1 4550 97 MUTATION-PROMOTING MOLECULAR NETWORKS OF UNCONTROLLED INFLAMMATION. MORE AND MORE STUDIES SHOW THAT CHRONIC INFLAMMATION CAN LEAD TO TUMOR FORMATION. THE COMPLEX INTERACTIONS OF INFLAMMATORY CELLS, STROMA AND TUMOR PARENCHYMAL CELL ARE CLOSELY RELATED TO TUMOR FORMATION. UNDER THE STATE OF CHRONIC INFLAMMATORY MICROENVIRONMENT, LONG-TERM INTERACTION OF INFLAMMATORY CELLS AND STROMAL CELLS AS WELL AS THE PARENCHYMAL CELLS MAKES SIGNALING PATHWAY IN PARENCHYMA CELLS DISORDERED. A SERIES OF GENE LEVEL EDITOR MODIFICATION, EPIGENETIC CHANGES, AND THE REGULATION OF TRANSCRIPTION AND TRANSLATION CHANGES WILL HAPPEN BASED ON SIGNALING PATHWAY DISORDER. THE CHANGES ULTIMATELY LEAD TO CELL MUTATIONS AND PHENOTYPIC TRANSFORMATION OCCURRED. RECENT FINDINGS PROVIDE AN OBJECTIVE BASIS FOR CANCER TREATMENT AND PREVENTION. HOWEVER, FURTHER DISCUSSES AT THE CORE OF THE POSSIBLE MOLECULAR IN TUMOR FORMATION PROVIDE A THEORETICAL FOUNDATION FOR FUTURE STUDY OF THE PATHOGENESIS AND MOLECULAR TARGETED THERAPY OF CANCER. THIS REVIEW SUMMARIZES THE RESEARCH IN THE FIELD OF CHRONIC INFLAMMATION AND CANCER IN RECENT YEARS, AND ANALYZE THE MOLECULES NETWORK IN THE PROCESS OF THE CARCINOGENIC INFLAMMATION COMPREHENSIVELY. BEYOND THAT, THIS REVIEW INTENDS TO DESCRIBE POSSIBLE CARCINOGENIC INFLAMMATION CORE MOLECULAR AND PROVIDES A THEORETICAL BASIS FOR FUTURE STUDY OF THE PATHOGENESIS, CHEMOPREVENTION AND MOLECULAR TARGETED THERAPY OF CANCER. 2017 2 3640 27 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 3 3964 27 LONG NONCODING RNAS IN LUNG CANCER. DESPITE GREAT PROGRESS IN RESEARCH AND TREATMENT OPTIONS, LUNG CANCER REMAINS THE LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE. ONCOGENIC DRIVER MUTATIONS IN PROTEIN-ENCODING GENES WERE DEFINED AND ALLOW FOR PERSONALIZED THERAPIES BASED ON GENETIC DIAGNOSES. NONETHELESS, DIAGNOSIS OF LUNG CANCER MOSTLY OCCURS AT LATE STAGES, AND CHRONIC TREATMENT IS FOLLOWED BY A FAST ONSET OF CHEMORESISTANCE. HENCE, THERE IS AN URGENT NEED FOR RELIABLE BIOMARKERS AND ALTERNATIVE TREATMENT OPTIONS. WITH THE ERA OF WHOLE GENOME AND TRANSCRIPTOME SEQUENCING TECHNOLOGIES, LONG NONCODING RNAS EMERGED AS A NOVEL CLASS OF VERSATILE, FUNCTIONAL RNA MOLECULES. ALTHOUGH FOR MOST OF THEM THE MECHANISM OF ACTION REMAINS TO BE DEFINED, ACCUMULATING EVIDENCE CONFIRMS THEIR INVOLVEMENT IN VARIOUS ASPECTS OF LUNG TUMORIGENESIS. THEY ARE FUNCTIONAL ON THE EPIGENETIC, TRANSCRIPTIONAL, AND POSTTRANSCRIPTIONAL LEVEL AND ARE REGULATORS OF PATHOPHYSIOLOGICAL KEY PATHWAYS INCLUDING CELL GROWTH, APOPTOSIS, AND METASTASIS. LONG NONCODING RNAS ARE GAINING INCREASING ATTENTION AS POTENTIAL BIOMARKERS AND A NOVEL CLASS OF DRUGGABLE MOLECULES. IT HAS BECOME CLEAR THAT WE ARE ONLY BEGINNING TO UNDERSTAND THE COMPLEXITY OF TUMORIGENIC PROCESSES. THE CLINICAL INTEGRATION OF LONG NONCODING RNAS IN TERMS OF PROGNOSTIC AND PREDICTIVE BIOMARKER SIGNATURES AND ADDITIONAL CANCER TARGETS COULD PROVIDE A CHANCE TO INCREASE THE THERAPEUTIC BENEFIT. HERE, WE REVIEW THE CURRENT KNOWLEDGE ABOUT THE EXPRESSION, REGULATION, BIOLOGICAL FUNCTION, AND CLINICAL RELEVANCE OF LONG NONCODING RNAS IN LUNG CANCER. 2016 4 1872 21 EMERGING ROLE OF LONG NON-CODING RNAS IN ENDOTHELIAL DYSFUNCTION AND THEIR MOLECULAR MECHANISMS. LONG NON-CODING RNAS (LNCRNAS) ARE THE NOVEL CLASS OF TRANSCRIPTS INVOLVED IN TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, TRANSLATIONAL, AND POST-TRANSLATIONAL REGULATION OF PHYSIOLOGY AND THE PATHOLOGY OF DISEASES. STUDIES HAVE EVIDENCED THAT THE IMPAIRMENT OF ENDOTHELIUM IS A CRITICAL EVENT IN THE PATHOGENESIS OF ATHEROSCLEROSIS AND ITS COMPLICATIONS. ENDOTHELIAL DYSFUNCTION IS CHARACTERIZED BY AN IMBALANCE IN VASODILATION AND VASOCONSTRICTION, OXIDATIVE STRESS, PROINFLAMMATORY FACTORS, AND NITRIC OXIDE BIOAVAILABILITY. DISRUPTION OF THE ENDOTHELIAL BARRIER PERMEABILITY, THE FIRST STEP IN DEVELOPING ATHEROSCLEROTIC LESIONS IS A CONSEQUENCE OF ENDOTHELIAL DYSFUNCTION. THOUGH SEVERAL FACTORS INTERFERE WITH THE NORMAL FUNCTIONING OF THE ENDOTHELIUM, INTRINSIC EPIGENETIC MECHANISMS GOVERNING ENDOTHELIAL FUNCTION ARE REGULATED BY LNCRNAS AND PERTURBATIONS CONTRIBUTE TO THE PATHOGENESIS OF THE DISEASE. THIS REVIEW COMPREHENSIVELY ADDRESSES THE BIOGENESIS OF LNCRNA AND MOLECULAR MECHANISMS UNDERLYING AND REGULATION IN ENDOTHELIAL FUNCTION. AN INSIGHT CORRELATING LNCRNAS AND ENDOTHELIAL DYSFUNCTION-ASSOCIATED DISEASES CAN POSITIVELY IMPACT THE DEVELOPMENT OF NOVEL BIOMARKERS AND THERAPEUTIC TARGETS IN ENDOTHELIAL DYSFUNCTION-ASSOCIATED DISEASES AND TREATMENT STRATEGIES. 2022 5 2460 21 EPIGENETIC THERAPIES FOR OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS AN AGE-ASSOCIATED DISEASE CHARACTERIZED BY CHRONIC JOINT PAIN RESULTING FROM DEGRADATION OF ARTICULAR CARTILAGE, INFLAMMATION OF THE SYNOVIAL LINING, AND CHANGES TO THE SUBCHONDRAL BONE. DESPITE THE WIDE PREVALENCE, NO FDA-APPROVED DISEASE-MODIFYING DRUGS EXIST. RECENT EVIDENCE HAS DEMONSTRATED THAT EPIGENETIC DYSREGULATION OF MULTIPLE MOLECULAR PATHWAYS UNDERLIES OA PATHOGENESIS, PROVIDING A NEW MECHANISTIC AND THERAPEUTIC AXIS WITH THE ADVANTAGE OF TARGETING MULTIPLE DEREGULATED PATHWAYS SIMULTANEOUSLY. IN THIS REVIEW, WE FOCUS ON THE EPIGENETIC REGULATORS THAT HAVE BEEN IMPLICATED IN OA, THEIR INDIVIDUAL ROLES, AND POTENTIAL CROSSTALK. FINALLY, WE DISCUSS THE PHARMACOLOGICAL MOLECULES THAT CAN MODULATE THEIR ACTIVITIES AND DISCUSS THE POTENTIAL ADVANTAGES AND CHALLENGES ASSOCIATED WITH EPIGENOME-BASED THERAPEUTICS FOR OA. 2020 6 2817 21 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 3273 22 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 8 3103 25 GENOMIC LANDSCAPE OF HCC. INTRODUCTION: HEPATOCELLULAR CARCINOMA (HCC) IS A LEADING CAUSE OF CANCER RELATED MORTALITY IN THE WORLD AND IT HAS LIMITED TREATMENT OPTIONS. UNDERSTANDING THE MOLECULAR DRIVERS OF HCC IS IMPORTANT TO DEVELOP NOVEL BIOMARKERS AND THERAPEUTICS. PURPOSE OF REVIEW: HCC ARISES IN A COMPLEX BACKGROUND OF CHRONIC HEPATITIS, FIBROSIS AND LIVER REGENERATION WHICH LEAD TO GENOMIC CHANGES. HERE, WE SUMMARIZE STUDIES THAT HAVE EXPANDED OUR UNDERSTANDING OF THE MOLECULAR LANDSCAPE OF HCC. RECENT FINDINGS: RECENT TECHNOLOGICAL ADVANCES IN NEXT GENERATION SEQUENCING (NGS) HAVE ELUCIDATED SPECIFIC GENETIC AND MOLECULAR PROGRAMS INVOLVED IN HEPATOCARCINOGENESIS. WE SUMMARIZE THE MAJOR SOMATIC MUTATIONS AND EPIGENETIC CHANGES HAVE BEEN IDENTIFIED IN NGS-BASED STUDIES. WE ALSO DESCRIBE PROMISING MOLECULAR THERAPIES AND IMMUNOTHERAPIES WHICH TARGET SPECIFIC GENETIC AND EPIGENETIC MOLECULAR EVENTS. SUMMARY: THE GENOMIC LANDSCAPE OF HCC IS INCREDIBLY COMPLEX AND HETEROGENEOUS. PROMISING NEW DEVELOPMENTS ARE HELPING US DECIPHER THE MOLECULAR DRIVERS OF HCC AND LEADING TO NEW THERAPIES. 2020 9 2413 25 EPIGENETIC SIGNALING AND RNA REGULATION IN CARDIOVASCULAR DISEASES. RNA EPIGENETICS IS PERHAPS THE MOST RECENT FIELD OF INTEREST FOR TRANSLATIONAL EPIGENETICISTS. RNA MODIFICATIONS CREATE SUCH AN EXTENSIVE NETWORK OF EPIGENETICALLY DRIVEN COMBINATIONS WHOSE ROLE IN PHYSIOLOGY AND PATHOPHYSIOLOGY IS STILL FAR FROM BEING ELUCIDATED. NOT SURPRISINGLY, SOME OF THE PLAYERS DETERMINING CHANGES IN RNA STRUCTURE ARE IN COMMON WITH THOSE INVOLVED IN DNA AND CHROMATIN STRUCTURE REGULATION, WHILE OTHER MOLECULES SEEM VERY SPECIFIC TO RNA. IT IS ENVISAGED, THEN, THAT NEW SMALL MOLECULES, ACTING SELECTIVELY ON RNA EPIGENETIC CHANGES, WILL BE REPORTED SOON, OPENING NEW THERAPEUTIC INTERVENTIONS BASED ON THE CORRECTION OF THE RNA EPIGENETIC LANDSCAPE. IN THIS REVIEW, WE SHALL SUMMARIZE SOME ASPECTS OF RNA EPIGENETICS LIMITED TO THOSE IN WHICH THE POTENTIAL CLINICAL TRANSLATABILITY TO CARDIOVASCULAR DISEASE IS EMERGING. 2020 10 5805 33 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 11 2283 31 EPIGENETIC REGULATION IN FIBROSIS PROGRESS. FIBROSIS, A COMMON PROCESS OF CHRONIC INFLAMMATORY DISEASES, IS DEFINED AS A REPAIR RESPONSE DISORDER WHEN ORGANS UNDERGO CONTINUOUS DAMAGE, ULTIMATELY LEADING TO SCAR FORMATION AND FUNCTIONAL FAILURE. AROUND THE WORLD, FIBROTIC DISEASES CAUSE HIGH MORTALITY, UNFORTUNATELY, WITH LIMITED TREATMENT MEANS IN CLINICAL PRACTICE. WITH THE DEVELOPMENT AND APPLICATION OF DEEP SEQUENCING TECHNOLOGY, COMPREHENSIVELY EXPLORING THE EPIGENETIC MECHANISM IN FIBROSIS HAS BEEN ALLOWED. EXTENSIVE REMODELING OF EPIGENETICS CONTROLLING VARIOUS CELLS PHENOTYPE AND MOLECULAR MECHANISMS INVOLVED IN FIBROGENESIS WAS SUBSEQUENTLY VERIFIED. IN THIS REVIEW, WE SUMMARIZE THE REGULATORY MECHANISMS OF DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNAS (NCRNAS) AND N6-METHYLADENOSINE (M6A) MODIFICATION IN ORGAN FIBROSIS, FOCUSING ON HEART, LIVER, LUNG AND KIDNEY. ADDITIONALLY, WE EMPHASIZE THE DIVERSITY OF EPIGENETICS IN THE CELLULAR AND MOLECULAR MECHANISMS RELATED TO FIBROSIS. FINALLY, THE POTENTIAL AND PROSPECT OF TARGETED THERAPY FOR FIBROSIS BASED ON EPIGENETIC IS DISCUSSED. 2021 12 6621 30 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 13 4336 27 MICRORNAS: THE UNDERLYING MEDIATORS OF PATHOGENETIC PROCESSES IN VASCULAR COMPLICATIONS OF DIABETES. DIABETES MELLITUS CAUSES CHRONIC COMPLICATIONS PRIMARILY AFFECTING THE VASCULATURE OF VARIOUS ORGANS, RISKING PATIENTS FOR RENAL FAILURE, VISION LOSS AND HEART FAILURE. A NEWLY DISCOVERED CLASS OF MOLECULES, MICRORNAS, MAY BE IMPORTANT IN THE GENESIS OF THESE PATHOLOGIC PROCESSES. MICRORNAS REGULATE GENE EXPRESSION AT THE POST-TRANSCRIPTIONAL LEVEL BY INHIBITING TARGET MESSENGER RNA TRANSLATION. IN DISEASE STATES, HOWEVER, THE EXPRESSION OF MICRORNAS OFTEN IS ALTERED, RESULTING IN FURTHER ALTERED EXPRESSION (MOSTLY OVEREXPRESSION) OF DOWNSTREAM TARGET GENES. INTERESTINGLY, RESTORING MICRORNA EXPRESSION TO NORMAL LEVELS CAN CORRECT DOWNSTREAM EFFECTS AND PREVENT DIABETES-ASSOCIATED CHANGES. INVESTIGATIONS INTO MICRORNA INVOLVED IN VARIOUS PATHOGENETIC PROCESSES MEDIATING DIABETIC NEPHROPATHY, RETINOPATHY AND CARDIOMYOPATHY ARE HIGHLIGHTED IN THIS REVIEW. FUTURE DIRECTIONS OF MICRORNA IN THERAPEUTICS AND DIAGNOSTICS ARE ALSO DISCUSSED. IT IS OUR INTENT TO HELP THE READER APPRECIATE THE DIVERSE INTERACTIONS MICRORNAS HAVE IN CELLULAR SIGNALLING AND HOW UNDERSTANDING EPIGENETIC ELEMENTS, SUCH AS MICRORNAS, POTENTIALLY CAN YIELD NEW THERAPEUTIC STRATEGIES. 2013 14 1864 28 EMERGING AVENUES LINKING INFLAMMATION AND CANCER. THE ROLE OF INFLAMMATION IN CARCINOGENESIS HAS BEEN EXTENSIVELY INVESTIGATED AND WELL DOCUMENTED. MANY BIOCHEMICAL PROCESSES THAT ARE ALTERED DURING CHRONIC INFLAMMATION HAVE BEEN IMPLICATED IN TUMORIGENESIS. THESE INCLUDE SHIFTING CELLULAR REDOX BALANCE TOWARD OXIDATIVE STRESS; INDUCTION OF GENOMIC INSTABILITY; INCREASED DNA DAMAGE; STIMULATION OF CELL PROLIFERATION, METASTASIS, AND ANGIOGENESIS; DEREGULATION OF CELLULAR EPIGENETIC CONTROL OF GENE EXPRESSION; AND INAPPROPRIATE EPITHELIAL-TO-MESENCHYMAL TRANSITION. A WIDE ARRAY OF PROINFLAMMATORY CYTOKINES, PROSTAGLANDINS, NITRIC OXIDE, AND MATRICELLULAR PROTEINS ARE CLOSELY INVOLVED IN PREMALIGNANT AND MALIGNANT CONVERSION OF CELLS IN A BACKGROUND OF CHRONIC INFLAMMATION. INAPPROPRIATE TRANSCRIPTION OF GENES ENCODING INFLAMMATORY MEDIATORS, SURVIVAL FACTORS, AND ANGIOGENIC AND METASTATIC PROTEINS IS THE KEY MOLECULAR EVENT IN LINKING INFLAMMATION AND CANCER. ABERRANT CELL SIGNALING PATHWAYS COMPRISING VARIOUS KINASES AND THEIR DOWNSTREAM TRANSCRIPTION FACTORS HAVE BEEN IDENTIFIED AS THE MAJOR CONTRIBUTORS IN ABNORMAL GENE EXPRESSION ASSOCIATED WITH INFLAMMATION-DRIVEN CARCINOGENESIS. THE POSTTRANSCRIPTIONAL REGULATION OF GENE EXPRESSION BY MICRORNAS ALSO PROVIDES THE MOLECULAR BASIS FOR LINKING INFLAMMATION TO CANCER. THIS REVIEW HIGHLIGHTS THE MULTIFACETED ROLE OF INFLAMMATION IN CARCINOGENESIS IN THE CONTEXT OF ALTERED CELLULAR REDOX SIGNALING. 2012 15 1712 33 DYSFUNCTIONAL VASCULAR ENDOTHELIUM AS A DRIVER OF ATHEROSCLEROSIS: EMERGING INSIGHTS INTO PATHOGENESIS AND TREATMENT. ATHEROSCLEROSIS, THE CHRONIC ACCUMULATION OF CHOLESTEROL-RICH PLAQUE WITHIN ARTERIES, IS ASSOCIATED WITH A BROAD SPECTRUM OF CARDIOVASCULAR DISEASES INCLUDING MYOCARDIAL INFARCTION, AORTIC ANEURYSM, PERIPHERAL VASCULAR DISEASE, AND STROKE. ATHEROSCLEROTIC CARDIOVASCULAR DISEASE REMAINS A LEADING CAUSE OF MORTALITY IN HIGH-INCOME COUNTRIES AND RECENT YEARS HAVE WITNESSED A NOTABLE INCREASE IN PREVALENCE WITHIN LOW- AND MIDDLE-INCOME REGIONS OF THE WORLD. CONSIDERING THIS PROMINENT AND EVOLVING GLOBAL BURDEN, THERE IS A NEED TO IDENTIFY THE CELLULAR MECHANISMS THAT UNDERLIE THE PATHOGENESIS OF ATHEROSCLEROSIS TO DISCOVER NOVEL THERAPEUTIC TARGETS FOR PREVENTING OR MITIGATING ITS CLINICAL SEQUELAE. DESPITE DECADES OF RESEARCH, WE STILL DO NOT FULLY UNDERSTAND THE COMPLEX CELL-CELL INTERACTIONS THAT DRIVE ATHEROSCLEROSIS, BUT NEW INVESTIGATIVE APPROACHES ARE RAPIDLY SHEDDING LIGHT ON THESE ESSENTIAL MECHANISMS. THE VASCULAR ENDOTHELIUM RESIDES AT THE INTERFACE OF SYSTEMIC CIRCULATION AND THE UNDERLYING VESSEL WALL AND PLAYS AN ESSENTIAL ROLE IN GOVERNING PATHOPHYSIOLOGICAL PROCESSES DURING ATHEROGENESIS. IN THIS REVIEW, WE PRESENT EMERGING EVIDENCE THAT IMPLICATES THE ACTIVATED ENDOTHELIUM AS A DRIVER OF ATHEROSCLEROSIS BY DIRECTING SITE-SPECIFICITY OF PLAQUE FORMATION AND BY PROMOTING PLAQUE DEVELOPMENT THROUGH INTRACELLULAR PROCESSES, WHICH REGULATE ENDOTHELIAL CELL PROLIFERATION AND TURNOVER, METABOLISM, PERMEABILITY, AND PLASTICITY. MOREOVER, WE HIGHLIGHT NOVEL MECHANISMS OF INTERCELLULAR COMMUNICATION BY WHICH ENDOTHELIAL CELLS MODULATE THE ACTIVITY OF KEY VASCULAR CELL POPULATIONS INVOLVED IN ATHEROGENESIS, AND DISCUSS HOW ENDOTHELIAL CELLS CONTRIBUTE TO RESOLUTION BIOLOGY - A PROCESS THAT IS DYSREGULATED IN ADVANCED PLAQUES. FINALLY, WE DESCRIBE IMPORTANT FUTURE DIRECTIONS FOR PRECLINICAL ATHEROSCLEROSIS RESEARCH, INCLUDING EPIGENETIC AND TARGETED THERAPIES, TO LIMIT THE PROGRESSION OF ATHEROSCLEROSIS IN AT-RISK OR AFFECTED PATIENTS. 2021 16 5309 25 PSORIASIS PATHOGENESIS AND TREATMENT. RESEARCH ON PSORIASIS PATHOGENESIS HAS LARGELY INCREASED KNOWLEDGE ON SKIN BIOLOGY IN GENERAL. IN THE PAST 15 YEARS, BREAKTHROUGHS IN THE UNDERSTANDING OF THE PATHOGENESIS OF PSORIASIS HAVE BEEN TRANSLATED INTO TARGETED AND HIGHLY EFFECTIVE THERAPIES PROVIDING FUNDAMENTAL INSIGHTS INTO THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES WITH A DOMINANT IL-23/TH17 AXIS. THIS REVIEW DISCUSSES THE MECHANISMS INVOLVED IN THE INITIATION AND DEVELOPMENT OF THE DISEASE, AS WELL AS THE THERAPEUTIC OPTIONS THAT HAVE ARISEN FROM THE DISSECTION OF THE INFLAMMATORY PSORIATIC PATHWAYS. OUR DISCUSSION BEGINS BY ADDRESSING THE INFLAMMATORY PATHWAYS AND KEY CELL TYPES INITIATING AND PERPETUATING PSORIATIC INFLAMMATION. NEXT, WE DESCRIBE THE ROLE OF GENETICS, ASSOCIATED EPIGENETIC MECHANISMS, AND THE INTERACTION OF THE SKIN FLORA IN THE PATHOPHYSIOLOGY OF PSORIASIS. FINALLY, WE INCLUDE A COMPREHENSIVE REVIEW OF WELL-ESTABLISHED WIDELY AVAILABLE THERAPIES AND NOVEL TARGETED DRUGS. 2019 17 2180 34 EPIGENETIC MECHANISMS OF PANCREATOBILIARY FIBROSIS. PURPOSE OF REVIEW: THE GOAL OF THIS MANUSCRIPT IS TO REVIEW THE CURRENT LITERATURE RELATED TO FIBROGENESIS IN THE PANCREATOBILIARY SYSTEM AND HOW THIS PROCESS CONTRIBUTES TO PANCREATIC AND BILIARY DISEASES. IN PARTICULAR, WE SEEK TO DEFINE THE CURRENT STATE OF KNOWLEDGE REGARDING THE EPIGENETIC MECHANISMS THAT GOVERN AND REGULATE TISSUE FIBROSIS IN THESE ORGANS. A BETTER UNDERSTANDING OF THESE UNDERLYING MOLECULAR EVENTS WILL SET THE STAGE FOR FUTURE EPIGENETIC THERAPEUTICS. RECENT FINDINGS: WE HIGHLIGHT THE SIGNIFICANT ADVANCES THAT HAVE BEEN MADE IN DEFINING THE PATHOGENESIS OF PANCREATOBILIARY FIBROSIS AS IT RELATES TO CHRONIC PANCREATITIS, PANCREATIC CANCER, AND THE FIBRO-OBLITERATIVE CHOLANGIOPATHIES. WE ALSO REVIEW THE CELL TYPES INVOLVED AS WELL AS CONCEPTS RELATED TO EPITHELIAL-MESENCHYMAL CROSSTALK. FURTHERMORE, WE OUTLINE IMPORTANT SIGNALING PATHWAYS (E.G., TGFBETA) AND DIVERSE EPIGENETIC PROCESSES (I.E., DNA METHYLATION, NON-CODING RNAS, HISTONE MODIFICATIONS, AND 3D CHROMATIN REMODELING) THAT REGULATE FIBROGENIC GENE NETWORKS IN THESE CONDITIONS. WE REVIEW A GROWING BODY OF SCIENTIFIC EVIDENCE LINKING EPIGENETIC REGULATORY EVENTS TO FIBROTIC DISEASE STATES IN THE PANCREAS AND BILIARY SYSTEM. ADVANCES IN THIS UNDERSTUDIED AREA WILL BE CRITICAL TOWARD DEVELOPING EPIGENETIC PHARMACOLOGICAL APPROACHES THAT MAY LEAD TO MORE EFFECTIVE TREATMENTS FOR THESE DEVASTATING AND DIFFICULT TO TREAT DISORDERS. 2019 18 6913 22 [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 19 6543 24 TRANSCRIPTOME REMODELING IN HYPOXIC INFLAMMATION. HYPOXIA IS AN INTEGRAL COMPONENT OF THE INFLAMED TISSUE MICROENVIRONMENT. TODAY, THE INFLUENCE OF HYPOXIA ON THE NATURAL EVOLUTION OF INFLAMMATORY RESPONSES IS WIDELY ACCEPTED; HOWEVER, MANY MOLECULAR AND CELLULAR MECHANISMS MEDIATING THIS RELATIONSHIP REMAIN TO BE CLARIFIED. HYPOXIC STRESS AFFECTS SEVERAL INDEPENDENT TRANSCRIPTIONAL REGULATORS RELATED TO INFLAMMATION IN WHICH HIF-1 AND NF-KAPPAB PLAY CENTRAL ROLES. TRANSCRIPTION FACTORS INTERACT WITH BOTH HATS AND HDACS, WHICH ARE COMPONENTS OF LARGE MULTIPROTEIN CO-REGULATORY COMPLEXES. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE ON HYPOXIA-RESPONSIVE TRANSCRIPTIONAL PATHWAYS IN INFLAMMATION AND THEIR IMPORTANCE IN THE ETIOLOGY OF CHRONIC INFLAMMATORY DISEASES, WITH THE PRIMARY FOCUS ON TRANSCRIPTIONAL CO-REGULATORS AND HISTONE MODIFICATIONS IN DEFINING GENE-SPECIFIC TRANSCRIPTIONAL RESPONSES IN HYPOXIA, AND ON THE RECENT PROGRESS IN THE UNDERSTANDING OF HYPOXIA-MEDIATED EPIGENETIC REPROGRAMMING. FURTHERMORE, THIS REVIEW DISCUSSES THE MOLECULAR CROSS-TALK BETWEEN GLUCOCORTICOID ANTI-INFLAMMATORY PATHWAYS AND HYPOXIA. 2010 20 4452 28 MOLECULAR MECHANISMS AND MANAGEMENT OF A CUTANEOUS INFLAMMATORY DISORDER: PSORIASIS. PSORIASIS IS A COMPLEX CHRONIC INFLAMMATORY CUTANEOUS DISORDER. TO DATE, ROBUST MOLECULAR MECHANISMS OF PSORIASIS HAVE BEEN REPORTED. AMONG DIVERSE ABERRANT IMMUNOPATHOGENETIC MECHANISMS, THE CURRENT MODEL EMPHASIZES THE ROLE OF TH1 AND THE IL-23/TH17 AXIS, SKIN-RESIDENT IMMUNE CELLS AND MAJOR SIGNAL TRANSDUCTION PATHWAYS INVOLVED IN PSORIASIS. THE MULTIPLE GENETIC RISK LOCI FOR PSORIASIS HAVE BEEN RAPIDLY REVEALED WITH THE ADVENT OF A NOVEL TECHNOLOGY. MOREOVER, IDENTIFYING EPIGENETIC MODIFICATIONS COULD BRIDGE THE GAP BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS IN PSORIASIS. THIS REVIEW WILL PROVIDE A BETTER UNDERSTANDING OF THE PATHOGENESIS OF PSORIASIS BY UNRAVELING THE COMPLICATED INTERPLAY AMONG IMMUNOLOGICAL ABNORMALITIES, GENETIC RISK FOCI, EPIGENETIC MODIFICATION AND ENVIRONMENTAL FACTORS OF PSORIASIS. WITH ADVANCES IN MOLECULAR BIOLOGY, DIVERSE NEW TARGETS ARE UNDER INVESTIGATION TO MANAGE PSORIASIS. THE RECENT ADVANCES IN TREATMENT MODALITIES FOR PSORIASIS BASED ON TARGETED MOLECULES ARE ALSO DISCUSSED. 2017