITION OF ECS, FROM A QUIESCENT STATE TO AN ACTIVATED DYSFUNCTIONAL STATE, CAN BE MEDIATED THROUGH ALTERATIONS IN THE SYNTHESIS OF CELLULAR PROTEINS. IN THIS REVIEW, WE DISCUSSED THE ROLES OF NON-CODING RNAS, SPECIFICALLY MICRORNAS (MIRNAS) AND LONG NON-CODING RNAS (LNCRNAS), IN SUCH PROCESSES. WE FURTHER OUTLINED OTHER EPIGENETIC MECHANISMS REGULATING THE BIOGENESIS AND/OR FUNCTION OF NON-CODING RNAS. OVERALL, WE BELIEVE THAT BETTER UNDERSTANDING OF SUCH MOLECULAR PROCESSES MAY LEAD TO THE DEVELOPMENT OF NOVEL BIOMARKERS AND THERAPEUTIC STRATEGIES IN THE FUTURE. 2019 15 4315 23 MICRORNAS AS NEW TARGETS OF DIETARY POLYPHENOLS. IN THE LASTS YEARS IT HAS BECOME EVIDENT THAT POLYPHENOLS MODIFY CELL FUNCTIONALITY THROUGH EPIGENETIC MECHANISMS, SUCH AS MODULATING MICRORNA (MIRNA) LEVELS. MIRNAS ARE SMALL NON-CODING RNAS OF ABOUT 22 NUCLEOTIDES IN LENGTH, THAT MODULATE GENE EXPRESSION AT THE POST-TRANSCRIPTIONAL LEVEL. MIRNAS ARE INVOLVED IN ALMOST ALL BIOLOGICAL PROCESSES, AFFECT MOST METABOLIC PATHWAYS AND RECENT EVIDENCE SUGGESTS THEIR DYSREGULATION IN A NUMBER OF METABOLIC DISORDERS AND DISEASES. IN THIS SENSE, MIRNAS ARE EMERGING AS POTENTIAL BIOMARKERS OF NUMEROUS PATHOLOGIES AND THEREFORE AS NEW THERAPEUTIC TARGETS. POLYPHENOLIC MODULATION OF MIRNAS IS VERY ATTRACTIVE AS A STRATEGY TO TARGET NUMEROUS CELL PROCESSES AND POTENTIALLY REDUCE THE RISK OF CHRONIC DISEASES. 2014 16 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 17 4830 24 OLD AND NEW BIOMARKERS ASSOCIATED WITH ENDOTHELIAL DYSFUNCTION IN CHRONIC HYPERGLYCEMIA. CHRONIC HYPERGLYCEMIA AND VASCULAR DAMAGE ARE STRICTLY RELATED. BIOMARKERS OF VASCULAR DAMAGE HAVE BEEN INTENSIVELY STUDIED IN THE RECENT YEARS IN THE QUEST OF RELIABLE CARDIOVASCULAR RISK ASSESSMENT TOOLS ABLE TO FACILITATE RISK STRATIFICATION AND EARLY DETECTION OF VASCULAR IMPAIRMENT. THE PRESENT STUDY IS A NARRATIVE REVIEW WITH THE AIM OF REVISING THE AVAILABLE EVIDENCE ON CURRENT AND NOVEL MARKERS OF HYPERGLYCEMIA-INDUCED VASCULAR DAMAGE. AFTER A DISCUSSION OF CLASSIC TOOLS USED TO INVESTIGATE ENDOTHELIAL DYSFUNCTION, WE PROVIDE AN IN-DEPTH DESCRIPTION OF NOVEL CIRCULATING BIOMARKERS (CHEMOKINES, EXTRACELLULAR VESICLES, AND EPIGENETIC AND METABOLOMIC BIOMARKERS). APPROPRIATE USE OF A SINGLE AS WELL AS A CLUSTER OF THE DISCUSSED BIOMARKERS MIGHT ENABLE IN A NEAR FUTURE (A) THE PROMPT IDENTIFICATION OF TARGETED AND CUSTOMIZED TREATMENT STRATEGIES AND (B) THE FOLLOW-UP OF CARDIOVASCULAR TREATMENT EFFICACY OVER TIME IN CLINICAL RESEARCH AND/OR IN CLINICAL PRACTICE. 2021 18 1136 27 COMPREHENSIVE OVERVIEW OF MICRORNA FUNCTION IN RHEUMATOID ARTHRITIS. MICRORNAS (MIRNAS), A CLASS OF ENDOGENOUS SINGLE-STRANDED SHORT NONCODING RNAS, HAVE EMERGED AS VITAL EPIGENETIC REGULATORS OF BOTH PATHOLOGICAL AND PHYSIOLOGICAL PROCESSES IN ANIMALS. THEY DIRECT FUNDAMENTAL CELLULAR PATHWAYS AND PROCESSES BY FINE-TUNING THE EXPRESSION OF MULTIPLE GENES AT THE POSTTRANSCRIPTIONAL LEVEL. GROWING EVIDENCE SUGGESTS THAT MIRNAS ARE IMPLICATED IN THE ONSET AND DEVELOPMENT OF RHEUMATOID ARTHRITIS (RA). RA IS A CHRONIC INFLAMMATORY DISEASE THAT MAINLY AFFECTS SYNOVIAL JOINTS. THIS COMMON AUTOIMMUNE DISORDER IS CHARACTERIZED BY A COMPLEX AND MULTIFACETED PATHOGENESIS, AND ITS MORBIDITY, DISABILITY AND MORTALITY RATES REMAIN CONSISTENTLY HIGH. MORE IN-DEPTH INSIGHTS INTO THE UNDERLYING MECHANISMS OF RA ARE REQUIRED TO ADDRESS UNMET CLINICAL NEEDS AND OPTIMIZE TREATMENT. HEREIN, WE COMPREHENSIVELY REVIEW THE DEREGULATED MIRNAS AND IMPAIRED CELLULAR FUNCTIONS IN RA TO SHED LIGHT ON SEVERAL ASPECTS OF RA PATHOGENESIS, WITH A FOCUS ON EXCESSIVE INFLAMMATION, SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DAMAGE. THIS REVIEW ALSO PROVIDES PROMISING TARGETS FOR INNOVATIVE THERAPIES OF RA. IN ADDITION, WE DISCUSS THE REGULATORY ROLES AND CLINICAL POTENTIAL OF EXTRACELLULAR MIRNAS IN RA, HIGHLIGHTING THEIR PROSPECTIVE APPLICATIONS AS DIAGNOSTIC AND PREDICTIVE BIOMARKERS. 2023 19 2357 33 EPIGENETIC REGULATION OF PULMONARY INFLAMMATION. PULMONARY DISEASE SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), ASTHMA, PULMONARY FIBROSIS AND PULMONARY HYPERTENSION ARE THE LEADING CAUSE OF DEATHS. MORE IMPORTANTLY, LUNG DISEASES ARE ON THE RISE AND ENVIRONMENTAL FACTORS INDUCED EPIGENETIC MODIFICATIONS ARE MAJOR PLAYERS ON THIS INCREASED PREVALENCE. IT HAS BEEN REPORTED THAT DYSREGULATION OF GENES INVOLVED IN EPIGENETIC REGULATION SUCH AS THE HISTONE DEACETYLASE (HDACS) AND HISTONE ACETYLTRANSFERASE (HATS) PLAY IMPORTANT ROLE IN LUNG HEALTH AND PULMONARY DISEASE PATHOGENESIS. INFLAMMATION IS AN ESSENTIAL COMPONENT OF RESPIRATORY DISEASES. INJURY AND INFLAMMATION TRIGGER RELEASE OF EXTRACELLULAR VESICLES THAT CAN ACT AS EPIGENETIC MODIFIERS THROUGH TRANSFER OF EPIGENETIC REGULATORS SUCH AS MICRORNAS (MIRNAS), LONG NON-CODING RNAS (LNCRNAS), PROTEINS AND LIPIDS, FROM ONE CELL TO ANOTHER. THE IMMUNE DYSREGULATIONS CAUSED BY THE CARGO CONTENTS ARE IMPORTANT CONTRIBUTORS OF RESPIRATORY DISEASE PATHOGENESIS. N6 METHYLATION OF RNA IS ALSO EMERGING TO BE A CRITICAL MECHANISM OF EPIGENETIC ALTERATION AND UPREGULATION OF IMMUNE RESPONSES TO ENVIRONMENTAL STRESSORS. EPIGENETIC CHANGES SUCH AS DNA METHYLATION ARE STABLE AND OFTEN LONG TERM AND CAUSE ONSET OF CHRONIC LUNG CONDITIONS. THESE EPIGENETIC PATHWAYS ARE ALSO BEING UTILIZED FOR THERAPEUTIC INTERVENTION IN SEVERAL LUNG CONDITIONS. 2023 20 4589 26 NANOPARTICLES IN THE DIAGNOSIS AND TREATMENT OF VASCULAR AGING AND RELATED DISEASES. AGING-INDUCED ALTERNATIONS OF VASCULATURE STRUCTURES, PHENOTYPES, AND FUNCTIONS ARE KEY IN THE OCCURRENCE AND DEVELOPMENT OF VASCULAR AGING-RELATED DISEASES. MULTIPLE MOLECULAR AND CELLULAR EVENTS, SUCH AS OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, VASCULAR INFLAMMATION, CELLULAR SENESCENCE, AND EPIGENETIC ALTERATIONS ARE HIGHLY ASSOCIATED WITH VASCULAR AGING PHYSIOPATHOLOGY. ADVANCES IN NANOPARTICLES AND NANOTECHNOLOGY, WHICH CAN REALIZE SENSITIVE DIAGNOSTIC MODALITIES, EFFICIENT MEDICAL TREATMENT, AND BETTER PROGNOSIS AS WELL AS LESS ADVERSE EFFECTS ON NON-TARGET TISSUES, PROVIDE AN AMAZING WINDOW IN THE FIELD OF VASCULAR AGING AND RELATED DISEASES. THROUGHOUT THIS REVIEW, WE PRESENTED CURRENT KNOWLEDGE ON CLASSIFICATION OF NANOPARTICLES AND THE RELATIONSHIP BETWEEN VASCULAR AGING AND RELATED DISEASES. IMPORTANTLY, WE COMPREHENSIVELY SUMMARIZED THE POTENTIAL OF NANOPARTICLES-BASED DIAGNOSTIC AND THERAPEUTIC TECHNIQUES IN VASCULAR AGING AND RELATED DISEASES, INCLUDING CARDIOVASCULAR DISEASES, CEREBROVASCULAR DISEASES, AS WELL AS CHRONIC KIDNEY DISEASES, AND DISCUSSED THE ADVANTAGES AND LIMITATIONS OF THEIR CLINICAL APPLICATIONS. 2022