1 5013 151 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 2 5805 52 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 3 5012 36 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AS A TARGET AND REGULATOR OF EPIGENETIC MECHANISMS IN NONALCOHOLIC FATTY LIVER DISEASE. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA) BELONGS TO THE SUPERFAMILY OF NUCLEAR RECEPTORS THAT CONTROL THE TRANSCRIPTION OF MULTIPLE GENES. ALTHOUGH IT IS FOUND IN MANY CELLS AND TISSUES, PPARGAMMA IS MOSTLY EXPRESSED IN THE LIVER AND ADIPOSE TISSUE. PRECLINICAL AND CLINICAL STUDIES SHOW THAT PPARGAMMA TARGETS SEVERAL GENES IMPLICATED IN VARIOUS FORMS OF CHRONIC LIVER DISEASE, INCLUDING NONALCOHOLIC FATTY LIVER DISEASE (NAFLD). CLINICAL TRIALS ARE CURRENTLY UNDERWAY TO INVESTIGATE THE BENEFICIAL EFFECTS OF PPARGAMMA AGONISTS ON NAFLD/NONALCOHOLIC STEATOHEPATITIS. UNDERSTANDING PPARGAMMA REGULATORS MAY THEREFORE AID IN UNRAVELING THE MECHANISMS GOVERNING THE DEVELOPMENT AND PROGRESSION OF NAFLD. RECENT ADVANCES IN HIGH-THROUGHPUT BIOLOGY AND GENOME SEQUENCING HAVE GREATLY FACILITATED THE IDENTIFICATION OF EPIGENETIC MODIFIERS, INCLUDING DNA METHYLATION, HISTONE MODIFIERS, AND NON-CODING RNAS AS KEY FACTORS THAT REGULATE PPARGAMMA IN NAFLD. IN CONTRAST, LITTLE IS STILL KNOWN ABOUT THE PARTICULAR MOLECULAR MECHANISMS UNDERLYING THE INTRICATE RELATIONSHIPS BETWEEN THESE EVENTS. THE PAPER THAT FOLLOWS OUTLINES OUR CURRENT UNDERSTANDING OF THE CROSSTALK BETWEEN PPARGAMMA AND EPIGENETIC REGULATORS IN NAFLD. ADVANCES IN THIS FIELD ARE LIKELY TO AID IN THE DEVELOPMENT OF EARLY NONINVASIVE DIAGNOSTICS AND FUTURE NAFLD TREATMENT STRATEGIES BASED ON PPARGAMMA EPIGENETIC CIRCUIT MODIFICATION. 2023 4 1255 40 CURRENT STATUS OF NOVEL ANTIFIBROTIC THERAPIES IN PATIENTS WITH CHRONIC LIVER DISEASE. FIBROSIS ACCUMULATION IS A DYNAMIC PROCESS RESULTING FROM A WOUND-HEALING RESPONSE TO ACUTE OR CHRONIC LIVER INJURY OF ALL CAUSES. THE CASCADE STARTS WITH HEPATOCYTE NECROSIS AND APOPTOSIS, WHICH INSTIGATE INFLAMMATORY SIGNALING BY CHEMOKINES AND CYTOKINES, RECRUITMENT OF IMMUNE CELL POPULATIONS, AND ACTIVATION OF FIBROGENIC CELLS, CULMINATING IN THE DEPOSITION OF EXTRACELLULAR MATRIX. THESE KEY ELEMENTS, ALONG WITH PATHWAYS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION, REPRESENT FERTILE THERAPEUTIC TARGETS. NEW THERAPIES INCLUDE DRUGS SPECIFICALLY DESIGNED AS ANTIFIBROTICS, AS WELL AS DRUGS ALREADY AVAILABLE WITH WELL-ESTABLISHED SAFETY PROFILES, WHOSE MECHANISM OF ACTION MAY ALSO BE ANTIFIBROTIC. AT THE SAME TIME, THE DEVELOPMENT OF NONINVASIVE FIBROGENIC MARKERS, AND TECHNIQUES (E.G. FIBROSCAN), AS WELL AS COMBINED SCORING SYSTEMS INCORPORATING SERUM AND CLINICAL FEATURES WILL ALLOW IMPROVED ASSESSMENT OF THERAPY RESPONSE. IN AGGREGATE, THE ADVANCES IN THE ELUCIDATION OF THE BIOLOGY OF FIBROSIS, COMBINED WITH IMPROVED TECHNOLOGIES FOR ASSESSMENT WILL PROVIDE A COMPREHENSIVE FRAMEWORK FOR DESIGN OF ANTIFIBROTICS AND THEIR ANALYSIS IN WELL-DESIGNED CLINICAL TRIALS. THESE EFFORTS MAY ULTIMATELY YIELD SUCCESS IN HALTING THE PROGRESSION OF, OR REVERSING, LIVER FIBROSIS. 2011 5 4976 41 PATHOPHYSIOLOGICAL MECHANISMS OF HEPATIC STELLATE CELLS ACTIVATION IN LIVER FIBROSIS. LIVER FIBROSIS IS A COMPLEX PATHOLOGICAL PROCESS CONTROLLED BY A VARIETY OF CELLS, MEDIATORS AND SIGNALING PATHWAYS. HEPATIC STELLATE CELLS PLAY A CENTRAL ROLE IN THE DEVELOPMENT OF LIVER FIBROSIS. IN CHRONIC LIVER DISEASE, HEPATIC STELLATE CELLS UNDERGO DRAMATIC PHENOTYPIC ACTIVATION AND ACQUIRE FIBROGENIC PROPERTIES. THIS REVIEW FOCUSES ON THE PATHOPHYSIOLOGICAL MECHANISMS OF HEPATIC STELLATE CELLS ACTIVATION IN LIVER FIBROSIS. THEY ENTER THE CELL CYCLE UNDER THE INFLUENCE OF VARIOUS TRIGGERS. THE "INITIATION" PHASE OF HEPATIC STELLATE CELLS ACTIVATION OVERLAPS AND CONTINUES WITH THE "PERPETUATION" PHASE, WHICH IS CHARACTERIZED BY A PRONOUNCED INFLAMMATORY AND FIBROGENIC REACTION. THIS IS FOLLOWED BY A RESOLUTION PHASE IF THE INJURY SUBSIDES. KNOWLEDGE OF THESE PATHOPHYSIOLOGICAL MECHANISMS PAVED THE WAY FOR DRUGS AIMED AT PREVENTING THE DEVELOPMENT AND PROGRESSION OF LIVER FIBROSIS. IN THIS RESPECT, IMPAIRMENTS IN INTRACELLULAR SIGNALING, EPIGENETIC CHANGES AND CELLULAR STRESS RESPONSE CAN BE THE TARGETS OF THERAPY WHERE THE GOAL IS TO DEACTIVATE HEPATIC STELLATE CELLS. POTENTIAL ANTIFIBROTIC THERAPY MAY FOCUS ON INDUCING HEPATIC STELLATE CELLS TO RETURN TO AN INACTIVE STATE THROUGH CELLULAR AGING, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS, AND SERVE AS POTENTIAL ANTIFIBROTIC THERAPY. IT IS ESPECIALLY IMPORTANT TO PREVENT THE FORMATION OF LIVER CIRRHOSIS SINCE THE ONLY RADICAL APPROACH TO ITS TREATMENT IS LIVER TRANSPLANTATION WHICH CAN BE PERFORMED IN ONLY A LIMITED NUMBER OF COUNTRIES. 2022 6 2817 39 FIBROSIS IN THE LIVER: ACUTE PROTECTION AND CHRONIC DISEASE. THE UNDERSTANDING OF THE CELLULAR AND MOLECULAR MECHANISMS OF THE FIBROTIC WOUND-HEALING RESPONSE OF THE LIVER HAS MADE DRAMATIC PROGRESS IN THE PAST 20 YEARS. HEPATIC STELLATE CELLS (HSCS), WHICH AFTER LIVER INJURY PROLIFERATE AND TRANSDIFFERENTIATE TO MYOFIBROBLASTS, HAVE EMERGED AS THE PRIMARY SOURCE OF THE FIBROTIC RESPONSE, EVEN THOUGH OTHER FIBROGENIC CELLS MAY ALSO CONTRIBUTE TO THE PRODUCTION OF EXTRACELLULAR MATRIX (ECM). ADVANCES IN THE UNDERSTANDING OF HSC REGULATION INCLUDE APOPTOTIC SIGNALING, ANGIOGENIC SIGNALING, AND RESPONSES TO OXIDATIVE STRESS. THE ECM HAS EMERGED NOT ONLY AS A STRUCTURAL SCAFFOLD, BUT ALSO AS A DYNAMIC AND INTERACTIVE MATRIX REGULATING STELLATE CELL ACTIVATION. ADDITIONALLY, THE INNATE IMMUNE SYSTEM AND IMMUNE SIGNALING, AS WELL AS A BROADENING UNDERSTANDING OF THE TRANSCRIPTIONAL REGULATION INCLUDING MICRORNAS AND EPIGENETIC EVENTS OFFER POTENTIAL THERAPEUTIC TARGETS. UNRAVELING GENETIC DETERMINANTS RELATED TO MECHANISMS OF HEPATIC FIBROGENESIS PROMISE INDIVIDUALIZED THERAPY OR PREVENTION. HEPATIC FIBROSIS AND CIRRHOSIS HAVE EMERGED AS TREATABLE AND POTENTIALLY REVERSIBLE CONSEQUENCE OF CHRONIC LIVER DISEASE. 2010 7 2691 32 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 8 6372 37 THE ROLE OF MIR-29A IN THE REGULATION, FUNCTION, AND SIGNALING OF LIVER FIBROSIS. BOTH FIBROSIS AND CIRRHOSIS OF THE LIVER ARE THE END RESULTS OF MOST KINDS OF CHRONIC LIVER DAMAGE AND REPRESENT A COMMON BUT DIFFICULT CLINICAL CHALLENGE THROUGHOUT THE WORLD. THE INHIBITION OF THE FIBROGENIC, PROLIFERATIVE, AND MIGRATORY EFFECTS OF HEPATIC STELLATE CELLS (HSCS) HAS BECOME AN EXPERIMENTAL THERAPY FOR PREVENTING AND EVEN REVERSING HEPATIC FIBROSIS. FURTHERMORE, A COMPLETE UNDERSTANDING OF THE FUNCTION OF NON-CODING RNA-MEDIATED EPIGENETIC MECHANISMS IN HSC ACTIVATION MAY IMPROVE OUR PERCEPTION OF LIVER FIBROSIS PATHOGENESIS. THIS REVIEW FOCUSES ON THE EVOLVING VIEW OF THE MOLECULAR MECHANISMS BY WHICH HSC ACTIVATION BY MIR-29A SIGNALING MAY MODERATE THE PROFIBROGENIC PHENOTYPE OF THESE CELLS, THUS SUPPORTING THE USE OF MIR-29A AGONISTS AS A POTENTIAL THERAPY FOR TREATING LIVER FIBROSIS IN THE FUTURE. 2018 9 2502 31 EPIGENETICS AND LIVER FIBROSIS. LIVER FIBROSIS ARISES BECAUSE PROLONGED INJURY COMBINED WITH EXCESSIVE SCAR DEPOSITION WITHIN HEPATIC PARENCHYMA ARISING FROM OVERACTIVE WOUND HEALING RESPONSE MEDIATED BY ACTIVATED MYOFIBROBLASTS. FIBROSIS IS THE COMMON END POINT FOR ANY TYPE OF CHRONIC LIVER INJURY INCLUDING ALCOHOLIC LIVER DISEASE, NONALCOHOLIC FATTY LIVER DISEASE, VIRAL HEPATITIS, AND CHOLESTATIC LIVER DISEASES. ALTHOUGH GENETIC INFLUENCES ARE IMPORTANT, IT IS EPIGENETIC MECHANISMS THAT HAVE BEEN SHOWN TO ORCHESTRATE MANY ASPECTS OF FIBROGENESIS IN THE LIVER. NEW DISCOVERIES IN THE FIELD ARE LEADING TOWARD THE DEVELOPMENT OF EPIGENETIC BIOMARKERS AND TARGETED THERAPIES. THIS REVIEW CONSIDERS EPIGENETIC MECHANISMS AS WELL AS RECENT ADVANCES IN EPIGENETIC PROGRAMMING IN THE CONTEXT OF HEPATIC FIBROSIS. 2017 10 2219 40 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 11 4448 46 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 12 2164 35 EPIGENETIC MECHANISMS IN HEPATIC STELLATE CELL ACTIVATION DURING LIVER FIBROSIS AND CARCINOGENESIS. LIVER FIBROSIS IS AN ESSENTIAL COMPONENT OF CHRONIC LIVER DISEASE (CLD) AND HEPATOCARCINOGENESIS. THE FIBROTIC STROMA IS A CONSEQUENCE OF SUSTAINED LIVER DAMAGE COMBINED WITH EXACERBATED EXTRACELLULAR MATRIX (ECM) ACCUMULATION. IN THIS CONTEXT, ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) PLAYS A KEY ROLE IN BOTH INITIATION AND PERPETUATION OF FIBROGENESIS. THESE CELLS SUFFER PROFOUND REMODELING OF GENE EXPRESSION IN THIS PROCESS. THIS REVIEW IS FOCUSED ON THE EPIGENETIC ALTERATIONS PARTICIPATING IN THE TRANSDIFFERENTIATION OF HSCS FROM THE QUIESCENT TO ACTIVATED STATE. RECENT ADVANCES IN THE FIELD OF DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS (PTM) OF HISTONES (ACETYLATION AND METHYLATION) PATTERNS ARE DISCUSSED HERE, TOGETHER WITH ALTERED EXPRESSION AND ACTIVITY OF EPIGENETIC REMODELERS. WE ALSO CONSIDER RECENT ADVANCES IN TRANSLATIONAL APPROACHES, INCLUDING THE USE OF EPIGENETIC MARKS AS BIOMARKERS AND THE PROMISING ANTIFIBROTIC PROPERTIES OF EPIGENETIC DRUGS THAT ARE CURRENTLY BEING USED IN PATIENTS. 2019 13 3245 36 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 14 1858 36 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 15 3275 28 HEPATOCELLULAR CARCINOMA: THERAPEUTIC ADVANCES IN SIGNALING, EPIGENETIC AND IMMUNE TARGETS. HEPATOCELLULAR CARCINOMA (HCC) REMAINS A GLOBAL MEDICAL BURDEN WITH RISING INCIDENCE DUE TO CHRONIC VIRAL HEPATITIS AND NON-ALCOHOLIC FATTY LIVER DISEASES. TREATMENT OF ADVANCED DISEASE STAGES IS STILL UNSATISFYING. BESIDES FIRST AND SECOND GENERATION TYROSINE KINASE INHIBITORS, IMMUNE CHECKPOINT INHIBITORS HAVE BECOME CENTRAL FOR THE TREATMENT OF HCC. NEW MODALITIES LIKE EPIGENETIC THERAPY USING HISTONE DEACETYLASE INHIBITORS (HDACI) AND CELL THERAPY APPROACHES WITH CHIMERIC ANTIGEN RECEPTOR T CELLS (CAR-T CELLS) ARE CURRENTLY UNDER INVESTIGATION IN CLINICAL TRIALS. DEVELOPMENT OF SUCH NOVEL DRUGS IS CLOSELY LINKED TO THE AVAILABILITY AND IMPROVEMENT OF NOVEL PRECLINICAL AND ANIMAL MODELS AND THE IDENTIFICATION OF PREDICTIVE BIOMARKERS. THE CURRENT STATUS OF TREATMENT OPTIONS FOR ADVANCED HCC, EMERGING NOVEL THERAPEUTIC APPROACHES AND DIFFERENT PRECLINICAL MODELS FOR HCC DRUG DISCOVERY AND DEVELOPMENT ARE REVIEWED HERE. 2019 16 4132 30 MECHANISMS OF HEPATIC FIBROGENESIS. SUBSTANTIAL IMPROVEMENTS IN THE TREATMENT OF CHRONIC LIVER DISEASE HAVE ACCELERATED INTEREST IN UNCOVERING THE MECHANISMS UNDERLYING HEPATIC FIBROSIS AND ITS RESOLUTION. ACTIVATION OF RESIDENT HEPATIC STELLATE CELLS INTO PROLIFERATIVE, CONTRACTILE, AND FIBROGENIC CELLS IN LIVER INJURY REMAINS A DOMINANT THEME DRIVING THE FIELD. HOWEVER, SEVERAL NEW AREAS OF RAPID PROGRESS IN THE PAST 5-10 YEARS ALSO HAVE TAKEN ROOT, INCLUDING: (1) IDENTIFICATION OF DIFFERENT FIBROGENIC POPULATIONS APART FROM RESIDENT STELLATE CELLS, FOR EXAMPLE, PORTAL FIBROBLASTS, FIBROCYTES, AND BONE-MARROW-DERIVED CELLS, AS WELL AS CELLS DERIVED FROM EPITHELIAL MESENCHYMAL TRANSITION; (2) EMERGENCE OF STELLATE CELLS AS FINELY REGULATED DETERMINANTS OF HEPATIC INFLAMMATION AND IMMUNITY; (3) ELUCIDATION OF MULTIPLE PATHWAYS CONTROLLING GENE EXPRESSION DURING STELLATE CELL ACTIVATION INCLUDING TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC MECHANISMS; (4) RECOGNITION OF DISEASE-SPECIFIC PATHWAYS OF FIBROGENESIS; (5) RE-EMERGENCE OF HEPATIC MACROPHAGES AS DETERMINANTS OF MATRIX DEGRADATION IN FIBROSIS RESOLUTION AND THE IMPORTANCE OF MATRIX CROSS-LINKING AND SCAR MATURATION IN DETERMINING REVERSIBILITY; AND (6) HINTS THAT HEPATIC STELLATE CELLS MAY CONTRIBUTE TO HEPATIC STEM CELL BEHAVIOR, CANCER, AND REGENERATION. CLINICAL AND TRANSLATIONAL IMPLICATIONS OF THESE ADVANCES HAVE BECOME CLEAR, AND HAVE BEGUN TO IMPACT SIGNIFICANTLY ON THE MANAGEMENT AND OUTLOOK OF PATIENTS WITH CHRONIC LIVER DISEASE. 2008 17 5533 45 ROLE AND MECHANISM OF DNA METHYLATION AND ITS INHIBITORS IN HEPATIC FIBROSIS. LIVER FIBROSIS IS A REPAIR RESPONSE TO INJURY CAUSED BY VARIOUS CHRONIC STIMULI THAT CONTINUALLY ACT ON THE LIVER. AMONG THEM, THE ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) AND THEIR TRANSFORMATION INTO A MYOFIBROBLAST PHENOTYPE IS A KEY EVENT LEADING TO LIVER FIBROSIS, HOWEVER THE MECHANISM HAS NOT YET BEEN ELUCIDATED. THE MOLECULAR BASIS OF HSC ACTIVATION INVOLVES CHANGES IN THE REGULATION OF GENE EXPRESSION WITHOUT CHANGES IN THE GENOME SEQUENCE, NAMELY, VIA EPIGENETIC REGULATION. DNA METHYLATION IS A KEY FOCUS OF EPIGENETIC RESEARCH, AS IT AFFECTS THE EXPRESSION OF FIBROSIS-RELATED, METABOLISM-RELATED, AND TUMOR SUPPRESSOR GENES. INCREASING STUDIES HAVE SHOWN THAT DNA METHYLATION IS CLOSELY RELATED TO SEVERAL PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES INCLUDING HSC ACTIVATION AND LIVER FIBROSIS. THIS REVIEW AIMED TO DISCUSS THE MECHANISM OF DNA METHYLATION IN THE PATHOGENESIS OF LIVER FIBROSIS, EXPLORE DNA METHYLATION INHIBITORS AS POTENTIAL THERAPIES FOR LIVER FIBROSIS, AND PROVIDE NEW INSIGHTS ON THE PREVENTION AND CLINICAL TREATMENT OF LIVER FIBROSIS. 2023 18 3273 36 HEPATOCELLULAR CARCINOMA: MOLECULAR PATHWAYS AND NEW THERAPEUTIC TARGETS. HEPATOCELLULAR CARCINOMA IS OFTEN DIAGNOSED AT AN ADVANCED STAGE, WHEN IT IS NOT AMENABLE TO CURATIVE THERAPIES. THERE IS NO EFFECTIVE CHEMOTHERAPY. ADVANCES IN CANCER BIOLOGY SUGGEST THAT A LIMITED NUMBER OF PATHWAYS ARE RESPONSIBLE FOR INITIATING AND MAINTAINING DYSREGULATED CELL PROLIFERATION, WHICH IS THE MAJOR CELLULAR ALTERATION RESPONSIBLE FOR THE CANCER PHENOTYPE. NEW TREATMENTS IN DEVELOPMENT TARGET SEVERAL OF THESE CRITICAL PATHWAYS, INCLUDING AGENTS TARGETING THE RECEPTOR TYROSINE KINASE PATHWAYS, THE WNT/BETA-CATENIN SIGNALING PATHWAY, THE UBIQUITIN/PROTEASOME DEGRADATION PATHWAY, THE EPIGENETIC DNA METHYLATION AND HISTONE DEACETYLATION PATHWAYS, THE PI3 KINASE/AKT/MTOR PATHWAY, ANGIOGENIC PATHWAYS, AND TELOMERASE. SEVERAL OF THESE APPROACHES HOLD SIGNIFICANT PROMISE FOR IMPROVING THE LONG-TERM OUTCOME OF PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA. BECAUSE OF THE HIGH PREVALENCE OF LIVER CIRRHOSIS IN HEPATOCELLULAR CARCINOMA PATIENTS, THESE APPROACHES MUST BE COUPLED WITH NEW STRATEGIES FOR HALTING OR REVERSING THE PROGRESSION OF CHRONIC LIVER DISEASE. 2005 19 2323 26 EPIGENETIC REGULATION OF HEPATIC STELLATE CELL ACTIVATION AND MACROPHAGE IN CHRONIC LIVER INFLAMMATION. CHRONIC LIVER INFLAMMATION IS A COMPLEX PATHOLOGICAL PROCESS UNDER DIFFERENT STRESS CONDITIONS, AND THE ROLES OF STELLATE CELLS AND MACROPHAGES IN CHRONIC LIVER INFLAMMATION HAVE BEEN WIDELY REPORTED. MODERATE LIVER INFLAMMATION CAN PROTECT THE LIVER FROM DAMAGE AND FACILITATE THE RECOVERY OF LIVER INJURY. HOWEVER, AN INFLAMMATORY RESPONSE THAT IS TOO INTENSE CAN RESULT IN MASSIVE DEATH OF HEPATOCYTES, WHICH LEADS TO IRREVERSIBLE DAMAGE TO THE LIVER PARENCHYMA. EPIGENETIC REGULATION PLAYS A KEY PART IN LIVER INFLAMMATION. THIS STUDY REVIEWS THE REGULATION OF EPIGENETICS ON STELLATE CELLS AND MACROPHAGES TO EXPLORE THE NEW MECHANISMS OF EPIGENETICS ON LIVER INFLAMMATION AND PROVIDE NEW IDEAS FOR THE TREATMENT OF LIVER DISEASE. 2021 20 3793 44 INTERLEUKIN-22 IN ALCOHOLIC HEPATITIS AND BEYOND. ALCOHOLIC HEPATITIS (AH) IS A CLINICAL SYNDROME CHARACTERIZED BY JAUNDICE AND PROGRESSIVE INFLAMMATORY LIVER INJURY IN PATIENTS WITH A HISTORY OF PROLONGED PERIODS OF EXCESS ALCOHOL CONSUMPTION AND RECENT HEAVY ALCOHOL ABUSE. SEVERE AH IS A LIFE-THREATENING FORM OF ALCOHOL-ASSOCIATED LIVER DISEASE WITH A HIGH SHORT-TERM MORTALITY RATE AROUND 30-50% AT ONE MONTH FROM THE INITIAL PRESENTATION. A LARGE NUMBER OF PRO-INFLAMMATORY MEDIATORS, METABOLIC PATHWAYS, TRANSCRIPTIONAL FACTORS AND EPIGENETIC FACTORS HAVE BEEN SUGGESTED TO BE ASSOCIATED WITH THE DEVELOPMENT AND PROGRESSION OF AH. SEVERAL FACTORS MAY CONTRIBUTE TO LIVER FAILURE AND MORTALITY IN PATIENTS WITH SEVERE AH INCLUDING HEPATOCYTE DEATH, INFLAMMATION, AND IMPAIRED LIVER REGENERATION. ALTHOUGH THE PATHOGENESES OF AH HAVE BEEN EXTENSIVELY INVESTIGATED AND MANY THERAPEUTIC TARGETS HAVE BEEN IDENTIFIED OVER THE LAST FIVE DECADES, NO NEW DRUGS FOR AH HAVE BEEN SUCCESSFULLY DEVELOPED. IN THIS REVIEW, WE DISCUSS INTERLEUKIN-22 (IL-22) BIOLOGY AND ITS ROLES OF ANTI-APOPTOSIS, ANTI-FIBROSIS, ANTI-OXIDATION, ANTI-BACTERIAL INFECTION AND REGENERATIVE STIMULATION IN PROTECTING AGAINST LIVER INJURY IN MANY PRECLINICAL MODELS INCLUDING SEVERAL RECENTLY DEVELOPED MODELS SUCH AS CHRONIC-PLUS-BINGE ETHANOL FEEDING, ACUTE-ON-CHRONIC LIVER FAILURE, C-X-C MOTIF CHEMOKINE LIGAND 1 PLUS HIGH-FAT DIET-INDUCED NONALCOHOLIC STEATOHEPATITIS. FINALLY, CLINICAL TRIALS OF IL-22 FOR THE TREATMENT OF AH ARE ALSO DISCUSSED, WHICH SHOWED SOME PROMISING BENEFITS FOR AH PATIENTS. 2020