1 3932 70 LIVER REGENERATION, LIVER CANCERS AND CYCLINS. ACCUMULATING EVIDENCE HAS REVEALED THAT MALIGNANT CELL GROWTH IS REGULATED BY COMPLEX MECHANISMS INVOLVED IN GENETIC AND EPIGENETIC FACTORS. AMONG HUMAN CANCERS, CANCER IN THE LIVER (HEPATOCELLULAR CARCINOMA (HCC)) IS CHARACTERIZED BY THE EVIDENCE THAT IT IS USUALLY BASED ON CHRONIC LIVER DISEASES SUCH AS LIVER CIRRHOSIS OR CHRONIC HEPATITIS, IN WHICH THE LIVER IS PERSISTENTLY REGENERATING FOLLOWING HEPATIC INJURY. THIS RAISES THE POSSIBILITY THAT REPEATED HEPATOCYTE PROLIFERATION MAY CAUSE DISORDER OF GENES THAT ARE REGULATING THE CELL CYCLE IN HEPATOCYTES, THUS CAUSING HCC. IN THIS ARTICLE, RECENT STUDIES FOCUSING ON LIVER REGENERATION AND CANCER ARE REVIEWED FROM THE VIEWPOINT OF THE CELL CYCLE THAT IS REGULATED BY CYCLIN AND THE ASSOCIATED PROTEINS. 1998 2 2323 20 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 3 4613 29 NEOVASCULARIZATION IS A KEY FEATURE OF LIVER FIBROSIS PROGRESSION: ANTI-ANGIOGENESIS AS AN INNOVATIVE WAY OF LIVER FIBROSIS TREATMENT. LIVER FIBROSIS AFFECTS OVER 100 MILLION PEOPLE IN THE WORLD; IT REPRESENTS A MULTIFACTORIAL, FIBRO-INFLAMMATORY DISORDER CHARACTERIZED BY EXACERBATED PRODUCTION OF EXTRACELLULAR MATRIX WITH CONSEQUENT ABERRATION OF HEPATIC TISSUE. THE AETIOLOGY OF THIS DISEASE IS VERY COMPLEX AND SEEMS TO INVOLVE A BROAD SPECTRUM OF FACTORS INCLUDING THE LIFESTYLE, ENVIRONMENT FACTORS, GENES AND EPIGENETIC CHANGES. MORE EVIDENCES INDICATE THAT ANGIOGENESIS, A PROCESS CONSISTING IN THE FORMATION OF NEW BLOOD VESSELS FROM PRE-EXISTING VESSELS, PLAYS A CRUCIAL ROLE IN THE PROGRESSION OF LIVER FIBROSIS. CENTRAL TO THE PATHOGENESIS OF LIVER FIBROSIS IS THE HEPATIC STELLATE CELLS (HSCS) WHICH REPRESENT A CROSSROAD AMONG INFLAMMATION, FIBROSIS AND ANGIOGENESIS. QUIESCENT HSCS CAN BE STIMULATED BY A HOST OF GROWTH FACTORS, PRO-INFLAMMATORY MEDIATORS PRODUCED BY DAMAGED RESIDENT LIVER CELL TYPES, AS WELL AS BY HYPOXIA, CONTRIBUTING TO NEOANGIOGENESIS, WHICH IN TURN CAN BE A BRIDGE BETWEEN ACUTE AND CHRONIC INFLAMMATION. AS MATTER OF FACT, STUDIES DEMONSTRATED THAT NEUTRALIZATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR AS WELL AS OTHER PROANGIOGENIC AGENTS CAN ATTENUATE THE PROGRESSION OF LIVER FIBROSIS. WITH THIS REVIEW, OUR INTENT IS TO DISCUSS THE CAUSE AND THE ROLE OF ANGIOGENESIS IN LIVER FIBROSIS FOCUSING ON THE CURRENT KNOWLEDGE ABOUT THE IMPACT OF ANTI-ANGIOGENETIC THERAPIES IN THIS PATHOLOGY. 2020 4 6913 19 [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 5 6797 31 [EPIDEMIOLOGY, NATURAL HISTORY AND PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS THE MAIN TYPE OF PRIMARY LIVER CANCERS AND THE THIRD MOST COMMON CAUSE OF CANCER MORTALITY WORLDWIDE. IN FRANCE, RISING NUMBER BETWEEN 5000 AND 6000 CASES ARE DIAGNOSED EACH YEAR. THE MAJOR RISK FACTOR FOR HEPATOCELLULAR CARCINOMA IS CHRONIC HEPATITIS: VIRAL HEPATITIS B, VIRAL HEPATITIS C, CONSUMPTION OF ALCOHOL, HEMOCHROMATOSIS. HEPATOCELLULAR CARCINOMA IS CLOSELY ASSOCIATED TO LIVER CIRRHOSIS, WHICH IS A TRUE PRECANCEROUS STATE. BECAUSE HEPATOCARCINOGENESIS IS A LONG AND HETEROGENEOUS PROCESS, THERE IS STILL MUCH TO UNDERSTAND. MANY GENETIC AND EPIGENETIC ALTERATIONS ARE DESCRIBED LEADING TO CHANGES IN CELLULAR SIGNALLING CASCADES INVOLVED IN REGULATION OF GROWTH, DIFFERENTIATION, APOPTOSIS, MOTILITY. HEPATITIS VIRUSES PLAY A DIRECT ONCOGENIC ROLE THROUGH THE INTERACTION BETWEEN VIRAL AND CELLULAR PROTEINS, WHICH CONTROL CELL HOMEOSTASIS, OR BY THE INTEGRATION OF HEPATITIS B VIRUS GENOME INTO THE HOST GENOME. FURTHERMORE, HEPATITIS VIRUSES PLAY AN INDIRECT ONCOGENIC ROLE BY CAUSING CHRONIC INFLAMMATION AND HEPATOCYTE REGENERATION RELATED TO VIRAL HEPATOPATHY. IN EXPECTATION OF A BETTER UNDERSTANDING OF HEPATOCARCINOGENESIS AND NEW TREATMENTS, PREVENTION FROM RISK FACTORS AND ULTRASONOGRAPHIC SCREENING OF PATIENTS WITH CIRRHOSIS SHOULD INCREASE PROGNOSIS. 2011 6 2502 21 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 7 3672 15 INFLAMMATION AND CANCER: AN ANCIENT LINK WITH NOVEL POTENTIALS. INFECTION AND CHRONIC INFLAMMATION CONTRIBUTE TO ABOUT 1 IN 4 OF ALL CANCER CASES. MEDIATORS OF THE INFLAMMATORY RESPONSE, E.G., CYTOKINES, FREE RADICALS, PROSTAGLANDINS AND GROWTH FACTORS, CAN INDUCE GENETIC AND EPIGENETIC CHANGES INCLUDING POINT MUTATIONS IN TUMOR SUPPRESSOR GENES, DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS, CAUSING ALTERATIONS IN CRITICAL PATHWAYS RESPONSIBLE FOR MAINTAINING THE NORMAL CELLULAR HOMEOSTASIS AND LEADING TO THE DEVELOPMENT AND PROGRESSION OF CANCER. RECENT DISCOVERY OF AN INTERACTION BETWEEN MICRORNAS AND INNATE IMMUNITY DURING INFLAMMATION HAS FURTHER STRENGTHENED THE ASSOCIATION BETWEEN INFLAMMATION AND CANCER. 2007 8 4897 20 OXIDATIVE STRESS IN ALCOHOL-RELATED LIVER DISEASE. ALCOHOL CONSUMPTION IS ONE OF THE LEADING CAUSES OF THE GLOBAL BURDEN OF DISEASE AND RESULTS IN HIGH HEALTHCARE AND ECONOMIC COSTS. HEAVY ALCOHOL MISUSE LEADS TO ALCOHOL-RELATED LIVER DISEASE, WHICH IS RESPONSIBLE FOR A SIGNIFICANT PROPORTION OF ALCOHOL-ATTRIBUTABLE DEATHS GLOBALLY. OTHER THAN REDUCING ALCOHOL CONSUMPTION, THERE ARE CURRENTLY NO EFFECTIVE TREATMENTS FOR ALCOHOL-RELATED LIVER DISEASE. OXIDATIVE STRESS REFERS TO AN IMBALANCE IN THE PRODUCTION AND ELIMINATION OF REACTIVE OXYGEN SPECIES AND ANTIOXIDANTS. IT PLAYS IMPORTANT ROLES IN SEVERAL ASPECTS OF ALCOHOL-RELATED LIVER DISEASE PATHOGENESIS. HERE, WE REVIEW HOW CHRONIC ALCOHOL USE RESULTS IN OXIDATIVE STRESS THROUGH INCREASED METABOLISM VIA THE CYTOCHROME P450 2E1 SYSTEM PRODUCING REACTIVE OXYGEN SPECIES, ACETALDEHYDE AND PROTEIN AND DNA ADDUCTS. THESE TRIGGER INFLAMMATORY SIGNALING PATHWAYS WITHIN THE LIVER LEADING TO EXPRESSION OF PRO-INFLAMMATORY MEDIATORS CAUSING HEPATOCYTE APOPTOSIS AND NECROSIS. REACTIVE OXYGEN SPECIES EXPOSURE ALSO RESULTS IN MITOCHONDRIAL STRESS WITHIN HEPATOCYTES CAUSING STRUCTURAL AND FUNCTIONAL DYSREGULATION OF MITOCHONDRIA AND UPREGULATING APOPTOTIC SIGNALING. THERE IS ALSO EVIDENCE THAT OXIDATIVE STRESS AS WELL AS THE DIRECT EFFECT OF ALCOHOL INFLUENCES EPIGENETIC REGULATION. INCREASED GLOBAL HISTONE METHYLATION AND ACETYLATION AND SPECIFIC HISTONE ACETYLATION INHIBITS ANTIOXIDANT RESPONSES AND PROMOTES EXPRESSION OF KEY PRO-INFLAMMATORY GENES. THIS REVIEW HIGHLIGHTS ASPECTS OF THE ROLE OF OXIDATIVE STRESS IN DISEASE PATHOGENESIS THAT WARRANT FURTHER STUDY INCLUDING MITOCHONDRIAL STRESS AND EPIGENETIC REGULATION. IMPROVED UNDERSTANDING OF THESE PROCESSES MAY IDENTIFY NOVEL TARGETS FOR THERAPY. 2020 9 3640 21 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 10 3965 21 LONG NONCODING RNAS IN THE METABOLIC CONTROL OF INFLAMMATION AND IMMUNE DISORDERS. THE METABOLIC CONTROL OF IMMUNE CELL DEVELOPMENT AND FUNCTION HAS BEEN SHOWN TO BE CRITICAL FOR THE MAINTENANCE OF IMMUNE HOMEOSTASIS AND IS ALSO INVOLVED IN THE PATHOGENESIS OF IMMUNE DISORDERS. PATHOGENIC INFECTIONS OR CANCERS MAY INDUCE METABOLIC REPROGRAMMING THROUGH DIFFERENT PATHWAYS TO MEET THE ENERGY AND METABOLITE DEMANDS FOR PATHOGEN PROPAGATION OR CANCER PROGRESSION. IN ADDITION, SOME DEREGULATED METABOLITES COULD TRIGGER OR REGULATE IMMUNE RESPONSES, THUS CAUSING CHRONIC INFLAMMATION OR IMMUNE DISORDERS, SUCH AS VIRAL INFECTION, CANCER AND OBESITY. THEREFORE, THE METHODS THROUGH WHICH METABOLISM IS REGULATED AND THE ROLE OF METABOLIC REGULATION IN INFLAMMATION AND IMMUNITY ATTRACT MUCH ATTENTION. EPIGENETIC REGULATION OF INFLAMMATION AND IMMUNITY IS AN EMERGING FIELD. LONG NONCODING RNAS (LNCRNAS) HAVE BEEN WELL DOCUMENTED TO PLAY CRUCIAL ROLES IN MANY BIOLOGICAL PROCESSES THROUGH DIVERSE MECHANISMS, INCLUDING IMMUNE REGULATION AND METABOLIC ALTERNATION. HERE, WE REVIEW THE FUNCTIONS AND MECHANISMS OF LNCRNAS IN THE METABOLIC REGULATION OF INFLAMMATORY IMMUNE DISORDERS, AIMING TO DEEPEN OUR UNDERSTANDING OF THE EPIGENETIC REGULATION OF INFLAMMATION AND IMMUNITY. 2019 11 376 23 AN EPI(C)GENETIC WAR: PATHOGENS, CANCER AND HUMAN GENOME. CANCER IS CHARACTERIZED BY INTER- AND INTRA-TUMOR HETEROGENEITY AND THIS IS ALSO OBSERVED IN THE CONTEXT OF CANCERS CAUSED BY PATHOGENS. NEARLY 20% OF ALL CANCERS ARE ATTRIBUTABLE TO PATHOGENIC ORGANISMS. PATHOGENIC INFECTIONS RESULT IN DEREGULATION OF GENE EXPRESSION BOTH BY GENETIC AND EPIGENETIC MECHANISMS, THEREBY CAUSING MALIGNANT TRANSFORMATION. ANOTHER CHARACTERISTIC OF PATHOGEN-INDUCED CANCERS IS THE OCCURRENCE OF CHRONIC INFLAMMATION DUE TO ACTIVATION OF THE INNATE AND ADAPTIVE ARMS OF THE IMMUNE SYSTEM. THIS REVIEW FOCUSES ON THE EPIGENETIC CHANGES INDUCED BY ONCOVIRUSES, PARASITES, CANCER-CAUSING BACTERIA AND 'ENDOGENOUS PATHOGENS' TO TRIGGER HOST CELL PROLIFERATION INDEFINITELY AS WELL AS THE INFLAMMATION ASSOCIATED WITH PATHOGEN-INDUCED CANCERS. THE OPPORTUNITY OF TARGETING COMPONENTS OF BOTH PATHOGEN AND HOST EPIGENETIC MACHINERY TO LIMIT TUMOR PROGRESSION IS ALSO DISCUSSED. 2018 12 1300 25 DEDIFFERENTIATION AND IN VIVO REPROGRAMMING OF COMMITTED CELLS IN WOUND REPAIR (REVIEW). ACCUMULATING EVIDENCE HAS SHOWN THAT CELL DEDIFFERENTIATION OR REPROGRAMMING IS A PIVOTAL PROCEDURE FOR ANIMALS TO DEAL WITH INJURY AND PROMOTE ENDOGENOUS TISSUE REPAIR. TISSUE DAMAGE IS A CRITICAL FACTOR THAT TRIGGERS CELL DEDIFFERENTIATION OR REPROGRAMMING IN VIVO. BY CONTRAST, MICROENVIRONMENTAL CHANGES, INCLUDING THE LOSS OF STEM CELLS, HYPOXIA, CELL SENESCENCE, INFLAMMATION AND IMMUNITY, CAUSED BY TISSUE DAMAGE CAN RETURN CELLS TO AN UNSTABLE STATE. IF THE WOUND PERSISTS IN THE LONG?TERM DUE TO CHRONIC DAMAGE, THEN DEDIFFERENTIATION OR REPROGRAMMING OF THE SURROUNDING CELLS MAY LEAD TO CARCINOGENESIS. IN RECENT YEARS, EXTENSIVE RESEARCH HAS BEEN PERFORMED INVESTIGATING CELL DEDIFFERENTIATION OR REPROGRAMMING IN VIVO, WHICH CAN HAVE SIGNIFICANT IMPLICATIONS FOR WOUND REPAIR, TREATMENT AND PREVENTION OF CANCER IN THE FUTURE. THE CURRENT REVIEW SUMMARIZES THE MOLECULAR EVENTS THAT ARE KNOWN TO DRIVE CELL DEDIFFERENTIATION DIRECTLY FOLLOWING TISSUE INJURY AND THE EFFECTS OF EPIGENETIC MODIFICATION ON DEDIFFERENTIATION OR REPROGRAMMING IN VIVO. IN ADDITION, THE PRESENT REVIEW EXPLORES THE INTRACELLULAR MECHANISM OF ENDOGENOUS TISSUE REPAIR AND ITS RELATIONSHIP WITH CANCER, WHICH IS ESSENTIAL FOR BALANCING THE RISK BETWEEN TISSUE REPAIR AND MALIGNANT TRANSFORMATION AFTER INJURY. 2022 13 4043 17 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 14 4888 32 OXIDATIVE DAMAGE IN THE PROGRESSION OF CHRONIC LIVER DISEASE TO HEPATOCELLULAR CARCINOMA: AN INTRICATE PATHWAY. THE HISTO-PATHOLOGIC AND MOLECULAR MECHANISMS LEADING TO INITIATION AND PROGRESSION OF HEPATOCELLULAR CARCINOMA (HCC) ARE STILL ILL-DEFINED; HOWEVER, THERE IS INCREASING EVIDENCE THAT THE GRADUAL ACCUMULATION OF MUTATIONS, GENETIC AND EPIGENETIC CHANGES WHICH OCCUR IN PRENEOPLASTIC HEPATOCYTES RESULTS IN THE DEVELOPMENT OF DYSPLASTIC FOCI, NODULES, AND FINALLY, OVERT HCC. AS WELL AS MANY OTHER NEOPLASIAS, LIVER CANCER IS CONSIDERED AN "INFLAMMATORY CANCER", ARISING FROM A CONTEXT OF INFLAMMATION, AND CHARACTERIZED BY INFLAMMATION-RELATED MECHANISMS THAT FAVOR TUMOR CELL SURVIVAL, PROLIFERATION, AND INVASION. MOLECULAR MECHANISMS THAT LINK INFLAMMATION AND NEOPLASIA HAVE BEEN WIDELY INVESTIGATED, AND IT HAS BEEN WELL ESTABLISHED THAT INFLAMMATORY CELLS RECRUITED AT THESE SITES WITH ONGOING INFLAMMATORY ACTIVITY RELEASE CHEMOKINES THAT ENHANCE THE PRODUCTION OF REACTIVE OXYGEN SPECIES. THE LATTER, IN TURN, PROBABLY HAVE A MAJOR PATHOGENIC ROLE IN THE CONTINUUM STARTING FROM HEPATITIS FOLLOWED BY CHRONIC INFLAMMATION, AND ULTIMATELY LEADING TO CANCER. THE RELATIONSHIP AMONGST CHRONIC LIVER INJURY, FREE RADICAL PRODUCTION, AND DEVELOPMENT OF HCC IS EXPLORED IN THE PRESENT REVIEW, PARTICULARLY IN THE LIGHT OF THE COMPLEX NETWORK THAT INVOLVES OXIDATIVE DNA DAMAGE, CYTOKINE SYNTHESIS, TELOMERE DYSFUNCTION, AND MICRORNA REGULATION. 2014 15 5493 15 REVIEW OF IN VITRO TEST SYSTEMS USING DNA DAMAGE AND REPAIR FOR SCREENING OF CHEMICAL CARCINOGENS. CHEMICAL CARCINOGENS ARE MECHANISTICALLY CLASSIFIED AS GENOTOXIC WHICH INTERACT DIRECTLY WITH DNA, AND EPIGENETIC WHICH CAUSE CHRONIC TISSUE INJURY, HORMONAL IMBALANCE, AND PROMOTIONAL EFFECTS. THIS REVIEW EVALUATES IN VITRO TESTS FOR THEIR CONTRIBUTION TO A BATTERY FOR IDENTIFYING GENOTOXIC CHEMICAL CARCINOGENS. IN ADDITION TO BACTERIAL MUTAGENIC ASSAYS, NONSPECIFIC DNA DAMAGE/REPAIR TESTS ARE RECOMMENDED FOR SCREENING CHEMICALS, IN PARTICULAR THE HEPATOCYTE PRIMARY CULTURE/DNA REPAIR TEST. 1979 16 4980 26 PATHOPHYSIOLOGY OF LIVER FIBROSIS. PROGRESSIVE ACCUMULATION OF FIBRILLAR EXTRACELLULAR MATRIX (ECM) IN THE LIVER IS THE CONSEQUENCE OF REITERATED LIVER TISSUE DAMAGE DUE TO INFECTIVE (MOSTLY HEPATITIS B AND C VIRUSES), TOXIC/DRUG-INDUCED, METABOLIC AND AUTOIMMUNE CAUSES, AND THE RELATIVE CHRONIC ACTIVATION OF THE WOUND-HEALING REACTION. THE PROCESS MAY RESULT IN CLINICALLY EVIDENT LIVER CIRRHOSIS AND HEPATIC FAILURE. ALTHOUGH CIRRHOSIS IS THE COMMON RESULT OF PROGRESSIVE FIBROGENESIS, THERE ARE DISTINCT PATTERNS OF FIBROTIC DEVELOPMENT RELATED TO THE UNDERLYING DISORDERS CAUSING THE FIBROSIS. THESE DIFFERENT PATTERNS OF FIBROGENIC EVOLUTION ARE RELATED TO DIFFERENT FACTORS AND PARTICULARLY: (1) THE TOPOGRAPHIC LOCALIZATION OF TISSUE DAMAGE, (2) THE RELATIVE CONCENTRATION OF PROFIBROGENIC FACTORS AND (3) THE PREVALENT PROFIBROGENIC MECHANISM(S). THE MECHANISMS RESPONSIBLE FOR THE FIBROGENIC EVOLUTION OF CHRONIC LIVER DISEASES CAN BE SUMMARIZED IN THREE MAIN GROUPS: CHRONIC ACTIVATION OF THE WOUND-HEALING REACTION, OXIDATIVE STRESS-RELATED MOLECULAR MECHANISMS, AND THE DERANGEMENT OF THE SO-CALLED 'EPITHELIAL-MESENCHYMAL' INTERACTION LEADING TO THE GENERATION OF REACTIVE CHOLANGIOCYTES AND PERIBILIARY FIBROSIS. MOST OF THE KNOWLEDGE ON THE CELL AND MOLECULAR BIOLOGY OF HEPATIC FIBROSIS DERIVES FROM IN VITRO STUDIES EMPLOYING CULTURE OF ACTIVATED HEPATIC STELLATE CELLS ISOLATED FROM RAT, MOUSE OR HUMAN LIVER. IT IS NOW EVIDENT THAT OTHER ECM-PRODUCING CELLS, I.E. FIBROBLASTS AND MYOFIBROBLASTS OF THE PORTAL TRACT AND CIRCULATING 'FIBROCYTES', ARE LIKELY TO CONTRIBUTE TO LIVER FIBROSIS. MORE RECENTLY, THE ATTENTION IS PROGRESSIVELY SHIFTING TO THE PROFIBROTIC MICROENVIRONMENT OF THE LIVER WITH INCREASING INTEREST FOR THE ROLE OF IMMUNE CELLS AND SPECIFIC SUBSETS OF MACROPHAGES REGULATING THE PROGRESSION OR THE REGRESSION OF FIBROSIS, THE ROLE OF INTESTINAL MICROBIOTA AND THE INFLUENCE OF TISSUE STIFFNESS. OTHER MAJOR AREAS OF DEVELOPMENT INCLUDE THE ROLE OF TISSUE HYPOXIA AND THE ESTABLISHMENT OF AN ANAEROBIC PROINFLAMMATORY ENVIRONMENT AND THE INFLUENCE OF EPIGENETIC MODIFICATION IN CONDITIONING THE PROGRESSION OF FIBROSIS. 2015 17 3244 31 HEPATIC STELLATE CELLS AND EXTRACELLULAR MATRIX IN HEPATOCELLULAR CARCINOMA: MORE COMPLICATED THAN EVER. HEPATOCELLULAR CARCINOMA (HCC) IS THE FIFTH MOST COMMON CANCER WORLDWIDE AND THE THIRD LEADING CAUSE OF CANCER DEATH. RECENT EPIDEMIOLOGICAL DATA INDICATE THAT THE MORTALITY RATE OF HCC WILL DOUBLE OVER THE NEXT DECADES IN THE USA AND EUROPE. LIVER CANCER PROGRESSES IN A LARGE PERCENTAGE OF CASES DURING THE CLINICAL COURSE OF CHRONIC FIBRO-INFLAMMATORY LIVER DISEASES LEADING TO CIRRHOSIS. THEREFORE, HCC DEVELOPMENT IS REGARDED AS THE RESULT OF DIFFERENT ENVIRONMENTAL RISK FACTORS EACH INVOLVING DIFFERENT GENETIC, EPIGENETIC- AND CHROMOSOMAL ALTERATIONS AND GENE MUTATIONS. DURING TUMOUR PROGRESSION, THE MALIGNANT HEPATOCYTES AND THE ACTIVATED HEPATIC STELLATE CELLS ARE ACCOMPANIED BY CANCER-ASSOCIATED FIBROBLASTS, MYOFIBROBLASTS AND IMMUNE CELLS GENERALLY CALLED TUMOUR STROMAL CELLS. THIS NEW AND DYNAMIC MILIEU FURTHER ENHANCES THE RESPONSIVENESS OF TUMOUR CELLS TOWARDS SOLUBLE MEDIATORS SECRETED BY TUMOUR STROMAL CELLS, THUS DIRECTLY AFFECTING THE MALIGNANT HEPATOCYTES. THIS RESULTS IN ALTERED MOLECULAR PATHWAYS WITH CELL PROLIFERATION AS THE MOST IMPORTANT MECHANISM OF LIVER CANCER PROGRESSION. GIVEN THIS CONTEXTUAL COMPLEXITY, IT IS OF UTMOST IMPORTANCE TO CHARACTERIZE THE MOLECULAR PATHOGENESIS OF HCC, AND TO IDENTIFY THE DOMINANT PATHWAYS/DRIVERS AND ABERRANT SIGNALLING PATHWAYS. THIS WILL ALLOW AN EFFECTIVE THERAPY FOR HCC THAT SHOULD COMBINE STRATEGIES AFFECTING BOTH CANCER AND THE TUMOUR STROMAL CELLS. THIS REVIEW PROVIDES AN OVERVIEW OF THE RECENT CHALLENGES AND ISSUES REGARDING HEPATIC STELLATE CELLS, EXTRACELLULAR MATRIX DYNAMICS, LIVER FIBROSIS/CIRRHOSIS AND THERAPY, TUMOUR MICROENVIRONMENT AND HCC. 2014 18 6850 26 [MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD LEADING CAUSE OF CANCER DEATH WORLDWIDE. HCC NEARLY ALMOST ALWAYS DEVELOPS IN CONNECTION WITH CHRONIC HEPATITIS OR LIVER CIRRHOSIS, MAINLY DUE TO HEPATITIS B VIRUS OR HEPATITIS C VIRUS INFECTION. SEVERAL FACTORS ARE SUPPOSED TO PLAY KEY ROLES IN THE DEVELOPMENT OF HCC, SUCH AS ABERRANT VIRAL PROTEIN EXPRESSION, GENOMIC INSTABILITY WITH/WITHOUT INSERTIONS OF VIRAL DNAS, GENE MUTATIONS, EPIGENETIC GENE MODIFICATION, OXIDATIVE STRESS, AND ALTERATION OF THE MICROENVIRONMENT INCLUDING INFLAMMATION, FIBROSIS, AND EMERGENCE OF STEM/PROGENITOR CELLS AS A RESULT OF REPEATED NECROSIS AND REGENERATION OF HEPATOCYTES. THE ELUCIDATION OF MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS HAS SUCCESSFULLY PROVIDED SMALL MOLECULE INHIBITORS TARGETING ABERRANTLY ACTIVATED SIGNALING IN HCC. DEVELOPMENT OF NOVEL CLASSIFICATION SYSTEMS BASED ON THE MOLECULAR PROFILES AND DRUG SENSITIVITIES AGAINST MOLECULARLY TARGETED COMPOUNDS IS CURRENTLY UNDERWAY TO FACILITATE NOVEL STRATEGIES FOR EFFECTIVE ERADICATION OF HCC. 2010 19 4475 28 MOLECULAR PATHOGENESIS OF HEPATITIS C VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. CHRONIC INFECTION WITH HEPATITIS C VIRUS (HCV) IS CAUSALLY ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). HCV IS NOT CYTOLYTIC AND REPLICATES ENTIRELY IN THE CYTOPLASM. VIRAL INTERACTION WITH THE HOST LEADS TO SUBVERSION OF IMMUNE RESPONSE AND OTHER DEFENSE MECHANISMS. THE RECENT DEVELOPMENT OF ROBUST CELL CULTURE SYSTEMS FOR HCV INFECTION PROVIDES NEW OPPORTUNITIES FOR THE STUDY OF VIRUS-CELL INTERACTION AND VIRAL PATHOGENESIS. HCV INFECTION CAUSES ACTIVE INFLAMMATION AND FIBROSIS, WHICH ULTIMATELY PROGRESSES TO CIRRHOSIS. THE ONSET OF CIRRHOSIS USUALLY PRECEDES THE MULTISTAGE PROCESS OF TUMOR DEVELOPMENT, IN WHICH COMMON THEMES OF VIRAL CARCINOGENESIS CAN BE IDENTIFIED. WHILE CHRONIC INFLAMMATION AND CIRRHOSIS ARE THOUGHT TO PLAY AN IMPORTANT ROLE IN TUMOR INITIATION, THE UNDERLYING MECHANISMS ARE INCOMPLETELY UNDERSTOOD. RECENT STUDIES HAVE REVEALED THAT INFECTION WITH HCV INDUCES GENOME INSTABILITY, LEADING TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS WHICH CONTRIBUTE TO THE FULL DEVELOPMENT OF HCC TUMOR. THE EXPRESSION OF VIRAL ONCOPROTEINS SUCH AS C AND NS5A IS CRITICALLY INVOLVED BOTH IN THE INDUCTION OF GENOME INSTABILITY AND IN DYSREGULATING CELLULAR CONTROL OF GROWTH AND SIGNAL TRANSDUCTION. A BETTER UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF HCV WILL REVEAL NOVEL STRATEGIES FOR THE PREVENTION AND TREATMENT OF RELATED DISEASES INCLUDING HCC. 2007 20 5805 31 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