1 3688 160 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 2 3516 49 IDO1 AND INFLAMMATORY NEOVASCULARIZATION: BRINGING NEW BLOOD TO TUMOR-PROMOTING INFLAMMATION. IN PARALLEL WITH THE GENETIC AND EPIGENETIC CHANGES THAT ACCUMULATE IN TUMOR CELLS, CHRONIC TUMOR-PROMOTING INFLAMMATION ESTABLISHES A LOCAL MICROENVIRONMENT THAT FOSTERS THE DEVELOPMENT OF MALIGNANCY. WHILE KNOWLEDGE OF THE SPECIFIC FACTORS THAT DISTINGUISH TUMOR-PROMOTING FROM NON-TUMOR-PROMOTING INFLAMMATION REMAINS INCHOATE, NEVERTHELESS, AS HIGHLIGHTED IN THIS SERIES ON THE 'HALLMARKS OF CANCER', IT IS CLEAR THAT TUMOR-PROMOTING INFLAMMATION IS ESSENTIAL TO NEOPLASIA AND METASTATIC PROGRESSION MAKING IDENTIFICATION OF SPECIFIC FACTORS CRITICAL. STUDIES OF IMMUNOMETABOLISM AND INFLAMOMETABOLISM HAVE REVEALED A ROLE FOR THE TRYPTOPHAN CATABOLIZING ENZYME IDO1 AS A CORE ELEMENT IN TUMOR-PROMOTING INFLAMMATION. AT ONE LEVEL, IDO1 EXPRESSION PROMOTES IMMUNE TOLERANCE TO TUMOR ANTIGENS, THEREBY HELPING TUMORS EVADE ADAPTIVE IMMUNE CONTROL. ADDITIONALLY, RECENT FINDINGS INDICATE THAT IDO1 ALSO PROMOTES TUMOR NEOVASCULARIZATION BY SUBVERTING LOCAL INNATE IMMUNITY. THIS NEWLY RECOGNIZED FUNCTION FOR IDO1 IS MEDIATED BY A UNIQUE MYELOID CELL POPULATION TERMED IDVCS (IDO1-DEPENDENT VASCULARIZING CELLS). INITIALLY IDENTIFIED IN METASTATIC LESIONS, IDVCS MAY EXERT BROADER EFFECTS ON PATHOLOGIC NEOVASCULARIZATION IN VARIOUS DISEASE SETTINGS. MECHANISTICALLY, INDUCTION OF IDO1 EXPRESSION IN IDVCS BY THE INFLAMMATORY CYTOKINE IFNGAMMA BLOCKS THE ANTAGONISTIC EFFECT OF IFNGAMMA ON NEOVASCULARIZATION BY STIMULATING THE EXPRESSION OF IL6, A POWERFUL PRO-ANGIOGENIC CYTOKINE. BY CONTRIBUTING TO VASCULAR ACCESS, THIS NEWLY ASCRIBED FUNCTION FOR IDO1 ALIGNS WITH ITS INVOLVEMENT IN OTHER CANCER HALLMARK FUNCTIONALITIES, (TUMOR-PROMOTING INFLAMMATION, IMMUNE ESCAPE, ALTERED CELLULAR METABOLISM, METASTASIS), WHICH MAY STEM FROM AN UNDERLYING ROLE IN NORMAL PHYSIOLOGICAL FUNCTIONS SUCH AS WOUND HEALING AND PREGNANCY. UNDERSTANDING THE NUANCES OF HOW IDO1 INVOLVEMENT IN THESE CANCER HALLMARK FUNCTIONALITIES VARIES BETWEEN DIFFERENT TUMOR SETTINGS WILL BE CRUCIAL TO THE FUTURE DEVELOPMENT OF SUCCESSFUL IDO1-DIRECTED THERAPIES. 2023 3 4613 41 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 6774 36 [AGE-RELATED VASCULAR CHANGES EXEMPLIFIED BY THE CAROTID ARTERY]. ONE OF THE MAIN RISK FACTORS FOR THE PRESENCE OF CAROTID STENOSIS AND CAROTID-RELATED STROKE IS AGE. THE AIM OF THIS REVIEW ARTICLE IS TO PRESENT THE CURRENT STATE OF KNOWLEDGE ON AGE-RELATED VASCULAR CHANGES USING CAROTID STENOSIS AS AN EXAMPLE.VASCULAR AGING (VASCULAR SENESCENCE) IS A DECREASE OF STRUCTURAL AND FUNCTIONAL PROPERTIES OF THE VESSEL WALL THAT TAKES PLACE ON DIFFERENT LEVELS. AT THE MULTICELLULAR LEVEL AN INCREASE IN VESSEL VOLUME AND DIAMETER AS WELL AS INTIMA MEDIA THICKNESS OCCURS WITH AGE MAINLY DUE TO ATHEROSCLEROTIC CHANGES IN THE VESSEL WALL. AT THE CELLULAR AND EXTRACELLULAR LEVELS THERE IS A DECREASE IN ELASTIN FIBERS, SMOOTH MUSCLE CELLS, AND TOTAL CELLULARITY, AN INCREASE IN LIPID, CHOLESTEROL, AND CALCIUM PHOSPHATE DEPOSITION AS WELL AS NEOVASCULARIZATION. THE CAUSES OF VASCULAR AGING AT THE MOLECULAR LEVEL INCLUDE, IN PARTICULAR OXIDATIVE STRESS, CHRONIC INFLAMMATORY RESPONSE, MITOCHONDRIAL DYSFUNCTION, EPIGENETIC CHANGES, DYSREGULATION OF THE EXPRESSION OF NON-CODING RNAS (NCRNAS), AND THE INCREASE IN SENESCENCE. AGE-RELATED LOSS OF TISSUE HEALING AND REPAIR CAPACITY MAKE PLAQUES MORE VULNERABLE AND, IN THE CASE OF THE CAROTID ARTERY, MORE SUSCEPTIBLE TO ISCHEMIC STROKE.INCREASING KNOWLEDGE OF THE INFLUENCE OF AGING ON THE EPIGENETICS AND NCRNAS IN ATHEROSCLEROTIC PLAQUES CAN IN THE FUTURE MORE ACCURATELY QUANTIFY INDIVIDUAL PATIENT RISK AND CONTRIBUTE TO THE DEVELOPMENT OF TARGETED THERAPEUTIC STRATEGIES; HOWEVER, FURTHER STUDIES ARE NEEDED IN THIS FIELD TO UNDERSTAND THE FULL EXTENT OF VASCULAR AGING AND ITS ASSOCIATED DISEASES SO THAT THESE CAN THEN BE SPECIFICALLY TARGETED. 2022 5 2378 28 EPIGENETIC REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING IN ATHEROSCLEROTIC ARTERY REMODELING: A MINI-REVIEW. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY EXTENSIVE REMODELING OF MEDIUM AND LARGE-SIZED ARTERIES. INWARD REMODELING (=LUMEN SHRINKAGE) OF THE VASCULAR WALLS IS THE UNDERLYING CAUSE FOR ISCHEMIA IN TARGET ORGANS. THEREFORE, INWARD REMODELING CAN BE CONSIDERED THE PREDOMINANT FEATURE OF ATHEROSCLEROTIC PATHOLOGY. OUTWARD REMODELING (=LUMEN ENLARGEMENT) IS A PHYSIOLOGICAL RESPONSE COMPENSATING FOR LUMEN SHRINKAGE CAUSED BY NEOINTIMAL HYPERPLASIA, BUT AS A PATHOLOGICAL RESPONSE TO CHANGES IN BLOOD FLOW, OUTWARD REMODELING LEADS TO SUBSTANTIAL ARTERIAL WALL THINNING. THINNED VASCULAR WALLS ARE PRONE TO RUPTURE, AND SUBSEQUENT THROMBUS FORMATION ACCOUNTS FOR THE MAJORITY OF ACUTE CARDIOVASCULAR EVENTS. PATHOLOGICAL REMODELING IS DRIVEN BY INFLAMMATORY CELLS WHICH INDUCE VASCULAR SMOOTH MUSCLE CELLS TO SWITCH FROM QUIESCENT TO A PROLIFERATIVE AND MIGRATORY PHENOTYPE. AFTER DECADES OF INTENSIVE RESEARCH, THE MOLECULAR MECHANISMS OF ARTERIAL REMODELING ARE STARTING TO UNFOLD. IN THIS MINI-REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING FROM THE CONTRACTILE TO THE SYNTHETIC PHENOTYPE INVOLVED IN ARTERIAL REMODELING AND DISCUSS POTENTIAL THERAPEUTIC OPTIONS. 2021 6 630 26 BIOLOGICAL AND MECHANICAL FACTORS AND EPIGENETIC REGULATION INVOLVED IN TENDON HEALING. TENDONS ARE AN IMPORTANT PART OF THE MUSCULOSKELETAL SYSTEM. CONNECTING MUSCLES TO BONES, TENDONS CONVERT FORCE INTO MOVEMENT. TENDON INJURY CAN BE ACUTE OR CHRONIC. NOTICEABLY, TENDON HEALING REQUIRES A LONG TIME SPAN AND INCLUDES INFLAMMATION, PROLIFERATION, AND REMODELING PROCESSES. THE MISMATCH BETWEEN ENDOGENOUS AND EXOGENOUS HEALING MAY LEAD TO ADHESION CAUSING FURTHER NEGATIVE EFFECTS. MANAGEMENT OF TENDON INJURIES AND COMPLICATIONS SUCH AS SUBSEQUENT ADHESION FORMATION ARE STILL CHALLENGES FOR CLINICIANS. DUE TO NUMEROUS FACTORS, TENDON HEALING IS A COMPLEX PROCESS. THIS REVIEW INTRODUCES THE ROLE OF VARIOUS BIOLOGICAL AND MECHANICAL FACTORS AND EPIGENETIC REGULATION PROCESSES INVOLVED IN TENDON HEALING. 2023 7 379 29 AN EPIGENETIC MECHANISM FOR HIGH, SYNERGISTIC EXPRESSION OF INDOLEAMINE 2,3-DIOXYGENASE 1 (IDO1) BY COMBINED TREATMENT WITH ZEBULARINE AND IFN-GAMMA: POTENTIAL THERAPEUTIC USE IN AUTOIMMUNE DISEASES. IDO1 CAN BE INDUCED BY INTERFERON GAMMA (IFN-GAMMA) IN MULTIPLE CELL TYPES. WE HAVE EARLIER DESCRIBED THAT THE DNA METHYLTRANSFERASE INHIBITOR ZEBULARINE ALSO INDUCES IDO1 IN SEVERAL RAT CELL CLONES. WE NOW DESCRIBE A SYNERGISTIC INDUCTION OF IDO1 EXPRESSION BY IFN-GAMMA AND ZEBULARINE. TO ELUCIDATE THE MECHANISM OF THE IDO1 INDUCTION WE HAVE STUDIED THE METHYLATION STATUS IN THE PROMOTER REGION OF THE IDO1 GENE FROM BOTH HUMAN MONOCYTIC THP-1 CELLS AND H1D2 RAT COLON CANCER CELLS. INTERESTINGLY, THE IDO1 PROMOTER IS HYPERMETHYLATED AND IFN-GAMMA IS SHOWN TO INDUCE A SIGNIFICANT DEMETHYLATION. THE SYNERGISM IN EFFECT OF ZEBULARINE AND IFN-GAMMA ON IDO1 EXPRESSION IS PARALLELED BY A SIMILAR SYNERGISTIC EFFECT ON EXPRESSION OF TWO OTHER IFN-GAMMA-RESPONSIVE GENES, THE TRANSCRIPTION FACTORS STAT1 AND IRF1 WITH BINDING SITES IN THE IDO1 PROMOTER REGION. THE DEMONSTRATED SYNERGISTIC ACTIVATION OF IDO1 EXPRESSION HAS IMPLICATIONS IN RELATION TO THERAPEUTIC INDUCTION OF IMMUNOSUPPRESSION IN AUTOIMMUNITY AND CHRONIC INFLAMMATION. 2012 8 3245 30 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 9 4660 53 NEW APPROACHES TO THE TREATMENT OF MYELODYSPLASIA. THE THERAPEUTIC DILEMMA THAT CONFRONTS THE MANAGEMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) IS ILLUSTRATED BY THE ABSENCE OF A FOOD AND DRUG ADMINISTRATION-APPROVED AGENT WITH AN INDICATION FOR THIS DISEASE. CLINICAL HETEROGENEITY AND INADEQUATE UNDERSTANDING OF THE DISEASE PATHOBIOLOGY HAVE LIMITED PROGRESS IN THE DEVELOPMENT OF NOVEL THERAPEUTICS. PRECLINICAL INVESTIGATIONS INDICATE THAT RECIPROCAL INTERACTION BETWEEN THE MALIGNANT CLONE AND THE MICROENVIRONMENT SERVE TO CREATE A HOSTILE MILIEU THAT REINFORCES INEFFECTIVE BLOOD CELL PRODUCTION. INEFFECTIVE HEMATOPOIESIS, THE HALLMARK OF MDS, ARISES FROM IMPAIRED PROGENITOR RESPONSIVENESS TO NORMAL TROPHIC SIGNALS AND EXCESS LOCAL GENERATION OF INHIBITORY CYTOKINES, WHICH PROMOTE ACCELERATED APOPTOTIC LOSS OF PROGENITORS AND THEIR PROGENY. EVIDENCE TO SUPPORT THIS MODEL DERIVES FROM CYTOKINE NEUTRALIZATION STUDIES AND THE DIRECT RELATIONSHIP BETWEEN PLASMA TUMOR NECROSIS FACTOR-ALPHA CONCENTRATION AND DNA OXIDATION AND GLUTATHIONE DEPLETION IN MALIGNANT CD34+ PROGENITORS. RECENT INVESTIGATIONS INDICATE THAT ANGIOGENIC MOLECULES GENERATED BY MALIGNANT MYELOMONOCYTIC PRECURSORS REPRESENT INTEGRAL DIFFUSABLE SIGNALS THAT REINFORCE LEUKEMIA PROGENITOR SELF-RENEWAL WHILE PROMOTING THE GENERATION OF PROAPOPTOTIC CYTOKINES AND MEDULLARY ANGIOGENIC RESPONSE. THE POTENTIAL FOR LEUKEMIA EVOLUTION IS COMPOUNDED BY EPIGENETIC EVENTS INCLUDING METHYLATION SILENCING OF THE P15 PROTO-ONCOGENE OR ACTIVATING RAS POINT MUTATIONS. DELINEATION OF SUCH BIOLOGIC FEATURES THAT ARE CENTRAL TO THE PATHOBIOLOGY OF MDS PROVIDES A RELIABLE FRAMEWORK FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. ANTIANGIOGENIC AGENTS IN CLINICAL TESTING INCLUDE VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) RECEPTOR TYROSINE KINASE INHIBITORS, THALIDOMIDE AND RELATED ANALOGUES, AND THE RECOMBINANT VEGF NEUTRALIZING ANTIBODY, BEVACIZUMAB. AGENTS WHOSE ACTIONS MAY RESTORE DIFFERENTIATION PROGRAMS, SUCH AS THE DNA METHYLTRANSFERASE INHIBITORS OR HISTONE DEACETYLASE INHIBITORS, OFFER THE PROSPECT TO PROMOTE EFFECTIVE HEMATOPOIESIS WHILE IMPACTING THE POTENTIAL FOR LEUKEMIA EVOLUTION. RAS FARNESYL TRANSFERASE INHIBITORS HAVE SHOWN ENCOURAGING PRELIMINARY RESULTS IN ACUTE MYELOID LEUKEMIA AND ARE CURRENTLY UNDER INVESTIGATION IN ADVANCED MDS AND CHRONIC MYELOMONOCYTIC LEUKEMIA. ARSENIC TRIOXIDE (ATO) INTERACTS WITH A SPECTRUM OF BIOLOGIC TARGETS THAT MAY BE UNIQUELY SUITED TO MDS. ATO IS A POTENT INDUCER OF APOPTOSIS IN THIOL-DEPLETED MALIGNANT PROGENITORS AND NEOVASCULAR ENDOTHELIUM, WHILE PROMOTING DIFFERENTIATION THROUGH HISTONE ACETYLATION AND INACTIVATION OF TRANSCRIPTIONAL COREPRESSORS. THE IDENTIFICATION OF RELEVANT BIOLOGIC TARGETS IN MDS HAS RAISED EXPECTATIONS FOR THE DEVELOPMENT OF DISEASE-SPECIFIC THERAPIES FOR MDS IN THE YEARS THAT FOLLOW. 2002 10 5239 36 PROGESTERONE ALLEVIATES ENDOMETRIOSIS VIA INHIBITION OF UTERINE CELL PROLIFERATION, INFLAMMATION AND ANGIOGENESIS IN AN IMMUNOCOMPETENT MOUSE MODEL. ENDOMETRIOSIS, DEFINED AS GROWTH OF THE ENDOMETRIAL CELLS OUTSIDE THE UTERUS, IS AN INFLAMMATORY DISORDER THAT IS ASSOCIATED WITH CHRONIC PELVIC PAIN AND INFERTILITY IN WOMEN OF CHILDBEARING AGE. ALTHOUGH THE ESTROGEN-DEPENDENCE OF ENDOMETRIOSIS IS WELL KNOWN, THE ROLE OF PROGESTERONE IN DEVELOPMENT OF THIS DISEASE REMAINS POORLY UNDERSTOOD. IN THIS STUDY, WE DEVELOPED A DISEASE MODEL IN WHICH ENDOMETRIOSIS WAS INDUCED IN THE PERITONEAL CAVITIES OF IMMUNOCOMPETENT FEMALE MICE, AND MAINTAINED WITH EXOGENOUS ESTROGEN. THE ENDOMETRIOSIS-LIKE LESIONS THAT WERE IDENTIFIED AT A VARIETY OF ECTOPIC LOCATIONS EXHIBITED ABUNDANT BLOOD SUPPLY AND EXTENSIVE ADHESIONS. HISTOLOGICAL EXAMINATION REVEALED THAT THESE LESIONS HAD A WELL-ORGANIZED ENDOMETRIAL ARCHITECTURE AND FIBROTIC RESPONSE, RESEMBLING THOSE RECOVERED FROM CLINICAL PATIENTS. IN ADDITION, AN EXTENSIVE PROLIFERATION, INFLAMMATORY RESPONSE, AND LOSS OF ESTROGEN RECEPTOR ALPHA (ERALPHA) AND PROGESTERONE RECEPTOR (PR) EXPRESSION WERE ALSO OBSERVED IN THESE LESIONS. INTERESTINGLY, ADMINISTRATION OF PROGESTERONE BEFORE, BUT NOT AFTER, LESION INDUCTION SUPPRESSED LESION EXPANSION AND MAINTAINED ERALPHA AND PR EXPRESSIONS. THESE PROGESTERONE-PRETREATED LESIONS EXHIBITED ATTENUATION IN KI67, CD31, AND PRO-INFLAMMATORY CYTOKINE EXPRESSION AS WELL AS MACROPHAGE INFILTRATION, INDICATING THAT PROGESTERONE AMELIORATES ENDOMETRIOSIS PROGRESSION BY INHIBITING CELL PROLIFERATION, INFLAMMATION AND NEOVASCULARIZATION. OUR STUDIES FURTHER SHOWED THAT SUPPRESSION OF GLOBAL DNA METHYLATION BY APPLICATION OF DNA METHYLTRANSFERASE INHIBITOR TO FEMALE MICE BEARING ECTOPIC LESIONS RESTRAINED LESION EXPANSION AND RESTORED ERALPHA AND PR EXPRESSION IN EUTOPIC ENDOMETRIUM AND ECTOPIC LESIONS. THESE RESULTS INDICATE THAT EPIGENETIC REGULATION OF TARGET GENE EXPRESSION VIA DNA METHYLATION CONTRIBUTES, AT LEAST IN PART, TO PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. 2016 11 5987 28 TGF-BETA SIGNAL SHIFTING BETWEEN TUMOR SUPPRESSION AND FIBRO-CARCINOGENESIS IN HUMAN CHRONIC LIVER DISEASES. PERTURBATION OF TRANSFORMING GROWTH FACTOR (TGF)-BETA SIGNALING IN HEPATOCYTES PERSISTENTLY INFECTED WITH HEPATITIS VIRUSES PROMOTES BOTH FIBROGENESIS AND CARCINOGENESIS (FIBRO-CARCINOGENESIS). INSIGHTS INTO HEPATOCYTIC FIBRO-CARCINOGENESIS HAVE EMERGED FROM RECENT DETAILED ANALYSES OF CONTEXT-DEPENDENT AND CELL TYPE-SPECIFIC TGF-BETA SIGNALING PROCESSES DIRECTED BY MULTIPLE PHOSPHORYLATED FORMS (PHOSPHO-ISOFORMS) OF SMAD MEDIATORS. IN THE COURSE OF HEPATITIS VIRUS-RELATED CHRONIC LIVER DISEASES, CHRONIC INFLAMMATION, ONGOING VIRAL INFECTION, AND HOST GENETIC/EPIGENETIC ALTERATIONS ADDITIVELY SHIFT HEPATOCYTIC SMAD PHOSPHO-ISOFORM SIGNALING FROM TUMOR SUPPRESSION TO FIBRO-CARCINOGENESIS, ACCELERATING LIVER FIBROSIS AND INCREASING RISK OF HEPATOCELLULAR CARCINOMA (HCC). AFTER SUCCESSFUL ANTIVIRAL THERAPY, PATIENTS WITH CHRONIC HEPATITIS CAN EXPERIENCE LESS RISK OF HCC OCCURRENCE BY REVERSING SMAD PHOSPHO-ISOFORM SIGNALING FROM FIBRO-CARCINOGENESIS TO TUMOR SUPPRESSION. HOWEVER, PATIENTS WITH CIRRHOSIS CAN STILL DEVELOP HCC OWING TO SUSTAINED, INTENSE FIBRO-CARCINOGENIC SIGNALING. RECENT PROGRESS IN UNDERSTANDING SMAD PHOSPHO-ISOFORM SIGNALING SHOULD PERMIT USE OF SMAD PHOSPHORYLATION AS A TOOL PREDICTING THE LIKELIHOOD OF LIVER DISEASE PROGRESSION, AND AS A BIOMARKER FOR ASSESSING THE EFFECTIVENESS OF INTERVENTIONS AIMED AT REDUCING FIBROSIS AND CANCER RISK. 2014 12 6591 43 TUMOR-ASSOCIATED MACROPHAGES AS A PARADIGM OF MACROPHAGE PLASTICITY, DIVERSITY, AND POLARIZATION: LESSONS AND OPEN QUESTIONS. MACROPHAGES ARE PRESENT IN ALL BODY COMPARTMENTS, INCLUDING CANCEROUS TISSUES, AND THEIR FUNCTIONS ARE PROFOUNDLY AFFECTED BY SIGNALS FROM THE MICROENVIRONMENT UNDER HOMEOSTATIC AND PATHOLOGICAL CONDITIONS. TUMOR-ASSOCIATED MACROPHAGES ARE A MAJOR CELLULAR COMPONENT OF CANCER-RELATED INFLAMMATION AND HAVE SERVED AS A PARADIGM FOR THE PLASTICITY AND FUNCTIONAL POLARIZATION OF MONONUCLEAR PHAGOCYTES. TUMOR-ASSOCIATED MACROPHAGES CAN EXERT DUAL INFLUENCE OF CANCER DEPENDING ON THE ACTIVATION STATE, WITH CLASSICALLY ACTIVATED (M1) AND ALTERNATIVELY ACTIVATED (M2) CELLS GENERALLY EXERTING ANTITUMORAL AND PROTUMORAL FUNCTIONS, RESPECTIVELY. THESE ARE EXTREMES IN A CONTINUUM OF POLARIZATION STATES IN A UNIVERSE OF DIVERSITY. TUMOR-ASSOCIATED MACROPHAGES AFFECT VIRTUALLY ALL ASPECTS OF TUMOR TISSUES, INCLUDING STEM CELLS, METABOLISM, ANGIOGENESIS, INVASION, AND METASTASIS. PROGRESS HAS BEEN MADE IN DEFINING SIGNALING MOLECULES, TRANSCRIPTION FACTORS, EPIGENETIC CHANGES, AND REPERTOIRE OF MICRORNAS UNDERLYING MACROPHAGE POLARIZATION. PRECLINICAL AND EARLY CLINICAL DATA SUGGEST THAT MACROPHAGES MAY SERVE AS TOOLS FOR THE DEVELOPMENT OF INNOVATIVE DIAGNOSTIC AND THERAPEUTIC STRATEGIES IN CANCER AND CHRONIC NONRESOLVING INFLAMMATORY DISEASES. 2013 13 6621 38 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 14 6214 41 THE INTRACELLULAR SIGNALING PATHWAYS GOVERNING MACROPHAGE ACTIVATION AND FUNCTION IN HUMAN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY LIPID ACCUMULATION AND PLAQUE FORMATION IN ARTERIAL VESSEL WALLS. ATHEROSCLEROTIC PLAQUES NARROW THE ARTERIAL LUMEN TO INCREASE THE RISK OF HEART ATTACKS, ISCHEMIC STROKE AND PERIPHERAL VASCULAR DISEASE, WHICH ARE MAJOR AND WORLDWIDE HEALTH AND ECONOMIC BURDENS. MACROPHAGE ACCUMULATION WITHIN PLAQUES IS CHARACTERISTIC OF ALL STAGES OF ATHEROSCLEROSIS AND THEIR PRESENCE IS A POTENTIAL MARKER OF DISEASE ACTIVITY AND PLAQUE STABILITY. MACROPHAGES ENGULF LIPIDS AND MODIFIED LIPOPROTEINS TO FORM FOAM CELLS THAT EXPRESS PRO-INFLAMMATORY AND CHEMOTACTIC EFFECTOR MOLECULES, STRESS INDUCING FACTORS AND REACTIVE OXYGEN SPECIES. THEY CONTROL PLAQUE STABILITY AND RUPTURE THROUGH SECRETION OF METALLOPROTEINASES AND EXTRACELLULAR MATRIX DEGRADATION. ALTHOUGH MACROPHAGES CAN WORSEN DISEASE BY PROPAGATING INFLAMMATION, THEY CAN STABILIZE ATHEROSCLEROTIC PLAQUES THROUGH TISSUE REMODELING, PROMOTING THE FORMATION OF A FIBROUS CAP, CLEARING APOPTOTIC CELLS TO PREVENT NECROTIC CORE FORMATION AND THROUGH VASCULAR REPAIR. IN ATHEROSCLEROSIS, MACROPHAGES RESPOND TO DYSLIPIDAEMIA, CYTOKINES, DYING CELLS, METABOLIC FACTORS, LIPIDS, PHYSICAL STIMULI AND EPIGENETIC FACTORS AND EXHIBIT HETEROGENEITY IN THEIR ACTIVATION DEPENDING ON THE STIMULI THEY RECEIVE. UNDERSTANDING THESE SIGNALS AND THE PATHWAYS DRIVING MACROPHAGE FUNCTION WITHIN DEVELOPING AND ESTABLISHED PLAQUES AND HOW THEY CAN BE PHARMACOLOGICALLY MODULATED, REPRESENTS A STRATEGY FOR THE PREVENTION AND TREATMENT OF ATHEROSCLEROSIS. THIS REVIEW FOCUSSES ON THE CURRENT UNDERSTANDING OF FACTORS CONTROLLING MACROPHAGE HETEROGENEITY AND FUNCTION IN ATHEROSCLEROSIS. PARTICULAR ATTENTION IS GIVEN TO THE MACROPHAGE INTRACELLULAR SIGNALING PATHWAYS AND TRANSCRIPTION FACTORS ACTIVATED BY BIOCHEMICAL AND BIOPHYSICAL STIMULI WITHIN PLAQUES, AND HOW THEY ARE INTEGRATED TO REGULATE PLAQUE FORMATION AND STABILITY. 2022 15 2800 46 FEEDBACK REGULATORS OF HYPOXIA-INDUCIBLE FACTORS AND THEIR ROLE IN CANCER BIOLOGY. MALIGNANT TUMORS ARE CHARACTERIZED BY REGIONS OF LOW OXYGEN CONCENTRATION (HYPOXIA). THE HYPOXIC TUMOR MICROENVIRONMENT CONTRIBUTES TO TUMOR PROGRESSION BY ACTIVATING A SET OF ADAPTIVE RESPONSES VIA THE KEY TRANSCRIPTIONAL REGULATORS HIF-1ALPHA AND HIF-2ALPHA. THESE FACTORS HAVE BEEN TRADITIONALLY LINKED TO AN AGGRESSIVE TUMOR PHENOTYPE BY PROMOTING PROCESSES ESSENTIAL FOR TUMOR GROWTH, SUCH AS ANGIOGENESIS, GLYCOLYSIS, METASTASIS AND INVASION, AS WELL AS DIFFERENTIATION AND SELF RENEWAL. NOTABLY, THE COMPLEX HIF PATHWAY ALSO INITIATES ANTI-TUMORIGENIC MECHANISMS THAT LEAD TO CELL CYCLE ARREST OR CELL DEATH, INDICATING THE NEED FOR A STRINGENT CONTROL OF THE EXTENT AND THE DIRECTION OF THE HYPOXIA RESPONSE. THE IMPORTANCE OF THIS CONTROL FOR TUMOR CELL SURVIVAL IS ILLUSTRATED BY THE INTRICATE REGULATION OF HIF ACTIVITY AT THE MRNA, PROTEIN AND EPIGENETIC LEVEL BY A COMPLEX NETWORK OF POSITIVE AND NEGATIVE FEEDBACK REGULATORS. WE PROPOSE THAT THESE FEEDBACK REGULATORS HELP TO FLEXIBLY ADJUST AND ADAPT HIF ACTIVATED RESPONSES TO THE FLUCTUATING OXYGEN CONCENTRATIONS WITHIN TUMORS DURING ACUTE AND CHRONIC HYPOXIA AND TO CURTAIL THE TUMOR-SUPPRESSING COMPONENTS OF THE HIF PATHWAY. MOREOVER, FEEDBACK REGULATION OF HIF INDUCES A SWITCH FROM HIF-1ALPHA TO HIF-2ALPHA DRIVEN RESPONSES UNDER CHRONIC HYPOXIA WHICH MAY HAVE ESSENTIAL FUNCTIONS IN THE REGULATION OF TUMOR CELL DIFFERENTIATION AND TUMOR STEM CELL MAINTENANCE. GIVEN THEIR CENTRAL ROLE IN CANCER BIOLOGY, HIF FEEDBACK REGULATORS MAY REPRESENT AN ATTRACTIVE AND NOVEL ANTI-TUMOR THERAPY TARGET TO OVERCOME CELL DEATH RESISTANCE IN TUMORS. 2010 16 4337 31 MICROTUBULES AS MAJOR REGULATORS OF ENDOTHELIAL FUNCTION: IMPLICATION FOR LUNG INJURY. ENDOTHELIAL DYSFUNCTION HAS BEEN ATTRIBUTED AS ONE OF THE MAJOR COMPLICATIONS IN COVID-19 PATIENTS, A GLOBAL PANDEMIC THAT HAS ALREADY CAUSED OVER 4 MILLION DEATHS WORLDWIDE. THE DYSFUNCTION OF ENDOTHELIAL BARRIER IS CHARACTERIZED BY AN INCREASE IN ENDOTHELIAL PERMEABILITY AND INFLAMMATORY RESPONSES, AND HAS EVEN BROADER IMPLICATIONS IN THE PATHOGENESIS OF ACUTE RESPIRATORY SYNDROMES SUCH AS ARDS, SEPSIS AND CHRONIC ILLNESSES REPRESENTED BY PULMONARY ARTERIAL HYPERTENSION AND INTERSTITIAL LUNG DISEASE. THE STRUCTURAL INTEGRITY OF ENDOTHELIAL BARRIER IS MAINTAINED BY CYTOSKELETON ELEMENTS, CELL-SUBSTRATE FOCAL ADHESION AND ADHESIVE CELL JUNCTIONS. AGONIST-MEDIATED CHANGES IN ENDOTHELIAL PERMEABILITY ARE DIRECTLY ASSOCIATED WITH REORGANIZATION OF ACTOMYOSIN CYTOSKELETON LEADING TO CELL CONTRACTION AND OPENING OF INTERCELLULAR GAPS OR ENHANCEMENT OF CORTICAL ACTIN CYTOSKELETON ASSOCIATED WITH STRENGTHENING OF ENDOTHELIAL BARRIER. THE ROLE OF ACTIN CYTOSKELETON REMODELING IN ENDOTHELIAL BARRIER REGULATION HAS TAKEN THE CENTRAL STAGE, BUT THE IMPACT OF MICROTUBULES IN THIS PROCESS REMAINS LESS EXPLORED AND UNDER-APPRECIATED. THIS REVIEW WILL SUMMARIZE THE CURRENT KNOWLEDGE ON THE CROSSTALK BETWEEN MICROTUBULES DYNAMICS AND ACTIN CYTOSKELETON REMODELING, DESCRIBE THE SIGNALING MECHANISMS MEDIATING THIS CROSSTALK, DISCUSS EPIGENETIC REGULATION OF MICROTUBULES STABILITY AND ITS NEXUS WITH ENDOTHELIAL BARRIER MAINTENANCE, AND OVERVIEW A ROLE OF MICROTUBULES IN TARGETED DELIVERY OF SIGNALING MOLECULES REGULATING ENDOTHELIAL PERMEABILITY AND INFLAMMATION. 2021 17 3289 41 HIF-1ALPHA MEDIATES TUMOR HYPOXIA TO CONFER A PERPETUAL MESENCHYMAL PHENOTYPE FOR MALIGNANT PROGRESSION. ALTHOUGH TUMOR PROGRESSION INVOLVES GENETIC AND EPIGENETIC ALTERATIONS TO NORMAL CELLULAR BIOLOGY, THE UNDERLYING MECHANISMS OF THESE CHANGES REMAIN OBSCURE. NUMEROUS STUDIES HAVE SHOWN THAT HYPOXIA-INDUCIBLE FACTOR 1ALPHA (HIF-1ALPHA) IS OVEREXPRESSED IN MANY HUMAN CANCERS AND UP-REGULATES A HOST OF HYPOXIA-RESPONSIVE GENES FOR CANCER GROWTH AND SURVIVAL. WE RECENTLY IDENTIFIED AN ALTERNATIVE MECHANISM OF HIF-1ALPHA FUNCTION THAT INDUCES GENETIC ALTERATIONS BY SUPPRESSING DNA REPAIR. HERE, WE SHOW THAT LONG-TERM HYPOXIA, WHICH MIMICS THE TUMOR MICROENVIRONMENT, DRIVES A PERPETUAL EPITHELIAL-MESENCHYMAL TRANSITION (EMT) THROUGH UP-REGULATION OF THE ZINC FINGER E-BOX BINDING HOMEOBOX PROTEIN ZEB2, WHEREAS SHORT-TERM HYPOXIA INDUCES A REVERSIBLE EMT THAT REQUIRES THE TRANSCRIPTION FACTOR TWIST1. MOREOVER, WE SHOW THAT THE PERPETUAL EMT DRIVEN BY CHRONIC HYPOXIA DEPENDS ON HIF-1ALPHA INDUCTION OF GENETIC ALTERATIONS RATHER THAN ITS CANONICAL TRANSCRIPTIONAL ACTIVATOR FUNCTION. THESE MESENCHYMAL TUMOR CELLS NOT ONLY ACQUIRE TUMORIGENICITY BUT ALSO DISPLAY CHARACTERISTICS OF ADVANCED CANCERS, INCLUDING NECROSIS, AGGRESSIVE INVASION, AND METASTASIS. HENCE, THESE RESULTS REVEAL A MECHANISM BY WHICH HIF-1ALPHA PROMOTES A PERPETUAL MESENCHYMAL PHENOTYPE, THEREBY ADVANCING TUMOR PROGRESSION. 2011 18 5939 41 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 19 3931 26 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 20 6910 30 [TRANSFORMING GROWTH FACTOR-BETA AND RENAL FIBROSIS]. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS A DRIVING FORCE OF RENAL FIBROSIS, WHICH MAY LEAD TO CHRONIC KIDNEY DISEASES AND EVEN END STAGE RENAL DISEASES. BY ACTIVATING CANONICAL AND NON-CANONICAL SIGNALING PATHWAYS, TGF-BETA PROMOTES THE SYNTHESIS OF EXTRACELLULAR MATRIX WHILE PREVENTING THEIR DEGRADATION. IN THE INJURED KIDNEY, TGF-BETA INDUCES APOPTOSIS, PROLIFERATION AND FIBROTIC RESPONSE OF RENAL CELLS INCLUDING EPITHELIAL CELLS, ENDOTHELIAL CELLS, PODOCYTES, FIBROBLASTS, PERICYTES AND MACROPHAGES, AND IT ALSO PROMOTES TRANSDIFFERENTIATION, ACTIVATION AND PROLIFERATION OF MYOFIBROBLASTS. ADDITIONALLY, TGF-BETA EXERTS PROFIBROTIC EFFECTS BY INTERPLAYING WITH OTHER SIGNALING PATHWAYS LIKE BMP-7, WNT/BETA-CATENIN AND MAP KINASE. SMAD3 IS THE CENTRAL PATHOLOGICAL GENE IN RENAL FIBROSIS, AND EPIGENETIC REGULATION OF TGF-BETA/SMAD3 IS A HOT TOPIC IN KIDNEY FIELD. ALTHOUGH DIRECT TARGETING TGF-BETA MAY CAUSE SIDE EFFECTS INCLUDING TUMORIGENESIS AND IMMUNE DISEASES, THE THERAPEUTIC STRATEGIES TARGETING THE BALANCE OF DOWNSTREAM SMAD3 AND SMAD7 MAY PREVENT OR DELAY THE PROGRESSION OF FIBROTIC KIDNEY DISEASE. 2018