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 3980 35 LONG-TERM EPIGENETIC ALTERATIONS IN A RAT MODEL OF GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) IS A CHRONIC, MULTISYMPTOM ILLNESS THAT AFFECTS 25% OF THE 700,000 US VETERANS DEPLOYED TO THE PERSIAN GULF DURING THE 1990-1991 GULF WAR. CENTRAL NERVOUS SYSTEM IMPAIRMENTS ARE AMONG THE MOST COMMON SYMPTOMS REPORTED, INCLUDING MEMORY DYSFUNCTION AND DEPRESSION. AFTER 25 YEARS, THE DIAGNOSIS REMAINS ELUSIVE, USEFUL TREATMENTS ARE LACKING, AND THE CAUSE IS POORLY UNDERSTOOD, ALTHOUGH EXPOSURES TO PYRIDOSTIGMINE BROMIDE (PB) AND PESTICIDES ARE CONSISTENTLY IDENTIFIED TO BE AMONG THE STRONGEST RISK FACTORS. EPIGENETIC CHANGES INCLUDING ALTERED MICRORNA (MIRNA) EXPRESSION AND DNA METHYLATION PLAY AN IMPORTANT ROLE IN LEARNING, MEMORY, AND EMOTION REGULATION AND HAVE BEEN IMPLICATED IN VARIOUS NEUROLOGICAL DISORDERS. IN THIS STUDY, WE USED AN ESTABLISHED RAT MODEL OF GWI TO DETERMINE WHETHER 1) CHRONIC ALTERATIONS IN MIRNA EXPRESSION AND GLOBAL DNA METHYLATION AND DNA HYDROXYMETHYLATION ARE MECHANISMS INVOLVED IN THE PATHOBIOLOGY OF GWI, AND 2) PLASMA EXOSOME SMALL RNAS MAY SERVE AS POTENTIAL NONINVASIVE BIOMARKERS OF THIS DEBILITATING DISEASE. ONE YEAR AFTER A 28-DAY EXPOSURE REGIMEN OF PB, DEET (N,N-DIETHYL-3-METHYLBENZAMIDE), PERMETHRIN, AND MILD STRESS, EXPRESSION OF 84 MATURE MIRNAS AND GLOBAL 5-METHYLCYTOSINE (5MC) AND 5-HYDROXYMETHYLCYTOSINE (5HMC) CONTENT WERE ANALYZED IN THE BRAINS OF GWI RATS AND VEHICLE CONTROLS BY PCR ARRAY AND ENZYME-LINKED IMMUNOSORBENT ASSAY, RESPECTIVELY. PLASMA EXOSOME RNA NEXT-GENERATION SEQUENCING ANALYSIS WAS PERFORMED IN POOLED SAMPLES TO DISCOVER POTENTIAL NONINVASIVE BIOMARKERS. WE FOUND THAT COMBINED EXPOSURE TO LOW DOSES OF GW-RELATED CHEMICALS AND MILD STRESS CAUSED EPIGENETIC MODIFICATIONS IN THE BRAIN THAT PERSISTED ONE YEAR AFTER EXPOSURE, INCLUDING INCREASED EXPRESSION OF MIR-124-3P AND MIR-29B-3P IN THE HIPPOCAMPUS AND REGIONAL ALTERATIONS IN GLOBAL 5MC AND 5HMC CONTENT. GW-RELEVANT EXPOSURES ALSO INDUCED THE DIFFERENTIAL EXPRESSION OF TWO PIWI-INTERACTING RNAS (PIRNAS) IN CIRCULATION (PIR-007899 AND PIR-019162). RESULTS FROM THIS STUDY IMPLICATE A ROLE FOR EPIGENETIC ALTERATIONS IN GWI. EVALUATION OF THE DIAGNOSTIC POTENTIAL OF PLASMA EXOSOME RNAS IN VETERANS WITH GWI IS WARRANTED. 2016 3 6328 23 THE ROLE OF CELL ORGANELLES IN RHEUMATOID ARTHRITIS WITH FOCUS ON EXOSOMES. AUTO-IMMUNE DISEASES INVOLVED AT LEAST 25% OF THE POPULATION IN WEALTHY COUNTRIES. SEVERAL FACTORS INCLUDING GENETIC, EPIGENETIC, AND ENVIRONMENTAL ELEMENTS ARE IMPLICATED IN DEVELOPMENT OF RHEUMATOID ARTHRITIS AS AN AUTOIMMUNE DISEASE. AUTOANTIBODIES CAUSE SYNOVIAL INFLAMMATION AND ARTHRITIS, IF LEFT UNTREATED OR BEING UNDER CONTINUAL EXTERNAL STIMULATION, COULD RESULT IN CHRONIC INFLAMMATION, JOINT INJURY, AND DISABILITY. T- AND B-CELLS, SIGNALING MOLECULES, PROINFLAMMATORY MEDIATORS, AND SYNOVIUM-SPECIFIC TARGETS ARE AMONG THE NEW THERAPEUTIC TARGETS. EXOSOMES COULD BE EMPLOYED AS THERAPEUTIC VECTORS IN THE TREATMENT OF AUTOIMMUNE DISEASES. HEREIN, THE ROLE OF CELL ORGANELLE PARTICULARLY EXOSOMES IN RHEUMATOID ARTHRITIS HAD DISCUSSED AND SOME THERAPEUTIC APPLICATIONS OF EXOSOME HIGHLIGHTED. 2021 4 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 5 5054 32 PHARMACOPROTEOMICS REVEAL NOVEL PROTECTIVE ACTIVITY OF BROMODOMAIN CONTAINING 4 INHIBITORS ON VASCULAR HOMEOSTASIS IN TLR3-MEDIATED AIRWAY REMODELING. SMALL MOLECULE INHIBITORS OF THE EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) ARE POTENTIAL THERAPEUTICS FOR VIRAL AND ALLERGEN-INDUCED AIRWAY REMODELING. A LIMITATION OF THEIR PRECLINICAL ADVANCEMENT IS THE LACK OF DETAILED UNDERSTANDING OF MECHANISMS OF ACTION AND BIOMARKERS OF EFFECT. WE REPORT A SYSTEMS-LEVEL PHARMACOPROTEOMICS IN A STANDARDIZED MURINE MODEL OF TOLL-LIKE RECEPTOR TLR3-NFKAPPAB/RELA INNATE INFLAMMATION IN THE ABSENCE OR PRESENCE OF A HIGHLY SELECTIVE BRD4 INHIBITOR (ZL0454) OR NONSELECTIVE BROMODOMAIN AND EXTRATERMINAL DOMAIN INHIBITOR (JQ1). PROTEOMICS OF BRONCHOALVEOLAR LAVAGE FLUID (BALF) SECRETOME AND EXOSOMAL PROTEINS FROM THIS MURINE MODEL REVEALED INCREASED, SELECTIVE, CAPILLARY LEAK ASSOCIATED WITH PERICYTE-MYOFIBROBLAST TRANSITION, A PHENOMENON BLOCKED BY BRD4 INHIBITORS. BALF PROTEOMICS ALSO SUGGESTED THAT ZL0454 BETTER REDUCED THE VASCULAR LEAKAGE AND EXTRACELLULAR MATRIX DEPOSITION THAN JQ1. A SIGNIFICANT SUBSET OF INFLAMMATION-MEDIATED REMODELING FACTORS WAS ALSO IDENTIFIED IN A MOUSE MODEL OF IDIOPATHIC PULMONARY FIBROSIS PRODUCED BY BLEOMYCIN. BALF EXOSOME ANALYSIS INDICATED THAT BRD4 INHIBITORS REDUCED THE INDUCTION OF EXOSOMES ENRICHED IN COAGULATION FACTORS WHOSE PRESENCE CORRELATED WITH INTERSTITIAL FIBRIN DEPOSITION. FINALLY, BALF SAMPLES FROM HUMANS WITH SEVERE ASTHMA DEMONSTRATED SIMILAR UPREGULATIONS OF ORM2, APCS, SPARCL1, FGA, AND FN1, SUGGESTING THEIR POTENTIAL AS BIOMARKERS FOR EARLY DETECTION OF AIRWAY REMODELING AND/OR MONITORING OF THERAPY RESPONSE. SIGNIFICANCE: REPETITIVE AND CHRONIC VIRAL UPPER RESPIRATORY TRACT INFECTIONS TRIGGER TOLL-LIKE RECEPTOR (TLR)3-NFKAPPAB/RELA MEDIATED AIRWAY REMODELING WHICH IS LINKED TO A PROGRESSIVE DECLINE IN PULMONARY FUNCTION IN PATIENTS WITH ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. SMALL MOLECULE INHIBITORS OF THE EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) ARE POTENTIAL THERAPEUTICS FOR VIRAL AND ALLERGEN-INDUCED AIRWAY REMODELING. A LIMITATION OF THEIR PRECLINICAL ADVANCEMENT IS THE LACK OF DETAILED UNDERSTANDING OF MECHANISMS OF ACTION AND BIOMARKERS OF EFFECT. OUR STUDY REVEALED THAT THE ACTIVATION OF (TLR)3-NFKAPPAB/RELA PATHWAY IN THE LUNG INDUCED AN ELEVATION IN COAGULATION, COMPLEMENT, AND PLATELET FACTORS, INDICATING THE INCREASED VASCULAR LEAK DURING AIRWAY REMODELING. THE MECHANISM OF VASCULAR LEAKAGE WAS CHRONIC INFLAMMATION-INDUCED PERICYTE-MYOFIBROBLAST TRANSITION, WHICH WAS BLOCKED BY BRD4 INHIBITORS. FINALLY, PROTEOMICS ANALYSIS OF THE BRONCHOALVEOLAR LAVAGE FLUID SAMPLES FROM HUMANS WITH SEVERE ASTHMA DEMONSTRATED SIMILAR FINDINGS THAT WE OBSERVED IN THE ANIMAL MODEL. 2019 6 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 7 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 8 5507 20 RHEUMATOID ARTHRITIS PROGRESSION MEDIATED BY ACTIVATED SYNOVIAL FIBROBLASTS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DESTRUCTION. RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS (RASFS) ARE LEADING CELLS IN JOINT EROSION AND CONTRIBUTE ACTIVELY TO INFLAMMATION. RASFS SHOW AN ACTIVATED PHENOTYPE THAT IS INDEPENDENT OF THE INFLAMMATORY ENVIRONMENT AND REQUIRES THE COMBINATION OF SEVERAL FACTORS. ALTHOUGH NEW ASPECTS REGARDING RASF ACTIVATION VIA MATRIX DEGRADATION PRODUCTS, EPIGENETIC MODIFICATIONS, INFLAMMATORY FACTORS, TOLL-LIKE RECEPTOR (TLR) ACTIVATION AND OTHERS HAVE RECENTLY BEEN UNCOVERED, THE PRIMARY PATHOPHYSIOLOGICAL PROCESSES IN EARLY ARTHRITIS LEADING TO PERMANENT ACTIVATION ARE MOSTLY UNKNOWN. HERE, WE REVIEW NEW FINDINGS REGARDING RASF ACTIVATION AND THEIR ALTERED BEHAVIOR THAT CONTRIBUTE TO MATRIX DESTRUCTION AND INFLAMMATION AS WELL AS THEIR POTENTIAL TO SPREAD RA. 2010 9 5451 37 REPROGRAMMING CELLS FROM GULF WAR VETERANS INTO NEURONS TO STUDY GULF WAR ILLNESS. GULF WAR ILLNESS (GWI), WHICH AFFLICTS AT LEAST 25% OF VETERANS WHO SERVED IN THE 1990-1991 WAR IN THE PERSIAN GULF, IS THOUGHT TO BE CAUSED BY DEPLOYMENT EXPOSURES TO VARIOUS NEUROTOXICANTS, INCLUDING PESTICIDES, ANTI-NERVE GAS PILLS, AND LOW-LEVEL NERVE AGENTS INCLUDING SARIN/CYCLOSARIN. GWI IS A MULTISYMPTOM DISORDER CHARACTERIZED BY FATIGUE, JOINT PAIN, COGNITIVE PROBLEMS, AND GASTROINTESTINAL COMPLAINTS. THE MOST PROMINENT SYMPTOMS OF GWI (MEMORY PROBLEMS, POOR ATTENTION/CONCENTRATION, CHRONIC HEADACHES, MOOD ALTERATIONS, AND IMPAIRED SLEEP) SUGGEST THAT THE DISEASE PRIMARILY AFFECTS THE CNS. DEVELOPMENT OF URGENTLY NEEDED TREATMENTS DEPENDS ON EXPERIMENTAL MODELS APPROPRIATE FOR TESTING MECHANISTIC HYPOTHESES AND FOR SCREENING THERAPEUTIC COMPOUNDS. RODENT MODELS HAVE BEEN USEFUL THUS FAR, BUT ARE LIMITED BY THEIR INABILITY TO ASSESS THE CONTRIBUTION OF GENETIC OR EPIGENETIC BACKGROUND TO THE DISEASE, AND BECAUSE DISEASE-VULNERABLE PROTEINS AND PATHWAYS MAY BE DIFFERENT IN HUMANS RELATIVE TO RODENTS. AS OF YET, NO POSTMORTEM TISSUE FROM THE VETERANS HAS BECOME AVAILABLE FOR RESEARCH. WE ARE MOVING FORWARD WITH A PARADIGM SHIFT IN THE STUDY OF GWI, WHICH UTILIZES CONTEMPORARY STEM CELL TECHNOLOGY TO CONVERT SOMATIC CELLS FROM GULF WAR VETERANS INTO PLURIPOTENT CELL LINES THAT CAN BE DIFFERENTIATED INTO VARIOUS CELL TYPES, INCLUDING NEURONS, GLIA, MUSCLE, OR OTHER RELEVANT CELL TYPES. SUCH CELL LINES ARE IMMORTAL AND WILL BE A RESOURCE FOR GWI RESEARCHERS TO PURSUE MECHANISTIC HYPOTHESES AND THERAPEUTICS. 2017 10 6741 25 WHERE TO STAND WITH STROMAL CELLS AND CHRONIC SYNOVITIS IN RHEUMATOID ARTHRITIS? THE SYNOVIUM EXERCISES ITS MAIN FUNCTION IN JOINT HOMEOSTASIS THROUGH THE SECRETION OF FACTORS (SUCH AS LUBRICIN AND HYALURONIC ACID) THAT ARE CRITICAL FOR THE JOINT LUBRICATION AND FUNCTION. THE MAIN SYNOVIUM CELL COMPONENTS ARE FIBROBLAST-LIKE SYNOVIOCYTES, MESENCHYMAL STROMAL/STEM CELLS AND MACROPHAGE-LIKE SYNOVIAL CELLS. IN THE SYNOVIUM, CELLS OF MESENCHYMAL ORIGIN MODULATE LOCAL INFLAMMATION AND FIBROSIS, AND INTERACT WITH DIFFERENT FIBROBLAST SUBTYPES AND WITH RESIDENT MACROPHAGES. IN PATHOLOGIC CONDITIONS, SUCH AS RHEUMATOID ARTHRITIS, FIBROBLAST-LIKE SYNOVIOCYTES PROLIFERATE ABNORMALLY, RECRUIT MESENCHYMAL STEM CELLS FROM SUBCHONDRAL BONE MARROW, AND INFLUENCE IMMUNE CELL ACTIVITY THROUGH EPIGENETIC AND METABOLIC ADAPTATIONS. THE RESULTING SYNOVIAL HYPERPLASIA LEADS TO SECONDARY CARTILAGE DESTRUCTION, JOINT SWELLING, AND PAIN. IN THE PRESENT REVIEW, WE SUMMARIZE RECENT FINDINGS ON THE MOLECULAR SIGNATURE AND THE ROLES OF STROMAL CELLS DURING SYNOVIAL PANNUS FORMATION AND RHEUMATOID ARTHRITIS PROGRESSION. 2019 11 90 34 A PILOT REVERSE VIRTUAL SCREENING STUDY SUGGESTS TOXIC EXPOSURES CAUSED LONG-TERM EPIGENETIC CHANGES IN GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) IS A CHRONIC ILLNESS THAT AFFECTS UPWARD OF 32% OF DEPLOYED VETERANS TO THE 1991 GULF WAR (GW). THE SYMPTOMS ARE MEDICALLY UNEXPLAINED, RANGING ACROSS COGNITIVE DEFICITS, FATIGUE, GASTROINTESTINAL PROBLEMS, AND MUSCULOSKELETAL PAIN. RESEARCH INDICATES THAT CHEMICAL WARFARE AGENTS PLAY A KEY ROLE IN THE ONSET AND PROGRESSION OF GWI. THE KHAMISIYAH AMMUNITION STORAGE THAT HOUSED CHEMICAL WARFARE AGENTS SUCH AS SARIN, AN ACETYLCHOLINESTERASE (ACHE) INHIBITOR, WAS DEMOLISHED DURING THE GW, RELEASING TOXICANTS INTO THE ATMOSPHERE AFFECTING DEPLOYED TROOPS. EXPOSURE TO OTHER CHEMICAL AGENTS SUCH AS PYRIDOSTIGMINE BROMIDE, N,N-DIETHYL-M-TOLUAMIDE, PERMETHRIN AND CHLORPYRIFOS, WERE ALSO PREVALENT DURING THE WAR. THESE ADDITIONAL CHEMICAL AGENTS HAVE ALSO BEEN SHOWN TO INHIBIT ACHE. ACHE INHIBITION INDUCES AN ACETYLCHOLINE BUILD-UP, DISRUPTING SIGNALS BETWEEN NERVES AND MUSCLES, WHICH IN HIGH DOSES LEADS TO ASPHYXIATION. LITTLE IS KNOWN ABOUT LOW DOSE EXPOSURE. AS BIOACTIVE COMPOUNDS TEND TO INTERACT WITH MULTIPLE PROTEINS WITH VARIOUS PHYSIOLOGICAL EFFECT, WE AIMED TO IDENTIFY OTHER POTENTIAL SHARED TARGETS TO UNDERSTAND THE EXTENT IN WHICH THESE CHEMICALS COULD LEAD TO GWI. WE FOLLOWED A REVERSE SCREENING APPROACH WHERE EACH CHEMICAL IS COMPUTATIONALLY DOCKED TO A LIBRARY OF PROTEIN TARGETS. THE PROGRAMS PHARMMAPPER AND TARGETNET WERE USED FOR THIS PURPOSE, AND FURTHER ANALYSES WERE CONDUCTED TO MARK SIGNIFICANT CHANGES IN PARTICIPANTS WITH GWI. PREVIOUSLY PUBLISHED WORK ON DNA METHYLATION STATUS IN GWI WAS REANALYZED FOCUSING SPECIFICALLY ON THE PREDICTED SHARED TARGETS INDICATING SIGNIFICANT CHANGES IN DNA METHYLATION OF THE ASSOCIATED GENES. OUR FINDINGS THUS SUGGEST THAT EXPOSURE TO GWI-RELATED AGENTS MAY CONVERGE ON SIMILAR TARGETS WITH ROLES IN INFLAMMATION, NEUROTRANSMITTER AND LIPID METABOLISM, AND DETOXIFICATION WHICH MAY HAVE IMPACTS ON NEURODEGENERATIVE-LIKE DISEASE AND OXIDATIVE STRESS IN VETERANS WITH GWI. 2022 12 4684 29 NEW POTENTIAL THERAPEUTIC APPROACHES TARGETING SYNOVIAL FIBROBLASTS IN RHEUMATOID ARTHRITIS. SYNOVIAL CELLS PLAY A KEY ROLE IN JOINT DESTRUCTION DURING CHRONIC INFLAMMATION. IN PARTICULAR, ACTIVATED SYNOVIAL FIBROBLASTS (SFS) UNDERGO INTRINSIC ALTERATIONS LEADING TO AN AGGRESSIVE PHENOTYPE MEDIATING CARTILAGE DESTRUCTION AND BONE EROSION IN RHEUMATOID ARTHRITIS (RA). RECENT RESEARCH HAS REVEALED A NUMBER OF TARGETS TO CONTROL ARTHRITOGENIC CHANGES IN SFS. THEREFORE, IDENTIFICATION OF SF PHENOTYPES, CONTROL OF EPIGENETIC CHANGES, MODULATION OF CELLULAR FUNCTIONS, OR REGULATION OF THE ACTIVITY OF CATION CHANNELS AND DIFFERENT SIGNALING PATHWAYS HAS BEEN INVESTIGATED. ALTHOUGH MANY OF THESE APPROACHES HAVE SHOWN EFFICACY IN VITRO AND IN ANIMAL MODELS OF RA, FURTHER RESEARCH IS NEEDED TO SELECT THE MOST RELEVANT TARGETS FOR DRUG DEVELOPMENT. THIS REVIEW IS FOCUSED ON THE ROLE OF SFS AS A POTENTIAL STRATEGY TO DISCOVER NOVEL THERAPEUTIC TARGETS IN RA AIMED AT PRESERVING JOINT ARCHITECTURE AND FUNCTION. 2021 13 1726 30 DYSREGULATION OF LNCRNAS IN RHEUMATOID ARTHRITIS: BIOMARKERS, PATHOGENESIS AND POTENTIAL THERAPEUTIC TARGETS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE OF UNKNOWN ETIOLOGY, MAINLY MANIFESTED BY PERSISTENT ABNORMAL PROLIFERATION OF FIBROBLAST-LIKE SYNOVIOCYTES (FLSS), INFLAMMATION, SYNOVIAL HYPERPLASIA AND CARTILAGE EROSION, ACCOMPANIED BY JOINT SWELLING AND JOINT DESTRUCTION. ABNORMAL EXPRESSION OR FUNCTION OF LONG NONCODING RNAS (LNCRNAS) ARE CLOSELY RELATED TO HUMAN DISEASES, INCLUDING CANCERS, MENTAL DISEASES, AUTOIMMUNE DISEASES AND OTHERS. THE ABNORMAL SEQUENCE AND SPATIAL STRUCTURE OF LNCRNAS, THE DISORDER EXPRESSION AND THE ABNORMAL INTERACTION WITH THE BINDING PROTEIN WILL LEAD TO THE CHANGE OF GENE EXPRESSION IN THE WAY OF EPIGENETIC MODIFICATION. INCREASING EVIDENCE DEMONSTRATED THAT LNCRNAS WERE INVOLVED IN THE ACTIVATION OF FLSS, WHICH PLAYED A KEY ROLE IN THE PATHOGENESIS OF RA. IN THIS REVIEW, THE RESEARCH PROGRESS OF LNCRNAS IN THE PATHOGENESIS OF RA WAS SYSTEMATICALLY SUMMARIZED, INCLUDING THE ROLE OF LNCRNAS IN THE DIAGNOSIS OF RA, THE REGULATORY MECHANISM OF LNCRNAS IN THE PATHOGENESIS OF RA, AND THE INTERVENTION ROLE OF LNCRNAS IN THE TREATMENT OF RA. FURTHERMORE, THE ACTIVATED SIGNAL PATHWAYS, THE ROLE OF DNA METHYLATION AND OTHER MECHANISM HAVE ALSO BEEN OVERVIEW IN THIS REVIEW. 2021 14 4412 20 MOLECULAR AND CELLULAR BASIS OF RHEUMATOID JOINT DESTRUCTION. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE ASSOCIATED WITH JOINT DESTRUCTION. SYNOVIAL FIBROBLASTS ARE KEY PLAYERS IN THIS PATHOLOGICAL PROCESS. THEY FAVORISE A PRO-INFLAMMATORY ENVIRONMENT IN THE SYNOVIAL TISSUE, INTERACT WITH THE IMMUNE SYSTEM AND REGULATE THE DIFFERENTIATION OF MONOCYTES INTO OSTEOCLASTS. SYNOVIAL HYPERPLASIA IS ANOTHER CHARACTERISTIC OF RA, REFLECTING NOT ONLY AN IMBALANCE BETWEEN PROLIFERATION AND APOPTOSIS, BUT ALSO THE MIGRATION OF CELLS INTO THE SYNOVIAL TISSUE. GENE TRANSFER EXPERIMENTS HAVE BEEN USED AS IMPORTANT TOOLS FOR THE UNDERSTANDING OF MOLECULAR AND CELLULAR CHANGES THAT CHARACTERIZE THE ACTIVATED RA SYNOVIAL FIBROBLASTS. ACTIVATED SYNOVIAL FIBROBLASTS CAN INVADE CARTILAGE AND BONE. SYNOVIAL ACTIVATION IS DRIVEN BY CYTOKINES, SUCH AS TNFALPHA AND IL-1, AS WELL AS IL-15, 16, 17, 18, 22, 23, BUT ALSO BY CYTOKINE-INDEPENDENT MECHANISMS THAT INVOLVE THE INNATE IMMUNE SYSTEM (I.E. TLRS), A UNIQUE COMMUNICATION NETWORK OF MICROPARTICLES AND EPIGENETIC CHANGES (E.G. L1 RETROELEMENTS). 2006 15 107 32 A REVIEW OF PRE-CLINICAL MODELS FOR GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) IS A CHRONIC MULTISYMPTOMATIC DISORDER THAT AFFLICTS OVER 1/3RD OF THE 1991 GW VETERANS. IT SPANS MULTIPLE BODILY SYSTEMS AND PRESENTS ITSELF AS A SYNDROME EXHIBITING DIVERSE SYMPTOMS INCLUDING FATIGUE, DEPRESSION, MOOD, AND MEMORY AND CONCENTRATION DEFICITS, MUSCULOSKELETAL PAIN AND GASTROINTESTINAL DISTRESS IN GW VETERANS. THE ETIOLOGY OF GWI IS COMPLEX AND MANY FACTORS, INCLUDING CHEMICAL, PHYSIOLOGICAL, AND ENVIRONMENTAL STRESSORS PRESENT IN THE GW ARENA, HAVE BEEN IMPLICATED FOR ITS DEVELOPMENT. IT HAS BEEN OVER 30 YEARS SINCE THE END OF THE GW BUT, GWI HAS BEEN PERSISTENT IN SUFFERING VETERANS WHO ARE ALSO DEALING WITH PAUCITY OF EFFECTIVE TREATMENTS. THE MULTIFACTORIAL ASPECT OF GWI ALONG WITH GENETIC HETEROGENEITY AND LACK OF AVAILABLE DATA SURROUNDING WAR-TIME EXPOSURES HAVE PROVED TO BE CHALLENGING IN DEVELOPING PRE-CLINICAL MODELS OF GWI. DESPITE THIS, OVER A DOZEN GWI ANIMAL MODELS EXIST IN THE LITERATURE. IN THIS ARTICLE, FOLLOWING A BRIEF DISCUSSION OF GW HISTORY, GWI DEFINITIONS, AND PROBABLE CAUSES FOR ITS PATHOGENESIS, WE WILL EXPAND UPON VARIOUS EXPERIMENTAL MODELS USED IN GWI LABORATORY RESEARCH. THESE ANIMAL MODELS WILL BE DISCUSSED IN THE CONTEXT OF THEIR ATTEMPTS AT MIMICKING GW-RELATED EXPOSURES WITH REGARDS TO THE VARIATIONS IN CHEMICAL COMBINATIONS, DOSES, AND FREQUENCY OF EXPOSURES. WE WILL DISCUSS THEIR ADVANTAGES AND LIMITATIONS IN MODELING GWI FOLLOWED BY A DISCUSSION OF BEHAVIORAL AND MOLECULAR FINDINGS IN THESE MODELS. THE MECHANISTIC DATA OBTAINED FROM THESE PRECLINICAL STUDIES HAVE OFFERED MULTIPLE MOLECULAR PATHWAYS INCLUDING CHRONIC INFLAMMATION, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, LIPID DISTURBANCES, CALCIUM HOMEOSTATIC ALTERATIONS, CHANGES IN GUT MICROBIOTA, AND EPIGENETIC MODIFICATIONS, AMONGST OTHERS FOR EXPLAINING GWI DEVELOPMENT AND ITS PERSISTENCE. FINALLY, THESE FINDINGS HAVE ALSO INFORMED US ON NOVEL DRUGGABLE TARGETS IN GWI. WHILE, IT HAS BEEN DIFFICULT TO CONCEIVE A SINGLE PRE-CLINICAL MODEL THAT COULD EXPRESS ALL THE GWI SIGNS AND EXHIBIT BIOLOGICAL COMPLEXITY REFLECTIVE OF THE CLINICAL PRESENTATION IN GWI, ANIMAL MODELS HAVE BEEN CRITICAL FOR IDENTIFYING MOLECULAR UNDERPINNINGS OF GWI AND EVALUATING TREATMENT STRATEGIES FOR GWI. 2021 16 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 17 2221 27 EPIGENETIC MODIFICATIONS IN RHEUMATOID ARTHRITIS, A REVIEW. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC JOINT INFLAMMATION AND PROGRESSIVE DESTRUCTION OF CARTILAGE AND BONE WHICH LEADS TO ULTIMATELY LOSS OF FUNCTION AND PAIN. ACTIVATED SYNOVIAL FIBROBLASTS ARE KEY EFFECTOR CELLS IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS. IN THE RECENT YEARS, EPIGENETIC CHANGES INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND OTHER HISTONE MODIFICATIONS WERE IDENTIFIED THAT ARE ASSOCIATED WITH AN INTRINSIC ACTIVATION AND THE AGGRESSIVE PHENOTYPE OF THESE CELLS. SO FAR, NO THERAPIES TARGETING RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS EXIST. THIS REVIEW COMPRISES RECENT RESEARCH EFFORTS THAT PROPOSE EPIGENETIC MECHANISMS BEHIND THE ACTIVATION OF RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS AND OTHER CELL TYPES. 2013 18 2557 32 EPIGENETICS IN RHEUMATOID ARTHRITIS; FIBROBLAST-LIKE SYNOVIOCYTES AS AN EMERGING PARADIGM IN THE PATHOGENESIS OF THE DISEASE. RHEUMATOID ARTHRITIS (RA) IS CHARACTERIZED BY IMMUNE DYSFUNCTIONS AND CHRONIC INFLAMMATION THAT MAINLY AFFECTS DIARTHRODIAL JOINTS. GENETICS HAS LONG BEEN SURVEYED IN SEARCHING FOR THE ETIOPATHOGENESIS OF THE DISEASE AND PARTIALLY CLARIFIED THE CONUNDRUMS WITHIN THIS CONTEXT. EPIGENETIC ALTERATIONS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND NONCODING RNAS, WHICH HAVE BEEN CONSIDERED TO BE INVOLVED IN RA PATHOGENESIS, LIKELY EXPLAIN THE NONGENETIC RISK FACTORS. EPIGENETIC MODIFICATIONS MAY INFLUENCE RA THROUGH FIBROBLAST-LIKE SYNOVIOCYTES (FLSS). IT HAS BEEN SHOWN THAT FLSS PLAY AN ESSENTIAL ROLE IN THE ONSET AND EXACERBATION OF RA, AND THEREFORE, THEY MAY ILLUSTRATE SOME ASPECTS OF RA PATHOGENESIS. THESE CELLS EXHIBIT A UNIQUE DNA METHYLATION PROFILE IN THE EARLY STAGE OF THE DISEASE THAT CHANGES WITH DISEASE PROGRESSION. HISTONE ACETYLATION PROFILE IN RA FLSS IS DISRUPTED THROUGH THE IMBALANCE OF HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASE ACTIVITY. FURTHERMORE, DYSREGULATION OF MICRORNAS (MIRNAS) IS IMMENSE. MOST OF THESE MIRNAS HAVE SHOWN AN ABERRANT EXPRESSION IN FLSS THAT ARE INVOLVED IN PROLIFERATION AND CYTOKINE PRODUCTION. BESIDES, DYSREGULATION OF LONG NONCODING RNAS IN FLSS HAS BEEN REVEALED AND ATTRIBUTED TO RA PATHOGENESIS. FURTHER INVESTIGATIONS ARE NEEDED TO GET A BETTER VIEW OF EPIGENETIC ALTERATIONS AND THEIR INTERACTIONS. WE ALSO DISCUSS THE ROLE OF THESE EPIGENETIC ALTERATIONS IN RA PATHOGENESIS AND THEIR THERAPEUTIC POTENTIAL. 2020 19 1257 25 CURRENT TRENDS IN EPIGENETIC, CELLULAR AND MOLECULAR PATHWAYS IN MANAGEMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS IS A SYSTEMIC CHRONIC POLYARTICULAR AUTOIMMUNE DISORDER OF JOINTS AND JOINT MEMBRANE MAINLY AFFECTING FEET AND HANDS. THE PATHOLOGICAL MANIFESTATION OF THE DISEASE INCLUDES INFILTRATION OF IMMUNE CELLS, HYPERPLASIA OF THE LINING OF SYNOVIUM, FORMATION OF PANNUS AND BONE AND CARTILAGE DESTRUCTION. IF LEFT UNTREATED, THE APPEARANCE OF SMALL FOCAL NECROSIS, ADHESION OF GRANULATION, AND FORMATION OF FIBROUS TISSUE ON THE SURFACE OF ARTICULAR CARTILAGE IS NOTED. THE DISEASE PRIMARILY AFFECTS NEARLY 1% OF THE POPULATION GLOBALLY, WOMEN BEING MORE AFFECTED THAN MEN WITH A RATIO 2:1 AND CAN INITIATE REGARDLESS OF ANY AGE. THE SYNOVIAL FIBROBLAST IN RHEUMATOID ARTHRITIS INDIVIDUALS EXHIBITS AN AGGRESSIVE PHENOTYPE WHICH UPREGULATES THE MANIFESTATION OF PROTOONCOGENES, ADHESIVE COMPOUNDS, INFLAMMATORY CYTOKINES AND MATRIX-DETERIORATING ENZYMES. APART FROM THE INFLAMMATORY EFFECTS OF CYTOKINES, CHEMOKINES ARE ALSO NOTED TO INDUCE SWELLING AND PAIN IN ARTHRITIC INDIVIDUALS BY RESIDING IN SYNOVIAL MEMBRANE AND FORMING PANNUS. THE CURRENT TREATMENT OF RHEUMATOID ARTHRITIS INCLUDES TREATMENT WITH NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, DISEASE-MODIFYING ANTIRHEUMATIC DRUGS, TREATMENT WITH BIOLOGICS SUCH AS INHIBITORS OF TNF-ALPHA, INTERLEUKINS, PLATELET ACTIVATING FACTOR, ETC. WHICH PROVIDES SIGNIFICANT RELIEF FROM SYMPTOMS AND AIDS IN MANAGEMENT OF THE DISEASE. THE CURRENT REVIEW HIGHLIGHTS THE PATHOGENESIS INVOLVED IN THE ONSET OF RHEUMATOID ARTHRITIS AND ALSO COVERS EPIGENETIC, CELLULAR AND MOLECULAR PARAMETERS ASSOCIATED WITH IT TO AID BETTER AND ADVANCED THERAPEUTIC APPROACHES FOR MANAGEMENT OF THE DEBILITATING DISEASE. 2023 20 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