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 4774 28 NUCLEIC ACID APTAMERS TARGETING EPIGENETIC REGULATORS: AN INNOVATIVE THERAPEUTIC OPTION. EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS OF HISTONES, CHROMATIN REMODELING FACTORS, AND POST TRANSCRIPTIONAL GENE REGULATION BY NONCODING RNAS. ALL TOGETHER, THESE PROCESSES REGULATE GENE EXPRESSION BY CHANGING CHROMATIN ORGANIZATION AND DNA ACCESSIBILITY. TARGETING ENZYMATIC REGULATORS RESPONSIBLE FOR DNA AND CHROMATIN MODIFICATIONS HOLD PROMISE FOR MODULATING THE TRANSCRIPTIONAL REGULATION OF GENES THAT ARE INVOLVED IN CANCER, AS WELL AS IN CHRONIC NONCOMMUNICABLE METABOLIC DISEASES LIKE OBESITY, DIABETES, AND CARDIOVASCULAR DISEASES. INCREASINGLY STUDIES ARE EMERGING, LEADING TO THE IDENTIFICATION OF SPECIFIC AND EFFECTIVE MOLECULES TARGETING EPIGENETIC PATHWAYS INVOLVED IN DISEASE ONSET. IN THIS REGARD, RNA INTERFERENCE, WHICH USES SMALL RNAS TO REDUCE GENE EXPRESSION AND NUCLEIC ACID APTAMERS ARE ARISING AS VERY PROMISING CANDIDATES IN THERAPEUTIC APPROACH. COMMON TO ALL THESE STRATEGIES IS THE IMPERATIVE CHALLENGE OF SPECIFICITY. IN THIS REGARD, NUCLEIC ACID APTAMERS HAVE EMERGED AS AN ATTRACTIVE CLASS OF CARRIER MOLECULES DUE TO THEIR ABILITY TO BIND WITH HIGH AFFINITY TO SPECIFIC LIGANDS, THEIR HIGH CHEMICAL FLEXIBILITY AS WELL AS TISSUE PENETRATION CAPABILITY. IN THIS REVIEW, WE WILL FOCUS ON THE RECENT PROGRESS IN THE FIELD OF APTAMERS USED AS TARGETING MOIETIES ABLE TO RECOGNIZE AND REVERT EPIGENETICS MARKS INVOLVED IN DISEASES ONSET. 2018 3 3245 23 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 4 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 5 2219 45 EPIGENETIC MODIFICATIONS IN HEPATIC STELLATE CELLS CONTRIBUTE TO LIVER FIBROSIS. LIVER FIBROSIS REPRESENTS THE FINAL COMMON PATHWAY OF VIRTUALLY ALL TYPES OF CHRONIC LIVER DISEASES, AND IT HAS BEEN A MAJOR PUBLIC HEALTH CONCERN. MANY GENES HAVE BEEN DEMONSTRATED TO BE INVOLVED IN THE PATHOGENESIS OF LIVER FIBROSIS, WHILE THE MECHANISMS UNDERLYING GENE REGULATION STILL NEEDS FURTHER RESEARCH. ON THE OTHER HAND, HEPATIC STELLATE CELLS (HSCS) ARE QUIESCENT CELLS IN THE PERISINUSOIDAL SPACE IN LIVER. HSCS FACILITATE HEPATOCYTES INTERACTIONS VIA RELEASING SOLUBLE INFLAMMATORY FACTORS AND PRODUCING EXTRACELLULAR MATRIX. HSCS CAN BE ACTIVATED IN RESPONSE TO LIVER INJURY, AND THEY DIFFERENTIATE TO MYOFIBROBLASTS, WHICH GREATLY CONTRIBUTE TO THE FIBROGENESIS PROCESS. VARIOUS EPIGENETIC PROCEDURES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND FORMATION OF PARTICULAR CHROMATIN STRUCTURE, PLAY CRUCIAL ROLES IN THE GENE TRANSCRIPTIONAL EXPRESSION IN HSCS, REGULATING VARIOUS VITAL PROCESSES. FOR INSTANCE, EPIGENETIC MODULATION ON THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR-GAMMA) GENE PROMOTER ACCOUNTS FOR HSC DIFFERENTIATION THROUGH INTERACTING PATHWAYS. ABERRANT EXPRESSION OF A SERIES OF HISTONES AND CHEMOKINES IN ACTIVATED HSCS CAN AGGRAVATE INFLAMMATION AND OXIDATIVE STRESS, WHICH IN TURN PROMOTES DIFFERENTIATION OF HSCS TO MYOFIBROBLASTS AND ENHANCES THE WHOLE FIBROGENESIS PROCESS. DEGRADATION OF EXTRACELLULAR MATRIX IS ALSO REGULATED THROUGH EPIGENETIC MODULATION ON MATRIX ASSOCIATED ENZYMES. MOREOVER, FIBROSIS-RELATED EPIGENETIC MODIFICATIONS IN THE PARENTAL GENERATION MAY BE INHERITED TO THEIR OFFSPRING. IN THIS REVIEW, WE FIRSTLY SUMMARIZE THE VITAL EPIGENETIC MODIFICATIONS OF FIBROSIS-RELATED GENES IN HSCS, AND HIGHLIGHT SPECIFIC NUCLEIC ACID SEQUENCES AND STRUCTURES IN GENE PROMOTERS AS IMPORTANT ACTION SITES, WHICH MAY PROVIDE INDICATORS FOR LIVER FIBROSIS DIAGNOSIS IN THE FUTURE. 2013 6 5013 36 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AS A THERAPEUTIC TARGET FOR HEPATIC FIBROSIS: FROM BENCH TO BEDSIDE. HEPATIC FIBROSIS IS A DYNAMIC CHRONIC LIVER DISEASE OCCURRING AS A CONSEQUENCE OF WOUND-HEALING RESPONSES TO VARIOUS HEPATIC INJURIES. THIS DISORDER IS ONE OF PRIMARY PREDICTORS FOR LIVER-ASSOCIATED MORBIDITY AND MORTALITY WORLDWIDE. TO DATE, NO PHARMACOLOGICAL AGENT HAS BEEN APPROVED FOR HEPATIC FIBROSIS OR COULD BE RECOMMENDED FOR ROUTINE USE IN CLINICAL CONTEXT. CELLULAR AND MOLECULAR UNDERSTANDING OF HEPATIC FIBROSIS HAS REVEALED THAT PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA), THE FUNCTIONING RECEPTOR FOR ANTIDIABETIC THIAZOLIDINEDIONES, PLAYS A PIVOTAL ROLE IN THE PATHOBIOLOGY OF HEPATIC STELLATE CELLS (HSCS), WHOSE ACTIVATION IS THE CENTRAL EVENT IN THE PATHOGENESIS OF HEPATIC FIBROSIS. ACTIVATION OF PPARGAMMA INHIBITS HSC COLLAGEN PRODUCTION AND MODULATES HSC ADIPOGENIC PHENOTYPE AT TRANSCRIPTIONAL AND EPIGENETIC LEVELS. THESE MOLECULAR INSIGHTS INDICATE PPARGAMMA AS A PROMISING DRUG TARGET FOR ANTIFIBROTIC CHEMOTHERAPY. INTENSIVE ANIMAL STUDIES HAVE DEMONSTRATED THAT STIMULATION OF PPARGAMMA REGULATORY SYSTEM THROUGH GENE THERAPY APPROACHES AND PPARGAMMA LIGANDS HAS THERAPEUTIC PROMISE FOR HEPATIC FIBROSIS INDUCED BY A VARIETY OF ETIOLOGIES. AT THE SAME TIME, THIAZOLIDINEDIONE AGENTS HAVE BEEN INVESTIGATED FOR THEIR CLINICAL BENEFITS PRIMARILY IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS, A COMMON METABOLIC LIVER DISORDER WITH HIGH POTENTIAL TO PROGRESS TO FIBROSIS AND LIVER-RELATED DEATH. ALTHOUGH SOME STUDIES HAVE SHOWN INITIAL PROMISE, NONE HAS ESTABLISHED LONG-TERM EFFICACY IN WELL-CONTROLLED RANDOMIZED CLINICAL TRIALS. THIS COMPREHENSIVE REVIEW COVERS THE 10-YEAR DISCOVERIES OF THE MOLECULAR BASIS FOR PPARGAMMA REGULATION OF HSC PATHOPHYSIOLOGY AND THEN FOCUSES ON THE ANIMAL INVESTIGATIONS AND CLINICAL TRIALS OF VARIOUS THERAPEUTIC MODALITIES TARGETING PPARGAMMA FOR HEPATIC FIBROSIS. 2013 7 841 30 CHEMOKINES FORM NANOPARTICLES WITH DNA AND CAN SUPERINDUCE TLR-DRIVEN IMMUNE INFLAMMATION. CHEMOKINES CONTROL THE MIGRATORY PATTERNS AND POSITIONING OF IMMUNE CELLS TO ORGANIZE IMMUNE RESPONSES TO PATHOGENS. HOWEVER, MANY CHEMOKINES HAVE BEEN ASSOCIATED WITH SYSTEMIC AUTOIMMUNE DISEASES THAT HAVE CHRONIC IFN SIGNATURES. WE REPORT THAT A SERIES OF CHEMOKINES, INCLUDING CXCL4, CXCL10, CXCL12, AND CCL5, CAN SUPERINDUCE TYPE I IFN (IFN-I) BY TLR9-ACTIVATED PLASMACYTOID DCS (PDCS), INDEPENDENTLY OF THEIR RESPECTIVE KNOWN CHEMOKINE RECEPTORS. MECHANISTICALLY, WE SHOW THAT CHEMOKINES SUCH AS CXCL4 MEDIATE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN PDCS, MOSTLY TARGETED TO THE IFN-I PATHWAYS. WE DESCRIBE THAT CHEMOKINES PHYSICALLY INTERACT WITH DNA TO FORM NANOPARTICLES THAT PROMOTE CLATHRIN-MEDIATED CELLULAR UPTAKE AND DELIVERY OF DNA IN THE EARLY ENDOSOMES OF PDCS. USING TWO SEPARATE MOUSE MODELS OF SKIN INFLAMMATION, WE OBSERVED THE PRESENCE OF CXCL4 ASSOCIATED WITH DNA IN VIVO. THESE DATA REVEAL A NONCANONICAL ROLE FOR CHEMOKINES TO SERVE AS NUCLEIC ACID DELIVERY VECTORS TO MODULATE TLR SIGNALING, WITH IMPLICATIONS FOR THE CHRONIC PRESENCE OF IFN-I BY PDCS IN AUTOIMMUNE DISEASES. 2022 8 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 9 5939 37 TARGETING MECHANOTRANSDUCTION AT THE TRANSCRIPTIONAL LEVEL: YAP AND BRD4 ARE NOVEL THERAPEUTIC TARGETS FOR THE REVERSAL OF LIVER FIBROSIS. LIVER FIBROSIS IS THE RESULT OF A DEREGULATED WOUND HEALING PROCESS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX. HEPATIC STELLATE CELLS (HSCS), WHICH ARE ACTIVATED IN RESPONSE TO LIVER INJURY, ARE THE MAJOR SOURCE OF EXTRACELLULAR MATRIX AND DRIVE THE WOUND HEALING PROCESS. HOWEVER, CHRONIC LIVER DAMAGE LEADS TO PERPETUAL HSC ACTIVATION, PROGRESSIVE FORMATION OF PATHOLOGICAL SCAR TISSUE AND ULTIMATELY, CIRRHOSIS AND ORGAN FAILURE. HSC ACTIVATION IS TRIGGERED LARGELY IN RESPONSE TO MECHANOSIGNALING FROM THE MICROENVIRONMENT, WHICH INDUCES A PROFIBROTIC NUCLEAR TRANSCRIPTION PROGRAM THAT PROMOTES HSC PROLIFERATION AND EXTRACELLULAR MATRIX SECRETION THEREBY SETTING UP A POSITIVE FEEDBACK LOOP LEADING TO MATRIX STIFFENING AND SELF-SUSTAINED, PATHOLOGICAL, HSC ACTIVATION. DESPITE THE SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF LIVER FIBROSIS, THE MOLECULAR MECHANISMS THROUGH WHICH THE EXTRACELLULAR MATRIX PROMOTES HSC ACTIVATION ARE NOT WELL UNDERSTOOD AND NO EFFECTIVE THERAPIES HAVE BEEN APPROVED TO DATE THAT CAN TARGET THIS EARLY, REVERSIBLE, STAGE IN LIVER FIBROSIS. SEVERAL NEW LINES OF INVESTIGATION NOW PROVIDE IMPORTANT INSIGHT INTO THIS AREA OF STUDY AND IDENTIFY TWO NUCLEAR TARGETS WHOSE INHIBITION HAS THE POTENTIAL OF REVERSING LIVER FIBROSIS BY INTERFERING WITH HSC ACTIVATION: YES-ASSOCIATED PROTEIN (YAP), A TRANSCRIPTIONAL CO-ACTIVATOR AND EFFECTOR OF THE MECHANOSENSITIVE HIPPO PATHWAY, AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC REGULATOR OF GENE EXPRESSION. YAP AND BRD4 ACTIVITY IS INDUCED IN RESPONSE TO MECHANICAL STIMULATION OF HSCS AND EACH PROTEIN INDEPENDENTLY CONTROLS WAVES OF EARLY GENE EXPRESSION NECESSARY FOR HSC ACTIVATION. SIGNIFICANTLY, INHIBITION OF EITHER PROTEIN CAN REVERT THE CHRONIC ACTIVATION OF HSCS AND IMPEDE PATHOLOGICAL PROGRESSION OF LIVER FIBROSIS IN CLINICALLY RELEVANT MODEL SYSTEMS. IN THIS REVIEW WE WILL DISCUSS THE ROLES OF THESE NUCLEAR CO-ACTIVATORS IN HSC ACTIVATION, THEIR MECHANISM OF ACTION IN THE FIBROTIC PROCESS IN THE LIVER AND OTHER ORGANS, AND THE POTENTIAL OF TARGETING THEIR ACTIVITY WITH SMALL MOLECULE DRUGS FOR FIBROSIS REVERSAL. 2016 10 3554 37 IMPACT OF ADVANCED GLYCATION END PRODUCTS (AGES) AND ITS RECEPTOR (RAGE) ON CANCER METABOLIC SIGNALING PATHWAYS AND ITS PROGRESSION. CANCER IS A COMPLEX DISEASE WITH A 5-10% HEREDITARY BASE, BUT NUTRITION, LIFESTYLE, AND THE ENVIRONMENT WE ARE EXPOSED TO INFLUENCE 90-95% OF CANCERS. DUE TO RAPID WESTERNIZATION, THE DIET WE CONSUME IS RICH IN ADVANCED GLYCATION END PRODUCTS (AGES). AGES ARE THE HETEROGENEOUS GROUP OF COMPOUNDS FORMED BY NON-ENZYMATIC REACTIONS BETWEEN REDUCING SUGARS AND AMINO GROUPS OF PROTEINS, LIPIDS, AND NUCLEIC ACIDS. ITS IMPLICATION IS CONFIRMED IN MANY CHRONIC CONDITIONS SUCH AS DIABETES, RENAL, CARDIOVASCULAR DISEASES, AND AGING HOWEVER ITS ROLE IN CANCER DEVELOPMENT HAS BEEN UNDERSTUDIED. CANCER CELLS ARE CONTINUOUSLY EXPOSED TO AGES DUE TO THEIR INCREASED PRODUCTION, OWING TO ITS HIGH METABOLIC RATE AND AEROBIC GLYCOLYSIS. AGES ACCUMULATION LED TO GLYCATIVE STRESS WHICH IN TURN STIMULATES OXIDATIVE STRESS AND INFLAMMATION, THROUGH ITS RECEPTOR KNOWN AS RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE). RAGE MEDIATES CROSSTALK BETWEEN THE TUMOUR CELLS AND ITS MICROENVIRONMENT COMPONENTS TO INDUCE HYPOXIA, MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS, AUTOPHAGY, EPIGENETIC MODIFICATION, AND CANCER STEMNESS. THIS EMPHASIZES AGES AS AN ESSENTIAL DRIVING FACTOR IN DIFFERENT ASPECTS OF CANCER DEVELOPMENT, BUT THE EXACT MOLECULAR MECHANISM HAS TO BE EXPLORED. THUS, THIS REVIEW GIVES AN INSIGHT INTO THE PATHOLOGICAL ROLE OF AGES AT THE BIO-MOLECULAR LEVEL IN THE TUMOURIGENESIS AND PROGRESSION OF CANCER IN TERMS OF THE TUMOUR MICROENVIRONMENT, INVASION, AND METASTASIS. FURTHER, THE COMPILED CLINICAL DATA RELATING TO THE AGE-RAGE AXIS ASSOCIATED WITH DIFFERENT CANCERS AND ITS POTENTIAL INHIBITORS HAVE BEEN DISCUSSED. 2021 11 2313 36 EPIGENETIC REGULATION OF ENDOTHELIAL CELL FUNCTION BY NUCLEIC ACID METHYLATION IN CARDIAC HOMEOSTASIS AND DISEASE. PATHOLOGICAL REMODELLING OF THE MYOCARDIUM, INCLUDING INFLAMMATION, FIBROSIS AND HYPERTROPHY, IN RESPONSE TO ACUTE OR CHRONIC INJURY IS CENTRAL IN THE DEVELOPMENT AND PROGRESSION OF HEART FAILURE (HF). WHILE BOTH RESIDENT AND INFILTRATING CARDIAC CELLS ARE IMPLICATED IN THESE PATHOPHYSIOLOGICAL PROCESSES, RECENT EVIDENCE HAS SUGGESTED THAT ENDOTHELIAL CELLS (ECS) MAY BE THE PRINCIPAL CELL TYPE RESPONSIBLE FOR ORCHESTRATING PATHOLOGICAL CHANGES IN THE FAILING HEART. EPIGENETIC MODIFICATION OF NUCLEIC ACIDS, INCLUDING DNA, AND MORE RECENTLY RNA, BY METHYLATION IS ESSENTIAL FOR PHYSIOLOGICAL DEVELOPMENT DUE TO THEIR CRITICAL REGULATION OF CELLULAR GENE EXPRESSION. AS ACCUMULATING EVIDENCE HAS HIGHLIGHTED ALTERED PATTERNS OF DNA AND RNA METHYLATION IN HF AT BOTH THE GLOBAL AND INDIVIDUAL GENE LEVELS, MUCH EFFORT HAS BEEN DIRECTED TOWARDS DEFINING THE PRECISE ROLE OF SUCH CELL-SPECIFIC EPIGENETIC CHANGES IN THE CONTEXT OF HF. CONSIDERING THE INCREASINGLY APPARENT CRUCIAL ROLE THAT ECS PLAY IN CARDIAC HOMEOSTASIS AND DISEASE, THIS ARTICLE WILL SPECIFICALLY FOCUS ON NUCLEIC ACID METHYLATION (BOTH DNA AND RNA) IN THE FAILING HEART, EMPHASISING THE KEY INFLUENCE OF THESE EPIGENETIC MECHANISMS IN GOVERNING EC FUNCTION. THIS REVIEW SUMMARISES CURRENT UNDERSTANDING OF DNA AND RNA METHYLATION ALTERATIONS IN HF, ALONG WITH THEIR SPECIFIC ROLE IN REGULATING EC FUNCTION IN RESPONSE TO STRESS (E.G. HYPERGLYCAEMIA, HYPOXIA). IMPROVED APPRECIATION OF THIS IMPORTANT RESEARCH AREA WILL AID IN FURTHER IMPLICATING DYSFUNCTIONAL ECS IN HF PATHOGENESIS, WHILST INFORMING DEVELOPMENT OF EC-TARGETED STRATEGIES AND ADVANCING POTENTIAL TRANSLATION OF EPIGENETIC-BASED THERAPIES FOR SPECIFIC TARGETING OF PATHOLOGICAL CARDIAC REMODELLING IN HF. 2021 12 5539 28 ROLE OF CYSTIC FIBROSIS BRONCHIAL EPITHELIUM IN NEUTROPHIL CHEMOTAXIS. A HALLMARK OF CYSTIC FIBROSIS (CF) CHRONIC RESPIRATORY DISEASE IS AN EXTENSIVE NEUTROPHIL INFILTRATE IN THE MUCOSA FILLING THE BRONCHIAL LUMEN, STARTING EARLY IN LIFE FOR CF INFANTS. THE GENETIC DEFECT OF THE CF TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR) ION CHANNEL PROMOTES DEHYDRATION OF THE AIRWAY SURFACE LIQUID, ALTERS MUCUS PROPERTIES, AND DECREASES MUCOCILIARY CLEARANCE, FAVORING THE ONSET OF RECURRENT AND, ULTIMATELY, CHRONIC BACTERIAL INFECTION. NEUTROPHIL INFILTRATES ARE UNABLE TO CLEAR BACTERIAL INFECTION AND, AS AN ADVERSE EFFECT, CONTRIBUTE TO MUCOSAL TISSUE DAMAGE BY RELEASING PROTEASES AND REACTIVE OXYGEN SPECIES. MOREOVER, THE RAPID CELLULAR TURNOVER OF LUMENAL NEUTROPHILS RELEASES NUCLEIC ACIDS THAT FURTHER ALTER THE MUCUS VISCOSITY. A PROMINENT ROLE IN THE RECRUITMENT OF NEUTROPHIL IN BRONCHIAL MUCOSA IS PLAYED BY CF BRONCHIAL EPITHELIAL CELLS CARRYING THE DEFECTIVE CFTR PROTEIN AND ARE EXPOSED TO WHOLE BACTERIA AND BACTERIAL PRODUCTS, MAKING PHARMACOLOGICAL APPROACHES TO REGULATE THE EXAGGERATED NEUTROPHIL CHEMOTAXIS IN CF A RELEVANT THERAPEUTIC TARGET. HERE WE REVISE: (A) THE MAJOR RECEPTORS, KINASES, AND TRANSCRIPTION FACTORS LEADING TO THE EXPRESSION, AND RELEASE OF NEUTROPHIL CHEMOKINES IN BRONCHIAL EPITHELIAL CELLS; (B) THE ROLE OF INTRACELLULAR CALCIUM HOMEOSTASIS AND, IN PARTICULAR, THE CALCIUM CROSSTALK BETWEEN ENDOPLASMIC RETICULUM AND MITOCHONDRIA; (C) THE EPIGENETIC REGULATION OF THE KEY CHEMOKINES; (D) THE ROLE OF MUTANT CFTR PROTEIN AS A CO-REGULATOR OF CHEMOKINES TOGETHER WITH THE HOST-PATHOGEN INTERACTIONS; AND (E) DIFFERENT PHARMACOLOGICAL STRATEGIES TO REGULATE THE EXPRESSION OF CHEMOKINES IN CF BRONCHIAL EPITHELIAL CELLS THROUGH NOVEL DRUG DISCOVERY AND DRUG REPURPOSING. 2020 13 2915 32 GENE THERAPY FOR CHRONIC HBV-CAN WE ELIMINATE CCCDNA? CHRONIC INFECTION WITH THE HEPATITIS B VIRUS (HBV) IS A GLOBAL HEALTH CONCERN AND ACCOUNTS FOR APPROXIMATELY 1 MILLION DEATHS ANNUALLY. AMONGST OTHER LIMITATIONS OF CURRENT ANTI-HBV TREATMENT, FAILURE TO ELIMINATE THE VIRAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) AND EMERGENCE OF RESISTANCE REMAIN THE MOST WORRISOME. VIRAL REBOUND FROM LATENT EPISOMAL CCCDNA RESERVOIRS OCCURS FOLLOWING CESSATION OF THERAPY, PATIENT NON-COMPLIANCE, OR THE DEVELOPMENT OF ESCAPE MUTANTS. SIMULTANEOUS VIRAL CO-INFECTIONS, SUCH AS BY HIV-1, FURTHER COMPLICATE THERAPEUTIC INTERVENTIONS. THESE CHALLENGES HAVE PROMPTED DEVELOPMENT OF NOVEL TARGETED HEPATITIS B THERAPIES. GIVEN THE EASE WITH WHICH HIGHLY SPECIFIC AND POTENT NUCLEIC ACID THERAPEUTICS CAN BE RATIONALLY DESIGNED, GENE THERAPY HAS GENERATED INTEREST FOR ANTIVIRAL APPLICATION. GENE THERAPY STRATEGIES DEVELOPED FOR HBV INCLUDE GENE SILENCING BY HARNESSING RNA INTERFERENCE, TRANSCRIPTIONAL INHIBITION THROUGH EPIGENETIC MODIFICATION OF TARGET DNA, GENOME EDITING BY DESIGNER NUCLEASES, AND IMMUNE MODULATION WITH CYTOKINES. DNA-BINDING DOMAINS AND EFFECTORS BASED ON THE ZINC FINGER (ZF), TRANSCRIPTION ACTIVATOR-LIKE EFFECTOR (TALE), AND CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEAT (CRISPR) SYSTEMS ARE REMARKABLY WELL SUITED TO TARGETING EPISOMAL CCCDNA. THIS REVIEW DISCUSSES RECENT DEVELOPMENTS AND CHALLENGES FACING THE FIELD OF ANTI-HBV GENE THERAPY, ITS POTENTIAL CURATIVE SIGNIFICANCE AND THE PROGRESS TOWARDS CLINICAL APPLICATION. 2018 14 6621 22 UNDERSTANDING FIBROSIS IN SYSTEMIC SCLEROSIS: SHIFTING PARADIGMS, EMERGING OPPORTUNITIES. FIBROSIS IN MULTIPLE ORGANS IS A PROMINENT PATHOLOGICAL FINDING AND DISTINGUISHING HALLMARK OF SYSTEMIC SCLEROSIS (SSC). FINDINGS DURING THE PAST 5 YEARS HAVE CONTRIBUTED TO A MORE COMPLETE UNDERSTANDING OF THE COMPLEX CELLULAR AND MOLECULAR UNDERPINNING OF FIBROSIS IN SSC. FIBROBLASTS, THE PRINCIPAL EFFECTOR CELLS, ARE ACTIVATED IN THE PROFIBROTIC CELLULAR MILIEU BY CYTOKINES AND GROWTH FACTORS, DEVELOPMENTAL PATHWAYS, ENDOTHELIN 1 AND THROMBIN. INNATE IMMUNE SIGNALING VIA TOLL-LIKE RECEPTORS, MATRIX-GENERATED BIOMECHANICAL STRESS SIGNALING VIA INTEGRINS, HYPOXIA AND OXIDATIVE STRESS SEEM TO BE IMPLICATED IN PERPETUATING THE PROCESS. BEYOND CHRONIC FIBROBLAST ACTIVATION, FIBROSIS REPRESENTS A FAILURE TO TERMINATE TISSUE REPAIR, COUPLED WITH AN EXPANDED POPULATION OF MESENCHYMAL CELLS ORIGINATING FROM BONE MARROW AND TRANSDIFFERENTIATION OF EPITHELIAL CELLS, ENDOTHELIAL CELLS AND PERICYTES. IN ADDITION, STUDIES HAVE IDENTIFIED INTRINSIC ALTERATIONS IN SSC FIBROBLASTS RESULTING FROM EPIGENETIC CHANGES, AS WELL AS ALTERED MICRORNA EXPRESSION THAT MIGHT UNDERLIE THE CELL-AUTONOMOUS, PERSISTENT ACTIVATION PHENOTYPE OF THESE CELLS. PRECISE CHARACTERIZATION OF THE DEREGULATED EXTRACELLULAR AND INTRACELLULAR SIGNALING PATHWAYS, MEDIATORS AND CELLULAR DIFFERENTIATION PROGRAMS THAT CONTRIBUTE TO FIBROSIS IN SSC WILL FACILITATE THE DEVELOPMENT OF SELECTIVE, TARGETED THERAPEUTIC STRATEGIES. EFFECTIVE ANTIFIBROTIC THERAPY WILL ULTIMATELY INVOLVE NOVEL COMPOUNDS AND REPURPOSING OF DRUGS THAT ARE ALREADY APPROVED FOR OTHER INDICATIONS. 2011 15 3931 19 LIVER INJURY AND THE ACTIVATION OF THE HEPATIC MYOFIBROBLASTS. LIVER FIBROSIS IS A WOUND HEALING PROCESS, THE END RESULT OF CHRONIC LIVER INJURY ELICITED BY DIFFERENT NOXIOUS STIMULI. ACTIVATED HEPATIC STELLATE CELLS OR MYOFIBROBLASTS AND PORTAL MYOFIBROBLASTS ARE CONSIDERED AS THE MAIN PRODUCERS OF THE EXTRACELLULAR MATRIX IN THE LIVER. UPON LIVER INJURY THE QUIESCENT STELLATE CELLS TRANSDIFFERENTIATE INTO MYOFIBROBLASTS A PROCESS HIGHLIGHTED BY THE LOSS OF VITAMIN A STORES, UPREGULATION OF INTERSTITIAL TYPE COLLAGENS, SMOOTH MUSCLE ALPHA ACTIN, MATRIX METALLOPROTEINASES, PROTEOGLYCANS, AND THE INDUCTION OF CELL SURVIVAL PATHWAYS. ACTIVATION OF HEPATIC STELLATE CELLS IS A RESULT OF A COMPLEX INTERPLAY BETWEEN THE PARENCHYMAL CELLS, IMMUNE CELLS, EXTRACELLULAR MATRIX MECHANICS AND EXTRAHEPATIC MILIEU SUCH AS THE GUT MICROBIOME. IN THIS REVIEW WE WILL FOCUS ON THE PATHOMECHANISM OF STELLATE CELL ACTIVATION FOLLOWING CHRONIC LIVER INJURY; WITH THE AIM OF IDENTIFYING POSSIBLE TREATMENT TARGETS FOR ANTI-FIBROGENIC AGENTS. 2013 16 5140 27 POTENTIAL REGULATORS OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE DURING SENESCENCE AND AGING. SENESCENT CELLS EXPRESS AND SECRETE A VARIETY OF EXTRACELLULAR MODULATORS THAT INCLUDE CYTOKINES, CHEMOKINES, PROTEASES, GROWTH FACTORS, AND SOME ENZYMES ASSOCIATED WITH EXTRACELLULAR MATRIX REMODELING, DEFINED AS THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). SASP REINFORCES SENESCENT CELL CYCLE ARREST, STIMULATES AND RECRUITS IMMUNE CELLS FOR IMMUNE-MEDIATED CLEARANCE OF POTENTIALLY TUMORIGENIC CELLS, LIMITS OR INDUCES FIBROSIS, AND PROMOTES WOUND HEALING AND TISSUE REGENERATION. ON THE OTHER HAND, SASP MEDIATES CHRONIC INFLAMMATION LEADING TO THE DESTRUCTION OF TISSUE STRUCTURE AND FUNCTION AND STIMULATING THE GROWTH AND SURVIVAL OF TUMOR CELLS. SASP IS HIGHLY HETEROGENEOUS AND THE ROLE OF SASP DEPENDS ON THE CONTEXT. THE REGULATION OF SASP OCCURS AT MULTIPLE LEVELS INCLUDING CHROMATIN REMODELING, TRANSCRIPTION, MRNA TRANSLATION, INTRACELLULAR TRAFFICKING, AND SECRETION. SEVERAL SASP MODULATORS HAVE ALREADY BEEN IDENTIFIED SETTING THE STAGE FOR FUTURE RESEARCH ON THEIR CLINICAL APPLICATIONS. IN THIS REVIEW, WE SUMMARIZE IN DETAIL THE POTENTIAL SIGNALING PATHWAYS THAT TRIGGER AND REGULATE SASP PRODUCTION DURING AGING AND SENESCENCE. 2022 17 6441 25 THERAPEUTIC APPROACHES FOR NONALCOHOLIC FATTY LIVER DISEASE: ESTABLISHED TARGETS AND DRUGS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), AS A MULTISYSTEMIC DISEASE, IS THE MOST PREVALENT CHRONIC LIVER DISEASE CHARACTERIZED BY EXTREMELY COMPLEX PATHOGENIC MECHANISMS AND MULTIFACTORIAL ETIOLOGY, WHICH OFTEN DEVELOPS AS A CONSEQUENCE OF OBESITY, METABOLIC SYNDROME. PATHOPHYSIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF NAFLD INCLUDE DIET, OBESITY, INSULIN RESISTANCE (IR), GENETIC AND EPIGENETIC DETERMINANTS, INTESTINAL DYSBIOSIS, OXIDATIVE/NITROSATIVE STRESS, AUTOPHAGY DYSREGULATION, HEPATIC INFLAMMATION, GUT-LIVER AXIS, GUT MICROBES, IMPAIRED MITOCHONDRIAL METABOLISM AND REGULATION OF HEPATIC LIPID METABOLISM. SOME OF THE NEW DRUGS FOR THE TREATMENT OF NAFLD ARE INTRODUCED HERE. ALL OF THEM ACHIEVE THERAPEUTIC OBJECTIVES BY INTERFERING WITH CERTAIN PATHOPHYSIOLOGICAL PATHWAYS OF NAFLD, INCLUDING FIBROBLAST GROWTH FACTORS (FGF) ANALOGUES, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARS) AGONISTS, GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS, G PROTEIN-COUPLED RECEPTORS (GPCRS), SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS (SGLT-2I), FARNESOID X RECEPTOR (FXR), FATTY ACID SYNTHASE INHIBITOR (FASNI), ANTIOXIDANTS, ETC. THIS REVIEW DESCRIBES SOME PATHOPHYSIOLOGICAL MECHANISMS OF NAFLD AND ESTABLISHED TARGETS AND DRUGS. 2023 18 3678 33 INFLAMMATION AND REGENERATION IN THE DENTIN-PULP COMPLEX: A DOUBLE-EDGED SWORD. DENTAL TISSUE INFECTION AND DISEASE RESULT IN ACUTE AND CHRONIC ACTIVATION OF THE INNATE IMMUNE RESPONSE, WHICH IS MEDIATED BY MOLECULAR AND CELLULAR SIGNALING. DIFFERENT CELL TYPES WITHIN THE DENTIN-PULP COMPLEX ARE ABLE TO DETECT INVADING BACTERIA AT ALL STAGES OF THE INFECTION. INDEED, AT RELATIVELY EARLY DISEASE STAGES, ODONTOBLASTS WILL RESPOND TO BACTERIAL COMPONENTS, AND AS THE DISEASE PROGRESSES, CORE PULPAL CELLS INCLUDING FIBROBLASTS, STEMS CELLS, ENDOTHELIAL CELLS, AND IMMUNE CELLS WILL BECOME INVOLVED. PATTERN RECOGNITION RECEPTORS, SUCH AS TOLL-LIKE RECEPTORS EXPRESSED ON THESE CELL TYPES, ARE RESPONSIBLE FOR DETECTING BACTERIAL COMPONENTS, AND THEIR LIGAND BINDING LEADS TO THE ACTIVATION OF THE NUCLEAR FACTOR-KAPPA B AND P38 MITOGEN-ACTIVATED PROTEIN (MAP) KINASE INTRACELLULAR SIGNALING CASCADES. SUBSEQUENT NUCLEAR TRANSLOCATION OF THE TRANSCRIPTION FACTOR SUBUNITS FROM THESE PATHWAYS WILL LEAD TO PROINFLAMMATORY MEDIATOR EXPRESSION, INCLUDING INCREASES IN CYTOKINES AND CHEMOKINES, WHICH TRIGGER HOST CELLULAR DEFENSE MECHANISMS. THE COMPLEX MOLECULAR SIGNALING WILL RESULT IN THE RECRUITMENT OF IMMUNE SYSTEM CELLS TARGETED AT COMBATING THE INVADING MICROBES; HOWEVER, THE TRAFFICKING AND ANTIBACTERIAL ACTIVITY OF THESE CELLS CAN LEAD TO COLLATERAL TISSUE DAMAGE. RECENT EVIDENCE SUGGESTS THAT IF INFLAMMATION IS RESOLVED RELATIVELY LOW LEVELS OF PROINFLAMMATORY MEDIATORS MAY PROMOTE TISSUE REPAIR, WHEREAS IF CHRONIC INFLAMMATION ENSUES REPAIR MECHANISMS BECOME INHIBITED. THUS, THE EFFECTS OF MEDIATORS ARE TEMPORAL CONTEXT DEPENDENT. ALTHOUGH CONTAINMENT AND REMOVAL OF THE INFECTION ARE KEYS TO ENABLE DENTAL TISSUE REPAIR, IT IS FEASIBLE THAT THE DEVELOPMENT OF ANTI-INFLAMMATORY AND IMMUNOMODULATORY APPROACHES, BASED ON MOLECULAR, EPIGENETIC, AND PHOTOBIOMODULATORY TECHNOLOGIES, MAY ALSO BE BENEFICIAL FOR FUTURE ENDODONTIC TREATMENTS. 2014 19 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 20 4448 34 MOLECULAR MECHANISM AND TREATMENT OF VIRAL HEPATITIS-RELATED LIVER FIBROSIS. HEPATIC FIBROSIS IS A WOUND-HEALING RESPONSE TO VARIOUS CHRONIC STIMULI, INCLUDING VIRAL HEPATITIS B OR C INFECTION. ACTIVATED MYOFIBROBLASTS, PREDOMINANTLY DERIVED FROM THE HEPATIC STELLATE CELLS (HSCS), REGULATE THE BALANCE BETWEEN MATRIX METALLOPROTEINASES AND THEIR TISSUE INHIBITORS TO MAINTAIN EXTRACELLULAR MATRIX HOMEOSTASIS. TRANSFORMING GROWTH FACTOR-BETA AND PLATELET-DERIVED GROWTH FACTOR ARE CLASSIC PROFIBROGENIC SIGNALS THAT ACTIVATE HSC PROLIFERATION. IN ADDITION, PROINFLAMMATORY CYTOKINES AND CHEMOKINES COORDINATE MACROPHAGES, T CELLS, NK/NKT CELLS, AND LIVER SINUSOIDAL ENDOTHELIAL CELLS IN COMPLEX FIBROGENIC AND REGRESSION PROCESSES. IN ADDITION, FIBROGENESIS INVOLVES ANGIOGENESIS, METABOLIC REPROGRAMMING, AUTOPHAGY, MICRORNA, AND EPIGENETIC REGULATIONS. HEPATIC INFLAMMATION IS THE DRIVING FORCE BEHIND LIVER FIBROSIS; HOWEVER, HOST SINGLE NUCLEOTIDE POLYMORPHISMS AND VIRAL FACTORS, INCLUDING THE GENOTYPE, VIRAL LOAD, VIRAL MUTATION, AND VIRAL PROTEINS, HAVE BEEN ASSOCIATED WITH FIBROSIS PROGRESSION. ELIMINATING THE UNDERLYING ETIOLOGY IS THE MOST CRUCIAL ANTIFIBROTIC THERAPY. GROWING EVIDENCE HAS INDICATED THAT PERSISTENT VIRAL SUPPRESSION WITH ANTIVIRAL THERAPY CAN RESULT IN FIBROSIS REGRESSION, REDUCED LIVER DISEASE PROGRESSION, DECREASED HEPATOCELLULAR CARCINOMA, AND IMPROVED CHANCES OF SURVIVAL. PRECLINICAL STUDIES AND CLINICAL TRIALS ARE CURRENTLY EXAMINING SEVERAL INVESTIGATIONAL AGENTS THAT TARGET KEY FIBROGENIC PATHWAYS; THE RESULTS ARE PROMISING AND SHED LIGHT ON THIS DEBILITATING ILLNESS. 2014