1 3640 101 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 2 3374 22 HISTONE POST-TRANSLATIONAL MODIFICATIONS AS POTENTIAL THERAPEUTIC TARGETS FOR PAIN MANAGEMENT. EFFECTIVE PHARMACOLOGICAL MANAGEMENT OF PAIN ASSOCIATED WITH TISSUE PATHOLOGY IS AN UNMET MEDICAL NEED. TRANSCRIPTIONAL MODIFICATIONS IN NOCICEPTIVE PATHWAYS ARE PIVOTAL FOR THE DEVELOPMENT AND THE MAINTENANCE OF PAIN ASSOCIATED WITH TISSUE DAMAGE. ACCUMULATING EVIDENCE HAS SHOWN THE IMPORTANCE OF THE EPIGENETIC CONTROL OF TRANSCRIPTION IN NOCICEPTIVE PATHWAYS VIA HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS). HENCE, HISTONE PTMS COULD BE TARGETS FOR NOVEL EFFECTIVE ANALGESICS. HERE, WE DISCUSS THE CURRENT UNDERSTANDING OF HISTONE PTMS IN THE MODULATION OF GENE EXPRESSION AFFECTING NOCICEPTION AND PAIN PHENOTYPES FOLLOWING TISSUE INJURY. WE ALSO PROVIDE A CRITICAL VIEW OF THE TRANSLATIONAL IMPLICATIONS OF PRECLINICAL MODELS AND DISCUSS OPPORTUNITIES AND CHALLENGES OF TARGETING HISTONE PTMS TO RELIEVE PAIN IN CLINICALLY RELEVANT TISSUE INJURIES. 2021 3 4380 31 MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS IN RHEUMATOID ARTHRITIS. CONTROL OF EXCESSIVE MITOCHONDRIAL OXIDATIVE STRESS COULD PROVIDE NEW TARGETS FOR BOTH PREVENTIVE AND THERAPEUTIC INTERVENTIONS IN THE TREATMENT OF CHRONIC INFLAMMATION OR ANY PATHOLOGY THAT DEVELOPS UNDER AN INFLAMMATORY SCENARIO, SUCH AS RHEUMATOID ARTHRITIS (RA). INCREASING EVIDENCE HAS DEMONSTRATED THE ROLE OF MITOCHONDRIAL ALTERATIONS IN AUTOIMMUNE DISEASES MAINLY DUE TO THE INTERPLAY BETWEEN METABOLISM AND INNATE IMMUNITY, BUT ALSO IN THE MODULATION OF INFLAMMATORY RESPONSE OF RESIDENT CELLS, SUCH AS SYNOVIOCYTES. THUS, MITOCHONDRIAL DYSFUNCTION DERIVED FROM SEVERAL DANGER SIGNALS COULD ACTIVATE TRICARBOXYLIC ACID (TCA) DISRUPTION, THEREBY FAVORING A VICIOUS CYCLE OF OXIDATIVE/MITOCHONDRIAL STRESS. MITOCHONDRIAL DYSFUNCTION CAN ACT THROUGH MODULATING INNATE IMMUNITY VIA REDOX-SENSITIVE INFLAMMATORY PATHWAYS OR DIRECT ACTIVATION OF THE INFLAMMASOME. BESIDES, MITOCHONDRIA ALSO HAVE A CENTRAL ROLE IN REGULATING CELL DEATH, WHICH IS DEEPLY ALTERED IN RA. ADDITIONALLY, MULTIPLE EVIDENCE SUGGESTS THAT PATHOLOGICAL PROCESSES IN RA CAN BE SHAPED BY EPIGENETIC MECHANISMS AND THAT IN TURN, MITOCHONDRIA ARE INVOLVED IN EPIGENETIC REGULATION. FINALLY, WE WILL DISCUSS ABOUT THE INVOLVEMENT OF SOME DIETARY COMPONENTS IN THE ONSET AND PROGRESSION OF RA. 2022 4 1872 36 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 3734 34 INNATE IMMUNE MEMORY IN MONOCYTES AND MACROPHAGES: THE POTENTIAL THERAPEUTIC STRATEGIES FOR ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A COMPLEX METABOLIC DISEASE CHARACTERIZED BY THE DYSFUNCTION OF LIPID METABOLISM AND CHRONIC INFLAMMATION IN THE INTIMAL SPACE OF THE VESSEL. AS THE MOST ABUNDANT INNATE IMMUNE CELLS, MONOCYTE-DERIVED MACROPHAGES PLAY A PIVOTAL ROLE IN THE INFLAMMATORY RESPONSE, CHOLESTEROL METABOLISM, AND FOAM CELL FORMATION. IN RECENT DECADES, IT HAS BEEN DEMONSTRATED THAT MONOCYTES AND MACROPHAGES CAN ESTABLISH INNATE IMMUNE MEMORY (ALSO TERMED TRAINED IMMUNITY) VIA ENDOGENOUS AND EXOGENOUS ATHEROGENIC STIMULI AND EXHIBIT A LONG-LASTING PROINFLAMMATORY PHENOTYPE. THE IMPORTANT CELLULAR METABOLISM PROCESSES, INCLUDING GLYCOLYSIS, OXIDATIVE PHOSPHORYLATION (OXPHOS), THE TRICARBOXYLIC ACID (TCA) CYCLE, FATTY ACID SYNTHESIS, AND CHOLESTEROL SYNTHESIS, ARE REPROGRAMMED. TRAINED MONOCYTES/MACROPHAGES WITH INNATE IMMUNE MEMORY CAN BE PERSISTENTLY HYPERACTIVATED AND CAN UNDERGO EXTENSIVE EPIGENETIC REWIRING, WHICH CONTRIBUTES TO THE PATHOPHYSIOLOGICAL DEVELOPMENT OF ATHEROSCLEROSIS VIA INCREASED PROINFLAMMATORY CYTOKINE PRODUCTION AND LIPID ACCUMULATION. HERE, WE PROVIDE AN OVERVIEW OF THE REGULATION OF CELLULAR METABOLIC PROCESSES AND EPIGENETIC MODIFICATIONS OF INNATE IMMUNE MEMORY IN MONOCYTES/MACROPHAGES AS WELL AS THE POTENTIAL ENDOGENOUS AND EXOGENOUS STIMULATIONS INVOLVED IN THE PROGRESSION OF ATHEROSCLEROSIS THAT HAVE BEEN REPORTED RECENTLY. THESE ELUCIDATIONS MIGHT BE BENEFICIAL FOR FURTHER UNDERSTANDING INNATE IMMUNE MEMORY AND THE DEVELOPMENT OF THERAPEUTIC STRATEGIES FOR INFLAMMATORY DISEASES AND ATHEROSCLEROSIS. 2022 6 4333 33 MICRORNAS: KEY PLAYERS IN MICROGLIA AND ASTROCYTE MEDIATED INFLAMMATION IN CNS PATHOLOGIES. THE SIGNIFICANCE OF MICROGLIA AND ASTROCYTES IN NEURAL DEVELOPMENT, IN MAINTAINING SYNAPTIC CONNECTIONS AND HOMEOSTASIS IN THE HEALTHY BRAIN IS WELL ESTABLISHED. MICROGLIA ARE DYNAMIC IMMUNE CELLS OF THE BRAIN THAT ELICIT AN IMMUNE RESPONSE DURING BRAIN DAMAGE AND ALSO PARTICIPATE IN TISSUE REPAIR AND REGENERATION, WHILE ASTROCYTES CONTRIBUTE TO THE LOCAL INFLAMMATORY RESPONSE BY PRODUCING PROINFLAMMATORY CYTOKINES AND RESOLVING NEURONAL DAMAGE THROUGH PRODUCTION OF ANTI-INFLAMMATORY CYTOKINES AND NEUROTROPHIC FACTORS. RECENT EFFORTS HAVE FOCUSED ON ELUCIDATING THE EPIGENETIC MECHANISMS WHICH REGULATE GLIAL CELL BEHAVIOR IN NORMAL AND PATHOLOGIC STATES. AN IMPORTANT CLASS OF EPIGENETIC REGULATORS IS MICRORNAS (MIRNAS) WHICH ARE SMALL NON-CODING RNA MOLECULES THAT REGULATE GENE EXPRESSION POSTTRANSCRIPTIONALLY. CERTAIN DYSREGULATED MIRNAS CONTRIBUTE TO CHRONIC MICROGLIAL INFLAMMATION IN THE BRAIN, THEREBY LEADING TO PROGRESSION OF NEUROLOGICAL DISEASES LIKE ALZHEIMER'S DISEASE, TRAUMATIC INJURY, AMYOTROPHIC LATERAL SCLEROSIS AND STROKE. FURTHER, SEVERAL MIRNAS ARE DIFFERENTIALLY EXPRESSED IN ASTROCYTES AFTER ISCHEMIA AND SPINAL CORD INJURY. DESPITE KNOWLEDGE ABOUT MIRNAS IN NEUROINFLAMMATION, LITTLE IS KNOWN ABOUT EFFECTIVE DELIVERY ROUTES AND PHARMACOKINETIC DATA FOR MIRNA BASED THERAPEUTICS. THIS REVIEW SUMMARIZES THE CURRENT RESEARCH ON THE ROLE OF MIRNAS IN PROMOTING AND INHIBITING INFLAMMATORY RESPONSE OF MICROGLIA AND ASTROCYTES IN A DISEASE-SPECIFIC MANNER. IN ADDITION, MIRNA DELIVERY AS A THERAPEUTIC STRATEGY TO TREAT NEUROINFLAMMATION IS DISCUSSED. 2016 7 5545 28 ROLE OF EPIGENETIC MECHANISMS IN CHRONIC PAIN. PAIN IS AN UNPLEASANT BUT ESSENTIAL-TO-LIFE SENSATION, USUALLY RESULTING FROM TISSUE DAMAGE. WHEN PAIN PERSISTS LONG AFTER THE INJURY HAS RESOLVED, IT BECOMES PATHOLOGICAL. THE PRECISE MOLECULAR AND CELLULAR MECHANISMS CAUSING THE TRANSITION FROM ACUTE TO CHRONIC PAIN ARE NOT FULLY UNDERSTOOD. A KEY ASPECT OF PAIN CHRONICITY IS THAT SEVERAL PLASTICITY EVENTS HAPPEN ALONG THE NEURAL PATHWAYS INVOLVED IN PAIN. THESE LONG-LASTING ADAPTIVE CHANGES ARE ENABLED BY ALTERATION IN THE EXPRESSION OF RELEVANT GENES. AMONG THE DIFFERENT MODULATORS OF GENE TRANSCRIPTION IN ADAPTIVE PROCESSES IN THE NERVOUS SYSTEM, EPIGENETIC MECHANISMS PLAY A PIVOTAL ROLE. IN THIS REVIEW, I WILL FIRST OUTLINE THE MAIN CLASSES OF EPIGENETIC MEDIATORS AND THEN DISCUSS THEIR IMPLICATIONS IN CHRONIC PAIN. 2022 8 799 43 CELLULAR SIGNALING AND POTENTIAL NEW TREATMENT TARGETS IN DIABETIC RETINOPATHY. DYSFUNCTION AND DEATH OF MICROVASCULAR CELLS AND IMBALANCE BETWEEN THE PRODUCTION AND THE DEGRADATION OF EXTRACELLULAR MATRIX (ECM) PROTEINS ARE A CHARACTERISTIC FEATURE OF DIABETIC RETINOPATHY (DR). GLUCOSE-INDUCED BIOCHEMICAL ALTERATIONS IN THE VASCULAR ENDOTHELIAL CELLS MAY ACTIVATE A CASCADE OF SIGNALING PATHWAYS LEADING TO INCREASED PRODUCTION OF ECM PROTEINS AND CELLULAR DYSFUNCTION/DEATH. CHRONIC DIABETES LEADS TO THE ACTIVATION OF A NUMBER OF SIGNALING PROTEINS INCLUDING PROTEIN KINASE C, PROTEIN KINASE B, AND MITOGEN-ACTIVATED PROTEIN KINASES. THESE SIGNALING CASCADES ARE ACTIVATED IN RESPONSE TO HYPERGLYCEMIA-INDUCED OXIDATIVE STRESS, POLYOL PATHWAY, AND ADVANCED GLYCATION END PRODUCT FORMATION AMONG OTHERS. THE ABERRANT SIGNALING PATHWAYS ULTIMATELY LEAD TO ACTIVATION OF TRANSCRIPTION FACTORS SUCH AS NUCLEAR FACTOR-KAPPAB AND ACTIVATING PROTEIN-1. THE ACTIVITY OF THESE TRANSCRIPTION FACTORS IS ALSO REGULATED BY EPIGENETIC MECHANISMS THROUGH TRANSCRIPTIONAL COACTIVATOR P300. THESE COMPLEX SIGNALING PATHWAYS MAY BE INVOLVED IN GLUCOSE-INDUCED ALTERATIONS OF ENDOTHELIAL CELL PHENOTYPE LEADING TO THE PRODUCTION OF INCREASED ECM PROTEINS AND VASOACTIVE EFFECTOR MOLECULES CAUSING FUNCTIONAL AND STRUCTURAL CHANGES IN THE MICROVASCULATURE. UNDERSTANDING OF SUCH MECHANISTIC PATHWAYS WILL HELP TO DEVELOP FUTURE ADJUVANT THERAPIES FOR DIABETIC RETINOPATHY. 2007 9 5726 20 SKIN WELL-BEING IN DIABETES: ROLE OF MACROPHAGES. MACROPHAGES ARE KEY PLAYERS IN WOUND HEALING- ALONG WITH MEDIATING THE ACUTE INFLAMMATORY RESPONSE, MACROPHAGES ACTIVATE CUTANEOUS EPITHELIAL CELLS AND PROMOTE TISSUE REPAIR. DIABETES COMPLICATIONS, INCLUDING DIABETIC CHRONIC WOUNDS, ARE ACCOMPANIED BY PERSISTENT INFLAMMATION AND MACROPHAGE MALFUNCTION. SEVERAL STUDIES INDICATE THAT HYPERGLYCEMIA INDUCES VARIOUS ALTERATIONS THAT AFFECT MACROPHAGE FUNCTION IN WOUND HEALING INCLUDING EPIGENETIC CHANGES, IMBALANCE BETWEEN PRO- AND ANTI-INFLAMMATORY MODULATORS, AND INSENSITIVITY TO PROLIFERATIVE STIMULI. IN THIS REVIEW, WE BRIEFLY SUMMARIZE RECENT STUDIES REGARDING THOSE ALTERATIONS AND THEIR IMPLICATIONS ON SKIN WELL-BEING IN DIABETES. 2020 10 6757 36 WNT SIGNALING IN LIVER FIBROSIS: PROGRESS, CHALLENGES AND POTENTIAL DIRECTIONS. LIVER FIBROSIS IS A COMMON WOUND-HEALING RESPONSE TO CHRONIC LIVER INJURIES, INCLUDING ALCOHOLIC OR DRUG TOXICITY, PERSISTENT VIRAL INFECTION, AND GENETIC FACTORS. MYOFIBROBLASTIC TRANSDIFFERENTIATION (MTD) IS THE PIVOTAL EVENT DURING LIVER FIBROGENESIS, AND RESEARCH IN THE PAST FEW YEARS HAS IDENTIFIED KEY MEDIATORS AND MOLECULAR MECHANISMS RESPONSIBLE FOR MTD OF HEPATIC STELLATE CELLS (HSCS). HSCS ARE UNDIFFERENTIATED CELLS WHICH PLAY AN IMPORTANT ROLE IN LIVER REGENERATION. RECENT EVIDENCE DEMONSTRATES THAT HSCS DERIVE FROM MESODERM AND AT LEAST IN PART VIA SEPTUM TRANSVERSUM AND MESOTHELIUM, AND HSCS EXPRESS MARKERS FOR DIFFERENT CELL TYPES WHICH DERIVE FROM MULTIPOTENT MESENCHYMAL PROGENITORS. THERE IS A REGULATORY COMMONALITY BETWEEN DIFFERENTIATION OF ADIPOCYTES AND THAT OF HSC, AND THE SHIFT FROM ADIPOGENIC TO MYOGENIC OR NEURONAL PHENOTYPE CHARACTERIZES HSC MTD. CENTRAL OF THIS SHIFT IS A LOSS OF EXPRESSION OF THE MASTER ADIPOGENIC REGULATOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA (PPARGAMMA). RESTORED EXPRESSION OF PPARGAMMA AND/OR OTHER ADIPOGENIC TRANSCRIPTION GENES CAN REVERSE MYOFIBROBLASTIC HSCS TO DIFFERENTIATED CELLS. VERTEBRATE WNT AND DROSOPHILA WINGLESS ARE HOMOLOGOUS GENES, AND THEIR TRANSLATED PROTEINS HAVE BEEN SHOWN TO PARTICIPATE IN THE REGULATION OF CELL PROLIFERATION, CELL POLARITY, CELL DIFFERENTIATION, AND OTHER BIOLOGICAL ROLES. MORE RECENTLY, WNT SIGNALING IS IMPLICATED IN HUMAN FIBROSING DISEASES, SUCH AS PULMONARY FIBROSIS, RENAL FIBROSIS, AND LIVER FIBROSIS. BLOCKING THE CANONICAL WNT SIGNAL PATHWAY WITH THE CO-RECEPTOR ANTAGONIST DICKKOPF-1 (DKK1) ABROGATES THESE EPIGENETIC REPRESSIONS AND RESTORES THE GENE PPARGAMMA EXPRESSION AND HSC DIFFERENTIATION. THE IDENTIFIED MORPHOGEN MEDIATED EPIGENETIC REGULATION OF PPARGAMMA AND HSC DIFFERENTIATION ALSO SERVES AS NOVEL THERAPEUTIC TARGETS FOR LIVER FIBROSIS AND LIVER REGENERATION. IN CONCLUSION, THE WNT SIGNALING PROMOTES LIVER FIBROSIS BY ENHANCING HSC ACTIVATION AND SURVIVAL, AND WE HEREIN DISCUSS WHAT WE CURRENTLY KNOW AND WHAT WE EXPECT WILL COME IN THIS FIELD IN THE NEXT FUTURE. 2013 11 3920 19 LINKING IMMUNITY, EPIGENETICS, AND CANCER IN INFLAMMATORY BOWEL DISEASE. MOST OF WHAT IS KNOWN ABOUT THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE (IBD) PERTAINS TO COMPLEX INTERPLAY BETWEEN HOST GENETICS, IMMUNITY, AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS PLAY PIVOTAL ROLES IN INTESTINAL IMMUNITY AND MUCOSAL HOMEOSTASIS AS WELL AS MEDIATING GENE-ENVIRONMENT INTERACTIONS. IN THIS ARTICLE, WE PROVIDE A HISTORICAL ACCOUNT OF EPIGENETIC RESEARCH EITHER DIRECTLY RELATED OR PERTINENT TO THE PATHOGENESIS AND MANAGEMENT OF IBD. WE FURTHER COLLATE EMERGING EVIDENCE SUPPORTING ROLES FOR EPIGENETIC MECHANISMS IN RELEVANT ASPECTS OF IBD BIOLOGY, INCLUDING DEREGULATED IMMUNITY, HOST-PATHOGEN RECOGNITION AND MUCOSAL INTEGRITY. FINALLY, WE HIGHLIGHT KEY EPIGENETIC MECHANISMS THAT LINK CHRONIC INFLAMMATION TO SPECIFIC IBD COMORBIDITIES, INCLUDING COLITIS-ASSOCIATED CANCER AND DISCUSS THEIR POTENTIAL UTILITY AS NOVEL BIOMARKERS OR PHARMACOLOGIC TARGETS IN IBD THERAPY. 2014 12 6621 35 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 6214 32 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 14 3965 29 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 15 2218 31 EPIGENETIC MODIFICATIONS IN FIBROTIC DISEASES: IMPLICATIONS FOR PATHOGENESIS AND PHARMACOLOGICAL TARGETS. ORGAN FIBROSIS IS A COMPLEX AND CHRONIC DISORDER THAT RESULTS FROM A VARIETY OF ACUTE INJURIES AND CONTRIBUTES TO THIRTY PERCENT OF NATURALLY OCCURRING DEATHS WORLDWIDE. THE MAIN FEATURE OF ORGAN FIBROSIS IS THE EXCESSIVE ACCUMULATION AND DEPOSIT OF EXTRACELLULAR MATRIX, THEREBY LEADING TO ORGAN DYSFUNCTION, LOSS OF ELASTICITY, AND DEVELOPMENT OF A RIGID ORGAN. ACCUMULATING EVIDENCE SHOWS THAT EPIGENETIC REMODELING, INCLUDING ABERRANT DNA METHYLATION AND NONCODING RNA EXPRESSION AS WELL AS HISTONE POST-TRANSLATIONAL MODIFICATIONS, PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF FIBROSIS THROUGH THE REGULATION OF FIBROBLAST ACTIVATION, DIFFERENTIATION, AND APOPTOSIS, AS WELL AS COLLAGEN SYNTHESIS AND PROFIBROTIC GENE TRANSCRIPTION. IN THIS REVIEW, WE DISCUSS THE BASIC REGULATION OF DNA METHYLATION, NONCODING RNA EXPRESSION, AND HISTONE POST-TRANSLATIONAL MODIFICATION, AND THEIR PARTICIPATION IN THE PATHOGENESIS AND DEVELOPMENT OF ORGAN FIBROSIS. THIS REVIEW ALSO PROVIDES THE LATEST INSIGHTS INTO THE NOVEL BIOMARKERS AND THERAPEUTIC TARGETS FOR FIBROSIS THROUGH MODULATION OF EPIGENETIC REMODELING. 2015 16 4130 26 MECHANISMS OF FERROPTOSIS AND EMERGING LINKS TO THE PATHOLOGY OF NEURODEGENERATIVE DISEASES. NEURODEGENERATIVE DISEASES ARE A DIVERSE CLASS OF DISEASES ATTRIBUTED TO CHRONIC PROGRESSIVE NEURONAL DEGENERATION AND SYNAPTIC LOSS IN THE BRAIN AND/OR SPINAL CORD, INCLUDING ALZHEIMER'S DISEASE, PARKINSON'S DISEASE, HUNTINGTON'S DISEASE, AMYOTROPHIC LATERAL SCLEROSIS AND MULTIPLE SCLEROSIS. THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES IS COMPLEX AND DIVERSE, OFTEN INVOLVING MITOCHONDRIAL DYSFUNCTION, NEUROINFLAMMATION, AND EPIGENETIC CHANGES. HOWEVER, THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES HAS NOT BEEN FULLY ELUCIDATED. RECENTLY, ACCUMULATING EVIDENCE REVEALED THAT FERROPTOSIS, A NEWLY DISCOVERED IRON-DEPENDENT AND LIPID PEROXIDATION-DRIVEN TYPE OF PROGRAMMED CELL DEATH, PROVIDES ANOTHER EXPLANATION FOR THE OCCURRENCE AND PROGRESSION OF NEURODEGENERATIVE DISEASES. HERE, WE PROVIDE AN OVERVIEW OF THE PROCESS AND REGULATION MECHANISMS OF FERROPTOSIS, AND SUMMARIZE CURRENT RESEARCH PROGRESSES THAT SUPPORT THE CONTRIBUTION OF FERROPTOSIS TO THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES. A COMPREHENSIVE UNDERSTANDING OF THE EMERGING ROLES OF FERROPTOSIS IN NEURODEGENERATIVE DISEASES WILL SHED LIGHT ON THE DEVELOPMENT OF NOVEL THERAPEUTIC TECHNOLOGIES AND STRATEGIES FOR SLOWING DOWN THE PROGRESSION OF THESE DISEASES. 2022 17 1726 30 DYSREGULATION OF LNCRNAS IN RHEUMATOID ARTHRITIS: BIOMARKERS, PATHOGENESIS AND POTENTIAL THERAPEUTIC TARGETS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE OF UNKNOWN ETIOLOGY, MAINLY MANIFESTED BY PERSISTENT ABNORMAL PROLIFERATION OF FIBROBLAST-LIKE SYNOVIOCYTES (FLSS), INFLAMMATION, SYNOVIAL HYPERPLASIA AND CARTILAGE EROSION, ACCOMPANIED BY JOINT SWELLING AND JOINT DESTRUCTION. ABNORMAL EXPRESSION OR FUNCTION OF LONG NONCODING RNAS (LNCRNAS) ARE CLOSELY RELATED TO HUMAN DISEASES, INCLUDING CANCERS, MENTAL DISEASES, AUTOIMMUNE DISEASES AND OTHERS. THE ABNORMAL SEQUENCE AND SPATIAL STRUCTURE OF LNCRNAS, THE DISORDER EXPRESSION AND THE ABNORMAL INTERACTION WITH THE BINDING PROTEIN WILL LEAD TO THE CHANGE OF GENE EXPRESSION IN THE WAY OF EPIGENETIC MODIFICATION. INCREASING EVIDENCE DEMONSTRATED THAT LNCRNAS WERE INVOLVED IN THE ACTIVATION OF FLSS, WHICH PLAYED A KEY ROLE IN THE PATHOGENESIS OF RA. IN THIS REVIEW, THE RESEARCH PROGRESS OF LNCRNAS IN THE PATHOGENESIS OF RA WAS SYSTEMATICALLY SUMMARIZED, INCLUDING THE ROLE OF LNCRNAS IN THE DIAGNOSIS OF RA, THE REGULATORY MECHANISM OF LNCRNAS IN THE PATHOGENESIS OF RA, AND THE INTERVENTION ROLE OF LNCRNAS IN THE TREATMENT OF RA. FURTHERMORE, THE ACTIVATED SIGNAL PATHWAYS, THE ROLE OF DNA METHYLATION AND OTHER MECHANISM HAVE ALSO BEEN OVERVIEW IN THIS REVIEW. 2021 18 4097 24 MATRIX STIFFNESS REGULATES MACROPHAGE POLARIZATION IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE AND THE PATHOLOGICAL BASIS OF MANY FATAL CARDIOVASCULAR DISEASES. MACROPHAGES, THE MAIN INFLAMMATORY CELLS IN ATHEROSCLEROTIC PLAQUE, HAVE A PARADOX ROLE IN DISEASE PROGRESSION. IN RESPONSE TO DIFFERENT MICROENVIRONMENTS, MACROPHAGES MAINLY HAVE TWO POLARIZED DIRECTIONS: PRO-INFLAMMATORY MACROPHAGES AND ANTI-INFLAMMATORY MACROPHAGES. MORE AND MORE EVIDENCE SHOWS THAT MACROPHAGE IS MECHANOSENSITIVE AND MATRIX STIFFNESS REGULATE MACROPHAGE PHENOTYPES IN ATHEROSCLEROSIS. HOWEVER, THE MOLECULAR MECHANISM OF MATRIX STIFFNESS REGULATING MACROPHAGE POLARIZATION STILL LACKS IN-DEPTH RESEARCH, WHICH HINDERS THE DEVELOPMENT OF NEW ANTI-ATHEROSCLEROTIC THERAPIES. IN THIS REVIEW, WE DISCUSS THE IMPORTANT ROLE OF MATRIX STIFFNESS IN REGULATING MACROPHAGE POLARIZATION THROUGH MECHANICAL SIGNAL TRANSDUCTION (HIPPO, PIEZO, CYTOSKELETON, AND INTEGRIN) AND EPIGENETIC MECHANISMS (MIRNA, DNA METHYLATION, AND HISTONE). WE HOPE TO PROVIDE A NEW PERSPECTIVE FOR ATHEROSCLEROSIS THERAPY BY TARGETING MATRIX STIFFNESS AND MACROPHAGE POLARIZATION. 2022 19 3674 28 INFLAMMATION AND DYSREGULATED FIBROBLAST PROLIFERATION--NEW MECHANISMS? IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE MAY PRIMARILY BE DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS AND THE UNDERLYING MESENCHYME. THE MEDIATORS PRODUCED AND PRESENT IN THIS MICROENVIRONMENT INDUCE THE FORMATION OF FIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE DETAILED MECHANISMS THAT LINK IPF WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN, BUT SOME EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES MAY PLAY A ROLE. THIS REVIEW PROVIDES A BRIEF SYNOPSIS OF HIGHLIGHTS IN THE CURRENT UNDERSTANDING OF THE PATHOPHYSIOLOGY OF IPF, AS WELL AS NOVEL THERAPEUTICS BEING EXPLORED IN CLINICAL TRIALS FOR THE TREATMENT OF THIS DEVASTATING DISEASE. 2013 20 2342 22 EPIGENETIC REGULATION OF MACROPHAGE POLARIZATION AND FUNCTION. MACROPHAGE POLARIZATION REFERS TO DEVELOPMENT OF A SPECIFIC PHENOTYPE IMPORTANT FOR TISSUE HOMEOSTASIS OR HOST DEFENSE IN RESPONSE TO ENVIRONMENTAL CUES. ENVIRONMENTAL FACTORS THAT INDUCE MACROPHAGE POLARIZATION INCLUDE CYTOKINES AND MICROBIAL FACTORS PRODUCED BY PATHOGENS OR COMMENSAL MICROBIOTA. SIGNALING PATHWAYS UTILIZED BY THESE POLARIZING FACTORS HAVE BEEN WELL CHARACTERIZED, BUT IT IS LESS CLEAR HOW SIGNALS ARE CONVERTED INTO COMPLEX AND SUSTAINED PATTERNS OF GENE EXPRESSION, AND HOW MACROPHAGES ARE REPROGRAMMED DURING POLARIZATION TO ALTER THEIR RESPONSES TO SUBSEQUENT ENVIRONMENTAL CHALLENGES. EMERGING EVIDENCE, REVIEWED HERE, SUGGESTS AN IMPORTANT ROLE FOR EPIGENETIC MECHANISMS IN MODULATING AND TRANSMITTING SIGNALS DURING MACROPHAGE POLARIZATION AND REPROGRAMMING. DEEPER UNDERSTANDING OF EPIGENETIC REGULATION OF MACROPHAGE PHENOTYPE WILL ENABLE DEVELOPMENT OF GENE-SPECIFIC THERAPEUTIC APPROACHES TO ENHANCE HOST DEFENSE WHILE PRESERVING TISSUE INTEGRITY AND PREVENTING CHRONIC INFLAMMATORY DISEASES. 2013