1 320 135 ALCOHOLIC LIVER DISEASE: PATHOGENESIS AND NEW THERAPEUTIC TARGETS. ALCOHOLIC LIVER DISEASE (ALD) IS A MAJOR CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE AND CAN LEAD TO FIBROSIS AND CIRRHOSIS. THE LATEST SURVEILLANCE REPORT PUBLISHED BY THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM SHOWED THAT LIVER CIRRHOSIS WAS THE 12TH LEADING CAUSE OF DEATH IN THE UNITED STATES, WITH A TOTAL OF 29,925 DEATHS IN 2007, 48% OF WHICH WERE ALCOHOL RELATED. THE SPECTRUM OF ALD INCLUDES SIMPLE STEATOSIS, ALCOHOLIC HEPATITIS, FIBROSIS, CIRRHOSIS, AND SUPERIMPOSED HEPATOCELLULAR CARCINOMA. EARLY WORK ON THE PATHOGENESIS OF THE DISEASE FOCUSED ON ETHANOL METABOLISM-ASSOCIATED OXIDATIVE STRESS AND GLUTATHIONE DEPLETION, ABNORMAL METHIONINE METABOLISM, MALNUTRITION, AND PRODUCTION OF ENDOTOXINS THAT ACTIVATE KUPFFER CELLS. WE REVIEW FINDINGS FROM RECENT STUDIES THAT HAVE CHARACTERIZED SPECIFIC INTRACELLULAR SIGNALING PATHWAYS, TRANSCRIPTIONAL FACTORS, ASPECTS OF INNATE IMMUNITY, CHEMOKINES, EPIGENETIC FEATURES, MICRORNAS, AND STEM CELLS THAT ARE ASSOCIATED WITH ALD, IMPROVING OUR UNDERSTANDING OF ITS PATHOGENESIS. DESPITE THIS PROGRESS, NO TARGETED THERAPIES ARE AVAILABLE. THE CORNERSTONE OF TREATMENT FOR ALCOHOLIC HEPATITIS REMAINS AS IT WAS 40 YEARS AGO: ABSTINENCE, NUTRITIONAL SUPPORT, AND CORTICOSTEROIDS. THERE IS AN URGENT NEED TO DEVELOP NEW PATHOPHYSIOLOGY-ORIENTED THERAPIES. RECENT TRANSLATIONAL STUDIES OF HUMAN SAMPLES AND ANIMAL MODELS HAVE IDENTIFIED PROMISING THERAPEUTIC TARGETS. 2011 2 4659 75 NEW APPROACHES FOR STUDYING ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) IS MAJOR CAUSE OF CHRONIC LIVER INJURY WHICH RESULTS IN LIVER FIBROSIS AND CIRRHOSIS. ACCORDING TO THE SURVEILLANCE REPORT PUBLISHED BY THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM, LIVER CIRRHOSIS IS THE 12TH LEADING CAUSE OF DEATH IN THE UNITED STATES WITH 48 % OF THESE DEATHS BEING ATTRIBUTED TO EXCESSIVE ALCOHOL CONSUMPTION. ALD INCLUDES A SPECTRUM OF DISORDERS FROM SIMPLE STEATOSIS TO STEATOHEPATITIS, FIBROSIS, AND HEPATOCELLULAR CARCINOMA. SEVERAL MECHANISMS PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF ALD. THESE INCLUDE ETHANOL-INDUCED OXIDATIVE STRESS AND DEPLETION OF GLUTATHIONE, PATHOLOGICAL METHIONINE METABOLISM, INCREASED GUT PERMEABILITY AND RELEASE OF ENDOTOXINS INTO THE PORTAL BLOOD, RECRUITMENT AND ACTIVATION OF INFLAMMATORY CELLS INCLUDING BONE MARROW-DERIVED AND LIVER RESIDENT MACROPHAGES (KUPFFER CELLS). CHRONIC ALCOHOL CONSUMPTION RESULTS IN LIVER DAMAGE AND ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) AND MYOFIBROBLASTS, LEADING TO LIVER FIBROSIS. HERE WE DISCUSS THE CURRENT VIEW ON FACTORS THAT ARE SPECIFIC FOR DIFFERENT STAGES OF ALD AND THOSE THAT REGULATE ITS PROGRESSION, INCLUDING CYTOKINES AND CHEMOKINES, ALCOHOL-RESPONSIVE INTRACELLULAR SIGNALING PATHWAYS, AND TRANSCRIPTIONAL FACTORS. WE ALSO REVIEW RECENT STUDIES DEMONSTRATING THAT ALCOHOL-MEDIATED CHANGES CAN BE REGULATED ON AN EPIGENETIC LEVEL, INCLUDING MICRORNAS. FINALLY, WE DISCUSS THE REVERSIBILITY OF LIVER FIBROSIS AND INACTIVATION OF HSCS AS A POTENTIAL STRATEGY FOR TREATING ALCOHOL-INDUCED LIVER DAMAGE. 2014 3 321 51 ALCOHOLIC-RELATED LIVER DISEASE: PATHOGENESIS, MANAGEMENT AND FUTURE THERAPEUTIC DEVELOPMENTS. ALCOHOL-RELATED LIVER DISEASE (ALD) IS THE MOST FREQUENT CAUSE OF ADVANCED CHRONIC LIVER DISEASE WORLDWIDE. EXCESSIVE AND PROLONGED ALCOHOL USE LEADS TO ALD, WHICH RANGES FROM EARLY FORMS SUCH AS ALCOHOLIC FATTY LIVER (AFL) AND ALCOHOLIC STEATOHEPATITIS (ASH), THROUGH PROGRESSIVE FIBROSIS TO CIRRHOSIS AND THE DEVELOPMENT OF HEPATOCELLULAR CANCER (HCC). IN ADDITION, PATIENTS WITH UNDERLYING ALD AND CONTINUOUS ALCOHOL USE CAN DEVELOP ALCOHOLIC HEPATITIS (AH), WHICH PRESENTS A RAPID PROGRESSION OF LIVER FAILURE AND HAS A HIGH SHORT-TERM MORTALITY. GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS INFLUENCE THE PROGRESSION OF ALD TO MORE SEVERE FORMS. THE PATHOGENESIS OF ALD IS COMPLEX AND INVOLVES MULTIPLE PATHWAYS. RECENT TRANSLATIONAL STUDIES HAVE DEMONSTRATED A KEY ROLE OF THE GUT-LIVER AXIS AND INNATE IMMUNITY IN HEPATOCELLULAR DAMAGE AND FIBROSIS. IN SEVERE FORMS, HEPATOCELLULAR DE-DIFFERENTIATION AND SYSTEMIC INFLAMMATION CONTRIBUTE TO LIVER FAILURE AND MULTIORGAN FAILURE. ALCOHOL ABSTINENCE IS THE CORNERSTONE OF THERAPY FOR ALD AND THE PREVENTION OF ITS COMPLICATIONS, BUT THE EFFICACY AND ACCESSIBILITY OF PSYCHO-FAMILIAL-SOCIAL INTERVENTIONS IS STILL POOR AND EFFECTIVE PUBLIC HEALTH POLICIES TO LIMIT PROBLEMATIC ALCOHOL USE NEED TO BE IMPLEMENTED. PREDNISOLONE IS THE ONLY CURRENT OPTION FOR AH, WITH A TRANSIENT BENEFICIAL EFFECT OVER PLACEBO. FOR PATIENTS WITH DECOMPENSATED ALD-CIRRHOSIS AND/OR DEVELOPMENT OF HCC, LIVER TRANSPLANTATION (LT) MAY BE REQUIRED. IN RECENT YEARS, EARLY LT IS BEING INCREASINGLY OFFERED TO CAREFULLY SELECTED AH PATIENTS, WITH EXCELLENT LONG-TERM SURVIVAL. NEW TRIALS OF AH TREATMENTS ARE CURRENTLY ONGOING, AND TRANSLATIONAL STUDIES IN HUMAN SAMPLES ARE PAVING THE WAY TO NEW PROMISING TARGETED THERAPIES. 2020 4 5772 50 SPECTRUM, SCREENING, AND DIAGNOSIS OF ALCOHOL-RELATED LIVER DISEASE. ALCOHOL-RELATED LIVER DISEASE (ALD) REPRESENTS ONE OF THE LEADING CAUSES OF CHRONIC LIVER DISEASE AND IS A MAJOR CAUSE OF LIVER-RELATED DEATHS WORLDWIDE. ALD ENCOMPASSES A RANGE OF DISORDERS INCLUDING SIMPLE STEATOSIS, ALCOHOLIC STEATOHEPATITIS, FIBROSIS, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. PATIENTS WITH UNDERLYING ALD AND CONTINUED HEAVY ALCOHOL CONSUMPTION CAN ALSO DEVELOP AN EPISODE OF ACUTE-ON-CHRONIC LIVER INJURY CALLED ALCOHOL-ASSOCIATED HEPATITIS, THE MOST SEVERE FORM OF THE DISEASE, WHICH PORTENDS A POOR PROGNOSIS. THE MOST IMPORTANT RISK FACTOR FOR THE DEVELOPMENT OF ALD IS THE AMOUNT OF ALCOHOL CONSUMED. INDIVIDUAL SUSCEPTIBILITY TO PROGRESSION TO ADVANCED FIBROSIS AMONG HEAVY DRINKERS IS LIKELY DETERMINED BY A COMBINATION OF BEHAVIORAL, ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS, BUT THE MECHANISMS ARE LARGELY UNKNOWN. THE ONLY EFFECTIVE THERAPY FOR ALD IS PROLONGED ALCOHOL ABSTINENCE. DIAGNOSIS OF ALD INVOLVES ASSESSING PATIENTS FOR ALCOHOL USE DISORDER AND SIGNS OF ADVANCED LIVER DISEASE. IN CLINICAL PRACTICE, THE HISTOLOGICAL ASSESSMENT FOR ALD DIAGNOSIS IS UNCOMMON, AND IT IS USUALLY BASED ON THE MEDICAL HISTORY, CLINICAL MANIFESTATIONS, AND LABORATORY AND IMAGING TESTS. SEVERAL PROMISING BIOMARKERS THAT CAN HAVE BOTH DIAGNOSTIC AND PROGNOSTIC VALUE IN PATIENTS WITH ALD HAVE BEEN IDENTIFIED IN RECENT YEARS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CLINICAL SPECTRUM OF ALD, THE DIAGNOSTIC APPROACH OF THE DISEASE FROM DIFFERENT PERSPECTIVES AS WELL AS CURRENT DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. 2023 5 2691 25 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 6 319 46 ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) IS THE MOST PREVALENT TYPE OF CHRONIC LIVER DISEASE WORLDWIDE. ALD CAN PROGRESS FROM ALCOHOLIC FATTY LIVER (AFL) TO ALCOHOLIC STEATOHEPATITIS (ASH), WHICH IS CHARACTERIZED BY HEPATIC INFLAMMATION. CHRONIC ASH CAN EVENTUALLY LEAD TO FIBROSIS AND CIRRHOSIS AND IN SOME CASES HEPATOCELLULAR CANCER (HCC). IN ADDITION, SEVERE ASH (WITH OR WITHOUT CIRRHOSIS) CAN LEAD TO ALCOHOLIC HEPATITIS, WHICH IS AN ACUTE CLINICAL PRESENTATION OF ALD THAT IS ASSOCIATED WITH LIVER FAILURE AND HIGH MORTALITY. MOST INDIVIDUALS CONSUMING >40 G OF ALCOHOL PER DAY DEVELOP AFL; HOWEVER, ONLY A SUBSET OF INDIVIDUALS WILL DEVELOP MORE ADVANCED DISEASE. GENETIC, EPIGENETIC AND NON-GENETIC FACTORS MIGHT EXPLAIN THE CONSIDERABLE INTERINDIVIDUAL VARIATION IN ALD PHENOTYPE. THE PATHOGENESIS OF ALD INCLUDES HEPATIC STEATOSIS, OXIDATIVE STRESS, ACETALDEHYDE-MEDIATED TOXICITY AND CYTOKINE AND CHEMOKINE-INDUCED INFLAMMATION. DIAGNOSIS OF ALD INVOLVES ASSESSING PATIENTS FOR ALCOHOL USE DISORDER AND SIGNS OF ADVANCED LIVER DISEASE. THE DEGREE OF AFL AND LIVER FIBROSIS CAN BE DETERMINED BY ULTRASONOGRAPHY, TRANSIENT ELASTOGRAPHY, MRI, MEASUREMENT OF SERUM BIOMARKERS AND LIVER BIOPSY HISTOLOGY. ALCOHOL ABSTINENCE ACHIEVED BY PSYCHOSOMATIC INTERVENTION IS THE BEST TREATMENT FOR ALL STAGES OF ALD. IN THE CASE OF ADVANCED DISEASE SUCH AS CIRRHOSIS OR HCC, LIVER TRANSPLANTATION MAY BE REQUIRED. THUS, NEW THERAPIES ARE URGENTLY NEEDED. 2018 7 4045 35 MACROPHAGES IN THE AGING LIVER AND AGE-RELATED LIVER DISEASE. THE NUMBER OF INDIVIDUALS AGED 65 OR OLDER IS PROJECTED TO INCREASE GLOBALLY FROM 524 MILLION IN 2010 TO NEARLY 1. 5 BILLION IN 2050. AGED INDIVIDUALS ARE PARTICULARLY AT RISK FOR DEVELOPING CHRONIC ILLNESS, WHILE BEING LESS ABLE TO REGENERATE HEALTHY TISSUE AND TOLERATE WHOLE ORGAN TRANSPLANTATION PROCEDURES. IN THE LIVER, THESE AGE-RELATED DISEASES INCLUDE NON-ALCOHOLIC FATTY LIVER DISEASE, ALCOHOLIC LIVER DISEASE, HEPATITIS, FIBROSIS, AND CIRRHOSIS. HEPATIC MACROPHAGES, A POPULATION COMPRISED OF BOTH KUPFFER CELLS AND INFILTRATING MONOCYTE DERIVED MACROPHAGES, ARE IMPLICATED IN SEVERAL CHRONIC LIVER DISEASES AND ALSO PLAY IMPORTANT ROLES IN THE HOMEOSTATIC FUNCTIONS OF THE LIVER. THE EFFECTS OF AGING ON HEPATIC MACROPHAGE POPULATION DYNAMICS, POLARIZATION, AND FUNCTION ARE NOT WELL UNDERSTOOD. STUDIES PERFORMED ON MACROPHAGES DERIVED FROM OTHER AGED SOURCES, SUCH AS THE BONE MARROW, PERITONEAL CAVITY, LUNGS, AND BRAIN, DEMONSTRATE GENERAL REDUCTIONS IN AUTOPHAGY AND PHAGOCYTOSIS, DYSFUNCTION IN CYTOKINE SIGNALING, AND ALTERED MORPHOLOGY AND DISTRIBUTION, LIKELY MEDIATED BY EPIGENETIC CHANGES AND MITOCHONDRIAL DEFECTS, THAT MAY BE APPLICABLE TO HEPATIC MACROPHAGES. THIS REVIEW HIGHLIGHTS RECENT FINDINGS IN MACROPHAGE DEVELOPMENTAL BIOLOGY AND FUNCTION, PARTICULARLY IN THE LIVER, AND DISCUSSES THE ROLE OF MACROPHAGES IN VARIOUS AGE-RELATED LIVER DISEASES. A BETTER UNDERSTANDING OF THE BIOLOGY OF AGING THAT INFLUENCES HEPATIC MACROPHAGES AND THUS THE PROGRESSION OF CHRONIC LIVER DISEASE WILL BE CRUCIAL IN ORDER TO DEVELOP NEW INTERVENTIONS AND TREATMENTS FOR LIVER DISEASE IN AGING POPULATIONS. 2018 8 2544 31 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 9 3621 38 IN VIVO AND IN VITRO MODELS OF HEPATOCELLULAR CARCINOMA: CURRENT STRATEGIES FOR TRANSLATIONAL MODELING. HEPATOCELLULAR CARCINOMA (HCC) IS THE SIXTH MOST COMMON CANCER WORLDWIDE AND THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH GLOBALLY. HCC IS A COMPLEX MULTISTEP DISEASE AND USUALLY EMERGES IN THE SETTING OF CHRONIC LIVER DISEASES. THE MOLECULAR PATHOGENESIS OF HCC VARIES ACCORDING TO THE ETIOLOGY, MAINLY CAUSED BY CHRONIC HEPATITIS B AND C VIRUS INFECTIONS, CHRONIC ALCOHOL CONSUMPTION, AFLATOXIN-CONTAMINATED FOOD, AND NON-ALCOHOLIC FATTY LIVER DISEASE ASSOCIATED WITH METABOLIC SYNDROME OR DIABETES MELLITUS. THE ESTABLISHMENT OF HCC MODELS HAS BECOME ESSENTIAL FOR BOTH BASIC AND TRANSLATIONAL RESEARCH TO IMPROVE OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY AND UNRAVEL NEW MOLECULAR DRIVERS OF THIS DISEASE. THE IDEAL MODEL SHOULD RECAPITULATE KEY EVENTS OBSERVED DURING HEPATOCARCINOGENESIS AND HCC PROGRESSION IN VIEW OF ESTABLISHING EFFECTIVE DIAGNOSTIC AND THERAPEUTIC STRATEGIES TO BE TRANSLATED INTO CLINICAL PRACTICE. DESPITE CONSIDERABLE EFFORTS CURRENTLY DEVOTED TO LIVER CANCER RESEARCH, ONLY A FEW ANTI-HCC DRUGS ARE AVAILABLE, AND PATIENT PROGNOSIS AND SURVIVAL ARE STILL POOR. THE PRESENT PAPER PROVIDES A STATE-OF-THE-ART OVERVIEW OF IN VIVO AND IN VITRO MODELS USED FOR TRANSLATIONAL MODELING OF HCC WITH A SPECIFIC FOCUS ON THEIR KEY MOLECULAR HALLMARKS. 2021 10 3793 48 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 11 4104 33 MECHANISM AND THERAPEUTIC OPPORTUNITIES OF HISTONE MODIFICATIONS IN CHRONIC LIVER DISEASE. CHRONIC LIVER DISEASE (CLD) REPRESENTS A GLOBAL HEALTH PROBLEM, ACCOUNTING FOR THE HEAVY BURDEN OF DISABILITY AND INCREASED HEALTH CARE UTILIZATION. EPIGENOME ALTERATIONS PLAY AN IMPORTANT ROLE IN THE OCCURRENCE AND PROGRESSION OF CLD. HISTONE MODIFICATIONS, WHICH INCLUDE ACETYLATION, METHYLATION, AND PHOSPHORYLATION, REPRESENT AN ESSENTIAL PART OF EPIGENETIC MODIFICATIONS THAT AFFECT THE TRANSCRIPTIONAL ACTIVITY OF GENES. DIFFERENT FROM GENETIC MUTATIONS, HISTONE MODIFICATIONS ARE PLASTIC AND REVERSIBLE. THEY CAN BE MODULATED PHARMACOLOGICALLY WITHOUT CHANGING THE DNA SEQUENCE. THUS, THERE MIGHT BE CHANCES TO ESTABLISH INTERVENTIONAL SOLUTIONS BY TARGETING HISTONE MODIFICATIONS TO REVERSE CLD. HERE WE SUMMARIZED THE ROLES OF HISTONE MODIFICATIONS IN THE CONTEXT OF ALCOHOLIC LIVER DISEASE (ALD), METABOLIC ASSOCIATED FATTY LIVER DISEASE (MAFLD), VIRAL HEPATITIS, AUTOIMMUNE LIVER DISEASE, DRUG-INDUCED LIVER INJURY (DILI), AND LIVER FIBROSIS OR CIRRHOSIS. THE POTENTIAL TARGETS OF HISTONE MODIFICATIONS FOR TRANSLATION INTO THERAPEUTICS WERE ALSO INVESTIGATED. IN PROSPECT, HIGH EFFICACY AND LOW TOXICITY DRUGS THAT ARE SELECTIVELY TARGETING HISTONE MODIFICATIONS ARE REQUIRED TO COMPLETELY REVERSE CLD AND PREVENT THE DEVELOPMENT OF LIVER CIRRHOSIS AND MALIGNANCY. 2021 12 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 13 2954 38 GENETIC AND EPIGENETIC FACTORS DETERMINING NAFLD RISK. BACKGROUND: HEPATIC STEATOSIS IS A COMMON CHRONIC LIVER DISEASE THAT CAN PROGRESS INTO MORE SEVERE STAGES OF NAFLD OR PROMOTE THE DEVELOPMENT OF LIFE-THREATENING SECONDARY DISEASES FOR SOME OF THOSE AFFECTED. THESE INCLUDE THE LIVER ITSELF (NONALCOHOLIC STEATOHEPATITIS OR NASH; FIBROSIS AND CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA) OR OTHER ORGANS SUCH AS THE VESSELS AND THE HEART (CARDIOVASCULAR DISEASE) OR THE ISLETS OF LANGERHANS (TYPE 2 DIABETES). IN ADDITION TO ELEVATED CALORIC INTAKE AND A SEDENTARY LIFESTYLE, GENETIC AND EPIGENETIC PREDISPOSITION CONTRIBUTE TO THE DEVELOPMENT OF NAFLD AND THE SECONDARY DISEASES. SCOPE OF REVIEW: WE PRESENT DATA FROM GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND FUNCTIONAL STUDIES IN RODENTS WHICH DESCRIBE POLYMORPHISMS IDENTIFIED IN GENES RELEVANT FOR THE DISEASE AS WELL AS CHANGES CAUSED BY ALTERED DNA METHYLATION AND GENE REGULATION VIA SPECIFIC MIRNAS. THE REVIEW ALSO PROVIDES INFORMATION ON THE CURRENT STATUS OF THE USE OF GENETIC AND EPIGENETIC FACTORS AS RISK MARKERS. MAJOR CONCLUSION: WITH OUR OVERVIEW WE PROVIDE AN INSIGHT INTO THE GENETIC AND EPIGENETIC LANDSCAPE OF NAFLD AND ARGUE ABOUT THE APPLICABILITY OF CURRENTLY DEFINED RISK SCORES FOR RISK STRATIFICATION AND CONCLUDE THAT FURTHER EFFORTS ARE NEEDED TO MAKE THE SCORES MORE USABLE AND MEANINGFUL. 2021 14 309 36 ALCOHOL AND HEPATOCELLULAR CARCINOMA: ADDING FUEL TO THE FLAME. PRIMARY TUMORS OF THE LIVER REPRESENT THE FIFTH MOST COMMON TYPE OF CANCER IN THE WORLD AND THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH. CASE-CONTROL STUDIES FROM DIFFERENT COUNTRIES REPORT THAT CHRONIC ETHANOL CONSUMPTION IS ASSOCIATED WITH AN APPROXIMATELY 2-FOLD INCREASED ODDS RATIO FOR HEPATOCELLULAR CARCINOMA (HCC). DESPITE THE SUBSTANTIAL EPIDEMIOLOGIC DATA IN HUMANS DEMONSTRATING THAT CHRONIC ALCOHOL CONSUMPTION IS A MAJOR RISK FACTOR FOR HCC DEVELOPMENT, THE PATHWAYS CAUSING ALCOHOL-INDUCED LIVER CANCER ARE POORLY UNDERSTOOD. IN THIS OVERVIEW, WE SUMMARIZE THE EPIDEMIOLOGICAL EVIDENCE FOR THE ASSOCIATION BETWEEN ALCOHOL AND LIVER CANCER, REVIEW THE GENETIC, ONCOGENIC, AND EPIGENETIC FACTORS THAT DRIVE HCC DEVELOPMENT SYNERGISTICALLY WITH ETHANOL INTAKE AND DISCUSS THE ESSENTIAL MOLECULAR AND METABOLIC PATHWAYS INVOLVED IN ALCOHOL-INDUCED LIVER TUMORIGENESIS. 2017 15 6092 36 THE EFFECTS OF EPIGENETIC MODIFICATION ON THE OCCURRENCE AND PROGRESSION OF LIVER DISEASES AND THE INVOLVED MECHANISM. INTRODUCTION: EPIGENETIC MODIFICATION IS A TYPE OF GENE EXPRESSION AND REGULATION THAT DOES NOT INVOLVE CHANGES IN DNA SEQUENCES. AN INCREASING NUMBER OF STUDIES HAVE PROVEN THAT EPIGENETIC MODIFICATIONS PLAY AN IMPORTANT ROLE IN THE OCCURRENCE AND PROGRESSION OF LIVER DISEASES THROUGH THE GENE REGULATION AND PROTEIN EXPRESSIONS OF HEPATOCELLULAR LIPID METABOLISM, INFLAMMATORY REACTION, CELL PROLIFERATION, AND ACTIVATION, ETC.AREAS COVERED: IN THIS STUDY, WE ELABORATED AND ANALYZED THE UNDERLYING FUNCTIONAL MECHANISM OF EPIGENETIC MODIFICATION IN ALCOHOLIC LIVER DISEASE (ALD), NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), LIVER FIBROSIS (LF), VIRAL HEPATITIS, HEPATOCELLULAR CARCINOMA (HCC), AND RESEARCH PROGRESS OF RECENT YEARS.EXPERT OPINION: THE FURTHER UNDERSTANDING OF EPIGENETIC MECHANISMS THAT CAN REGULATE GENE EXPRESSION AND CELL PHENOTYPE LEADS TO NEW INSIGHTS IN EPIGENETIC CONTROL OF CHRONIC LIVER DISEASE. CURRENTLY, HEPATOLOGISTS ARE EXPLORING THE ROLE OF DNA METHYLATION, HISTONE/CHROMATIN MODIFICATION, AND NON-CODING RNA IN SPECIFIC LIVER PATHOLOGY. THESE FINDINGS HAVE LED TO ADVANCES IN DIRECT EPIGENETIC BIOMARKER TESTING OF PATIENT TISSUE OR BODY FLUID SPECIMENS, AS WELL AS QUANTITATIVE ANALYSIS. BASED ON THESE FINDINGS, DRUG VALIDATION OF SOME TARGETS INVOLVED IN THE EPIGENETIC MECHANISM OF LIVER DISEASE IS GRADUALLY BEING CARRIED OUT CLINICALLY. 2020 16 6913 31 [VARIOUS PATHWAYS LEADING TO THE PROGRESSION OF CHRONIC LIVER DISEASES]. AS THE RESULT OF VARIOUS EFFECTS (VIRUSES, METABOLIC DISEASES, NUTRITIONAL FACTORS, TOXIC AGENTS, AUTOIMMUNE PROCESSES) ABNORMAL LIVER FUNCTION, LIVER STEATOSIS AND CONNECTIVE TISSUE REMODELING MAY DEVELOP. PROGRESSION OF THIS PROCESS IS COMPLEX INCLUDING VARIOUS PATHWAYS AND A NUMBER OF FACTORS. THE AUTHORS SUMMARIZE THE FACTORS INVOLVED IN THE PROGRESSION OF CHRONIC LIVER DISEASE. THEY DESCRIBE THE ROLE OF CELLS AND THE PRODUCED INFLAMMATORY MEDIATORS AND CYTOKINES, AS WELL AS THE RELATIONSHIP BETWEEN THE DISEASE AND THE INTESTINAL FLORA. THEY EMPHASIZE THE ROLE OF OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION AND CELL DEATH IN DISEASE PROGRESSION. INSULIN RESISTANCE AND MICRO-ELEMENTS (IRON, COPPER) IN RELATION TO LIVER DAMAGE ARE ALSO DISCUSSED, AND GENETIC AND EPIGENETIC ASPECTS UNDERLYING DISEASE PROGRESSION ARE SUMMARIZED. DISCOVERY OF NOVEL TREATMENT OPTIONS, ASSESSMENT OF THE EFFECTIVENESS OF TREATMENT, AS WELL AS THE SUCCESS AND PROPER TIMING OF LIVER TRANSPLANTATION MAY DEPEND ON A BETTER UNDERSTANDING OF THE PROCESS OF DISEASE PROGRESSION. 2016 17 4705 38 NLRP3: A NEW THERAPEUTIC TARGET IN ALCOHOLIC LIVER DISEASE. THE LIVER IS IN CHARGE OF A WIDE RANGE OF CRITICAL PHYSIOLOGICAL PROCESSES AND IT PLAYS AN IMPORTANT ROLE IN ACTIVATING THE INNATE IMMUNE SYSTEM WHICH ELICITS THE INFLAMMATORY EVENTS. CHRONIC ETHANOL EXPOSURE DISRUPTS HEPATIC INFLAMMATORY MECHANISM AND LEADS TO THE RELEASE OF PROINFLAMMATORY MEDIATORS SUCH AS CHEMOKINES, CYTOKINES AND ACTIVATION OF INFLAMMASOMES. THE MECHANISM OF LIVER FIBROSIS/CIRRHOSIS INVOLVE ACTIVATION OF NLRP3 INFLAMMASOME, LEADING TO THE DESTRUCTION OF HEPATOCYTES AND SUBSEQUENT METABOLIC DYSREGULATION IN HUMANS. IN ADDITION, INCREASING EVIDENCE SUGGESTS THAT ALCOHOL INTAKE SIGNIFICANTLY MODIFIES LIVER EPIGENETICS, PROMOTING THE DEVELOPMENT OF ALCOHOLIC LIVER DISEASE (ALD). EPIGENETIC CHANGES INCLUDING HISTONE MODIFICATION, MICRORNA-INDUCED GENETIC MODULATION, AND DNA METHYLATION ARE CRUCIAL IN ALCOHOL-EVOKED CELL SIGNALING THAT AFFECTS GENE EXPRESSION IN THE HEPATIC SYSTEM. THOUGH WE ARE AT THE BEGINNING STAGE WITHOUT HAVING THE ENTIRE PRINT OF EPIGENETIC SIGNATURE, IT IS TIME TO FOCUS MORE ON NLRP3 INFLAMMASOME AND EPIGENETIC MODIFICATIONS. HERE WE REVIEW THE NOVEL ASPECT OF ALD PATHOLOGY LINKING TO INFLAMMATION AND HIGHLIGHTING THE ROLE OF EPIGENETIC MODIFICATION ASSOCIATED WITH NLRP3 INFLAMMASOME AND HOW IT COULD BE A THERAPEUTIC TARGET IN ALD. 2023 18 5805 46 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 19 4043 29 MACROPHAGES IN CHRONIC LIVER FAILURE: DIVERSITY, PLASTICITY AND THERAPEUTIC TARGETING. CHRONIC LIVER INJURY RESULTS IN IMMUNE-DRIVEN PROGRESSIVE FIBROSIS, WITH RISK OF CIRRHOSIS DEVELOPMENT AND IMPACT ON MORBIDITY AND MORTALITY. PERSISTENT LIVER CELL DAMAGE AND DEATH CAUSES IMMUNE CELL ACTIVATION AND INFLAMMATION. PATIENTS WITH ADVANCED CIRRHOSIS ADDITIONALLY EXPERIENCE PATHOLOGICAL BACTERIAL TRANSLOCATION, EXPOSURE TO MICROBIAL PRODUCTS AND CHRONIC ENGAGEMENT OF THE IMMUNE SYSTEM. BACTERIAL INFECTIONS HAVE A HIGH INCIDENCE IN CIRRHOSIS, WITH SPONTANEOUS BACTERIAL PERITONITIS BEING THE MOST COMMON, WHILE THE SUBSEQUENT SYSTEMIC INFLAMMATION, ORGAN FAILURE AND IMMUNE DYSREGULATION INCREASE THE MORTALITY RISK. TISSUE-RESIDENT AND RECRUITED MACROPHAGES PLAY A CENTRAL PART IN THE DEVELOPMENT OF INFLAMMATION AND FIBROSIS PROGRESSION. IN THE LIVER, ADIPOSE TISSUE, PERITONEUM AND INTESTINES, DIVERSE MACROPHAGE POPULATIONS EXHIBIT GREAT PHENOTYPIC AND FUNCTIONAL PLASTICITY DETERMINED BY THEIR ONTOGENY, EPIGENETIC PROGRAMMING AND LOCAL MICROENVIRONMENT. THESE CHANGES CAN, AT DIFFERENT TIMES, PROMOTE OR AMELIORATE DISEASE STATES AND THEREFORE REPRESENT POTENTIAL TARGETS FOR MACROPHAGE-DIRECTED THERAPIES. IN THIS REVIEW, WE DISCUSS THE EVIDENCE FOR MACROPHAGE PHENOTYPIC AND FUNCTIONAL ALTERATIONS IN TISSUE COMPARTMENTS DURING THE DEVELOPMENT AND PROGRESSION OF CHRONIC LIVER FAILURE IN DIFFERENT AETIOLOGIES AND HIGHLIGHT THE POTENTIAL OF MACROPHAGE MODULATION AS A THERAPEUTIC STRATEGY FOR LIVER DISEASE. 2021 20 2104 35 EPIGENETIC EVENTS IN LIVER CANCER RESULTING FROM ALCOHOLIC LIVER DISEASE. EPIGENETIC MECHANISMS PLAY AN EXTENSIVE ROLE IN THE DEVELOPMENT OF LIVER CANCER (I.E., HEPATOCELLULAR CARCINOMA [HCC]) ASSOCIATED WITH ALCOHOLIC LIVER DISEASE (ALD) AS WELL AS IN LIVER DISEASE ASSOCIATED WITH OTHER CONDITIONS. FOR EXAMPLE, EPIGENETIC MECHANISMS, SUCH AS CHANGES IN THE METHYLATION AND/OR ACETYLATION PATTERN OF CERTAIN DNA REGIONS OR OF THE HISTONE PROTEINS AROUND WHICH THE DNA IS WRAPPED, CONTRIBUTE TO THE REVERSION OF NORMAL LIVER CELLS INTO PROGENITOR AND STEM CELLS THAT CAN DEVELOP INTO HCC. CHRONIC EXPOSURE TO BEVERAGE ALCOHOL (I.E., ETHANOL) CAN INDUCE ALL OF THESE EPIGENETIC CHANGES. THUS, ETHANOL METABOLISM RESULTS IN THE FORMATION OF COMPOUNDS THAT CAN CAUSE CHANGES IN DNA METHYLATION AND INTERFERE WITH OTHER COMPONENTS OF THE NORMAL PROCESSES REGULATING DNA METHYLATION. ALCOHOL EXPOSURE ALSO CAN ALTER HISTONE ACETYLATION/DEACETYLATION AND METHYLATION PATTERNS THROUGH A VARIETY OF MECHANISMS AND SIGNALING PATHWAYS. ALCOHOL ALSO ACTS INDIRECTLY ON ANOTHER MOLECULE CALLED TOLL-LIKE RECEPTOR 4 (TLR4) THAT IS A KEY COMPONENT IN A CRUCIAL REGULATORY PATHWAY IN THE CELLS AND WHOSE DYSREGULATION IS INVOLVED IN THE DEVELOPMENT OF HCC. FINALLY, ALCOHOL USE REGULATES AN EPIGENETIC MECHANISM INVOLVING SMALL MOLECULES CALLED MIRNAS THAT CONTROL TRANSCRIPTIONAL EVENTS AND THE EXPRESSION OF GENES IMPORTANT TO ALD. 2013