1 4380 113 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 2 4130 30 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 3 3640 31 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 4 5933 40 TARGETING EPIGENETICS AND NON-CODING RNAS IN ATHEROSCLEROSIS: FROM MECHANISMS TO THERAPEUTICS. ATHEROSCLEROSIS, THE PRINCIPAL CAUSE OF CARDIOVASCULAR DEATH WORLDWIDE, IS A PATHOLOGICAL DISEASE CHARACTERIZED BY FIBRO-PROLIFERATION, CHRONIC INFLAMMATION, LIPID ACCUMULATION, AND IMMUNE DISORDER IN THE VESSEL WALL. AS THE ATHEROMATOUS PLAQUES DEVELOP INTO ADVANCED STAGE, THE VULNERABLE PLAQUES ARE PRONE TO RUPTURE, WHICH CAUSES ACUTE CARDIOVASCULAR EVENTS, INCLUDING ISCHEMIC STROKE AND MYOCARDIAL INFARCTION. EMERGING EVIDENCE HAS SUGGESTED THAT ATHEROSCLEROSIS IS ALSO AN EPIGENETIC DISEASE WITH THE INTERPLAY OF MULTIPLE EPIGENETIC MECHANISMS. THE EPIGENETIC BASIS OF ATHEROSCLEROSIS HAS TRANSFORMED OUR KNOWLEDGE OF EPIGENETICS FROM AN IMPORTANT BIOLOGICAL PHENOMENON TO A BURGEONING FIELD IN CARDIOVASCULAR RESEARCH. HERE, WE PROVIDE A SYSTEMATIC AND UP-TO-DATE OVERVIEW OF THE CURRENT KNOWLEDGE OF THREE DISTINCT BUT INTERRELATED EPIGENETIC PROCESSES (INCLUDING DNA METHYLATION, HISTONE METHYLATION/ACETYLATION, AND NON-CODING RNAS), IN ATHEROSCLEROTIC PLAQUE DEVELOPMENT AND INSTABILITY. MECHANISTIC AND CONCEPTUAL ADVANCES IN UNDERSTANDING THE BIOLOGICAL ROLES OF VARIOUS EPIGENETIC MODIFIERS IN REGULATING GENE EXPRESSION AND FUNCTIONS OF ENDOTHELIAL CELLS (VASCULAR HOMEOSTASIS, LEUKOCYTE ADHESION, ENDOTHELIAL-MESENCHYMAL TRANSITION, ANGIOGENESIS, AND MECHANOTRANSDUCTION), SMOOTH MUSCLE CELLS (PROLIFERATION, MIGRATION, INFLAMMATION, HYPERTROPHY, AND PHENOTYPIC SWITCH), AND MACROPHAGES (DIFFERENTIATION, INFLAMMATION, FOAM CELL FORMATION, AND POLARIZATION) ARE DISCUSSED. THE INHERENTLY DYNAMIC NATURE AND REVERSIBILITY OF EPIGENETIC REGULATION, ENABLES THE POSSIBILITY OF EPIGENETIC THERAPY BY TARGETING EPIGENETIC "WRITERS", "READERS", AND "ERASERS". SEVERAL FOOD DRUG ADMINISTRATION-APPROVED SMALL-MOLECULE EPIGENETIC DRUGS SHOW PROMISE IN PRE-CLINICAL STUDIES FOR THE TREATMENT OF ATHEROSCLEROSIS. FINALLY, WE DISCUSS POTENTIAL THERAPEUTIC IMPLICATIONS AND CHALLENGES FOR FUTURE RESEARCH INVOLVING CARDIOVASCULAR EPIGENETICS, WITH AN AIM TO PROVIDE A TRANSLATIONAL PERSPECTIVE FOR IDENTIFYING NOVEL BIOMARKERS OF ATHEROSCLEROSIS, AND TRANSFORMING PRECISION CARDIOVASCULAR RESEARCH AND DISEASE THERAPY IN MODERN ERA OF EPIGENETICS. 2019 5 4333 35 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 6 6621 33 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 7 1872 30 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 8 1136 43 COMPREHENSIVE OVERVIEW OF MICRORNA FUNCTION IN RHEUMATOID ARTHRITIS. MICRORNAS (MIRNAS), A CLASS OF ENDOGENOUS SINGLE-STRANDED SHORT NONCODING RNAS, HAVE EMERGED AS VITAL EPIGENETIC REGULATORS OF BOTH PATHOLOGICAL AND PHYSIOLOGICAL PROCESSES IN ANIMALS. THEY DIRECT FUNDAMENTAL CELLULAR PATHWAYS AND PROCESSES BY FINE-TUNING THE EXPRESSION OF MULTIPLE GENES AT THE POSTTRANSCRIPTIONAL LEVEL. GROWING EVIDENCE SUGGESTS THAT MIRNAS ARE IMPLICATED IN THE ONSET AND DEVELOPMENT OF RHEUMATOID ARTHRITIS (RA). RA IS A CHRONIC INFLAMMATORY DISEASE THAT MAINLY AFFECTS SYNOVIAL JOINTS. THIS COMMON AUTOIMMUNE DISORDER IS CHARACTERIZED BY A COMPLEX AND MULTIFACETED PATHOGENESIS, AND ITS MORBIDITY, DISABILITY AND MORTALITY RATES REMAIN CONSISTENTLY HIGH. MORE IN-DEPTH INSIGHTS INTO THE UNDERLYING MECHANISMS OF RA ARE REQUIRED TO ADDRESS UNMET CLINICAL NEEDS AND OPTIMIZE TREATMENT. HEREIN, WE COMPREHENSIVELY REVIEW THE DEREGULATED MIRNAS AND IMPAIRED CELLULAR FUNCTIONS IN RA TO SHED LIGHT ON SEVERAL ASPECTS OF RA PATHOGENESIS, WITH A FOCUS ON EXCESSIVE INFLAMMATION, SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DAMAGE. THIS REVIEW ALSO PROVIDES PROMISING TARGETS FOR INNOVATIVE THERAPIES OF RA. IN ADDITION, WE DISCUSS THE REGULATORY ROLES AND CLINICAL POTENTIAL OF EXTRACELLULAR MIRNAS IN RA, HIGHLIGHTING THEIR PROSPECTIVE APPLICATIONS AS DIAGNOSTIC AND PREDICTIVE BIOMARKERS. 2023 9 2722 29 EXOSOMES AS A NEW PAIN BIOMARKER OPPORTUNITY. EXOSOMES ARE EXTRACELLULAR MICROVESICLES IMPLICATED IN INTERCELLULAR COMMUNICATION WITH ABILITY TO TRANSFER CARGO MOLECULES, INCLUDING PROTEIN, LIPIDS, AND NUCLEIC ACIDS, AT BOTH CLOSE AND DISTANT TARGET SITES. IT HAS BEEN SHOWN THAT EXOSOMES ARE IMPLICATED IN PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES. IN RECENT YEARS, THE INTEREST ON EXOSOMES' ROLE IN MANY PAIN STATES HAS INCREASED. THEIR INVOLVEMENTS IN PAIN PROCESSES HAVE BEEN DEMONSTRATED BY STUDIES ON DIFFERENT CHRONIC PAIN DISEASES, BOTH INFLAMMATORY AND NEUROPATHIC, SUCH AS OSTEOARTHRITIS, RHEUMATOID ARTHRITIS, INFLAMMATORY BOWEL DISEASES, NEURODEGENERATIVE PATHOLOGIES, COMPLEX REGIONAL PAIN SYNDROME, AND PERIPHERAL NERVE INJURY. ANIMAL AND CLINICAL STUDIES INVESTIGATED EXOSOMES-BASED TREATMENTS, SHOWING THEIR ABILITY TO IMPROVE PAINFUL SYMPTOMS WITH FEWER SIDE EFFECTS, WITH POTENTIAL IMMUNOPROTECTIVE AND ANTI-INFLAMMATORY EFFECT. SPECIFIC MOLECULAR PATTERNS CHARACTERIZE EXOSOMES' CARGO ACCORDING TO THE CELLULAR ORIGIN, EPIGENETIC MODIFICATIONS, ENVIRONMENTAL STATE, AND STRESSOR FACTORS. THEREFORE, THE IDENTIFICATION OF SPECIFIC CARGO'S PROFILE ASSOCIATED TO PAIN STATES MAY LEAD TO RECOGNIZE SPECIFIC PATHOLOGICAL STATES AND TO CONSIDER THE USE OF EXOSOMES AS BIOMARKERS OF DISEASES. FURTHERMORE, EXOSOMES' ABILITY TO TRANSFER INFORMATION AND THEIR PRESENCE IN MANY ACCESSIBLE BIOLOGICAL FLUIDS SUGGEST A POTENTIAL USE AS NOVEL NON-INVASIVE THERAPEUTIC TOOLS IN PAIN FIELD. 2020 10 2291 29 EPIGENETIC REGULATION IN PATHOLOGY OF ATHEROSCLEROSIS: A NOVEL PERSPECTIVE. ATHEROSCLEROSIS, CHARACTERIZED BY ATHEROSCLEROTIC PLAQUES, IS A COMPLEX PATHOLOGICAL PROCESS THAT INVOLVES DIFFERENT CELL TYPES AND CAN BE SEEN AS A CHRONIC INFLAMMATORY DISEASE. IN THE ADVANCED STAGE, THE RUPTURED ATHEROSCLEROTIC PLAQUE CAN INDUCE DEADLY ACCIDENTS INCLUDING ISCHEMIC STROKE AND MYOCARDIAL INFARCTION. EPIGENETICS REGULATION, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA MODIFICATION. MAINTAINS CELLULAR IDENTITY VIA AFFECTING THE CELLULAR TRANSCRIPTOME. THE EPIGENETIC MODIFICATION PROCESS, MEDIATING BY EPIGENETIC ENZYMES, IS DYNAMIC UNDER VARIOUS STIMULI, WHICH CAN BE REVERSELY ALTERED. RECENTLY, NUMEROUS STUDIES HAVE EVIDENCED THE CLOSE RELATIONSHIP BETWEEN ATHEROSCLEROSIS AND EPIGENETIC REGULATIONS IN ATHEROSCLEROSIS, PROVIDING US WITH A NOVEL PERSPECTIVE IN RESEARCHING MECHANISMS AND FINDING NOVEL THERAPEUTIC TARGETS OF THIS SERIOUS DISEASE. HERE, WE CRITICALLY REVIEW THE RECENT DISCOVERIES BETWEEN EPIGENETIC REGULATION MECHANISMS IN ATHEROSCLEROSIS. 2021 11 1712 42 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 12 3829 30 INVOLVEMENT OF EPIGENETICS IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS THE MOST PREVALENT CHRONIC AGE-RELATED ARTHRITIC DISEASE THAT MAINLY AFFECTS THE DIARTHRODIAL JOINTS. NEVERTHELESS, THERE IS NO TREATMENT CURRENTLY AVAILABLE THAT CAN EFFECTIVELY REDUCE SYMPTOMS OR SLOW DOWN OR STOP DISEASE PROGRESSION. THE LACK OF DISEASE-MODIFYING THERAPIES COULD BE EXPLAINED BY THE COMPLEX PATHOGENESIS OF OA, WHICH IS STILL NOT COMPLETELY UNDERSTOOD. INTERTWINED EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND NONCODING RNAS (NCRNAS) HAVE BEEN INDICATED AS IMPORTANT CELLULAR TOOLS TO MAINTAIN TISSUE HOMEOSTASIS UPON ENVIRONMENTAL CHALLENGES. THE CURRENT REVIEW ILLUSTRATES THAT DYSFUNCTIONAL EPIGENETIC CONTROL MECHANISMS IN THE ARTICULAR CARTILAGE LIKELY PLAY AN IMPORTANT ROLE IN DRIVING OA PATHOPHYSIOLOGY. 2017 13 3540 30 IMMUNE-DERIVED CYTOKINES IN THE NERVOUS SYSTEM: EPIGENETIC INSTRUCTIVE SIGNALS OR NEUROPATHOGENIC MEDIATORS? THE INVESTIGATION OF THE EFFECTS OF INFLAMMATORY CYTOKINES (IC) ON THE GROWTH AND DIFFERENTIATION OF NEURAL CELLS HAS PROVIDED NEW INSIGHTS ON THE ROLE OF SUCH SOLUBLE MEDIATORS IN NERVOUS SYSTEM DEVELOPMENT AND/OR PLASTIC REMODELING AS WELL AS IN THE PATHOGENESIS OF INFLAMMATORY NEURODEGENERATIVE DISORDERS, WHICH ARE CHARACTERIZED BY CHRONIC IC DYSREGULATION IN THE CENTRAL NERVOUS SYSTEM (CNS). THUS, THE STUDY OF THE INTERACTION BETWEEN CNS AND IMMUNE-DERIVED SOLUBLE SIGNALS IN PHYSIOLOGICAL OR PATHOLOGICAL CONDITIONS IS OF INCREASING INTEREST. THIS REVIEW FIRST DISCUSSES EXPERIMENTAL EVIDENCE SUPPORTING THE INSTRUCTIVE/PERMISSIVE ROLE OF IMMUNE-DERIVED CYTOKINES ON CNS DEVELOPMENT AND PLASTICITY. NEXT, WE FOCUS ON HUMAN NEUROLOGICAL DISEASE STATES SUCH AS MULTIPLE SCLEROSIS AND THE NEURODEGENERATION ASSOCIATED TO THE ACQUIRED IMMUNE DEFICIENCY SYNDROME IN WHICH DIFFERENT INFLAMMATORY CYTOKINES HAVE BEEN PROPOSED AS POTENTIAL NEUROPATHOGENIC MEDIATORS. 1999 14 4981 31 PATHOPHYSIOLOGY OF SYSTEMIC SCLEROSIS: CURRENT UNDERSTANDING AND NEW INSIGHTS. INTRODUCTION: SYSTEMIC SCLEROSIS (SSC) IS A COMPLEX AUTOIMMUNE CONNECTIVE TISSUE DISEASE CHARACTERIZED BY CHRONIC AND PROGRESSIVE TISSUE AND ORGAN FIBROSIS WITH BROAD PATIENT-TO-PATIENT VARIABILITY. SOME RISK FACTORS ARE KNOWN AND INCLUDE COMBINATION OF PERSISTENT RAYNAUD'S PHENOMENON, STEROID HORMONE IMBALANCE, SELECTED CHEMICALS, THERMAL, OR OTHER INJURIES. ENDOGENOUS AND/OR EXOGENOUS ENVIRONMENTAL TRIGGER/RISK FACTORS PROMOTE EPIGENETIC MECHANISMS IN GENETICALLY PRIMED SUBJECTS. DISEASE PATHOGENESIS PRESENTS EARLY MICROVASCULAR CHANGES WITH ENDOTHELIAL CELL DYSFUNCTION, FOLLOWED BY THE ACTIVATION OF MECHANISMS PROMOTING THEIR TRANSITION INTO MYOFIBROBLASTS. A COMPLEX AUTOIMMUNE RESPONSE, INVOLVING INNATE AND ADAPTIVE IMMUNITY WITH SPECIFIC/FUNCTIONAL AUTOANTIBODY PRODUCTION, CHARACTERIZES THE DISEASE. PROGRESSIVE FIBROSIS AND ISCHEMIA INVOLVE SKIN AND VISCERAL ORGANS RESULTING IN THEIR IRREVERSIBLE DAMAGE/FAILURE. PROGENITOR CIRCULATING CELLS (MONOCYTES, FIBROCYTES), TOGETHER WITH GROWTH FACTORS AND CYTOKINES PARTICIPATE IN DISEASE DIFFUSION AND EVOLUTION. EPIGENETIC, VASCULAR AND IMMUNOLOGIC MECHANISMS IMPLICATED IN SYSTEMIC FIBROSIS, REPRESENT MAJOR TARGETS FOR INCOMING DISEASE MODIFYING THERAPEUTIC APPROACHES. AREAS COVERED: THIS REVIEW DISCUSSES CURRENT UNDERSTANDING AND NEW INSIGHTS OF SSC PATHOGENESIS, THROUGH AN OVERVIEW OF THE MOST RELEVANT ADVANCEMENTS TO PRESENT ASPECTS AND MECHANISMS INVOLVED IN DISEASE PATHOGENESIS. EXPERT OPINION: CONSIDERING SSC INTRICACY/HETEROGENEITY, EARLY COMBINATION THERAPY WITH VASODILATORS, IMMUNOSUPPRESSIVE AND ANTIFIBROTIC DRUGS SHOULD SUCCESSFULLY DOWNREGULATE THE DISEASE PROGRESSION, ESPECIALLY IF STARTED FROM THE BEGINNING. 2019 15 3344 26 HISTONE DEACETYLASES (HDACS) AND ATHEROSCLEROSIS: A MECHANISTIC AND PHARMACOLOGICAL REVIEW. ATHEROSCLEROSIS (AS), THE MOST COMMON UNDERLYING PATHOLOGY FOR CORONARY ARTERY DISEASE, IS A CHRONIC INFLAMMATORY, PROLIFERATIVE DISEASE IN LARGE- AND MEDIUM-SIZED ARTERIES. THE VASCULAR ENDOTHELIUM IS IMPORTANT FOR MAINTAINING VASCULAR HEALTH. ENDOTHELIAL DYSFUNCTION IS A CRITICAL EARLY EVENT LEADING TO AS, WHICH IS A MAJOR RISK FACTOR FOR STROKE AND MYOCARDIAL INFARCTION. ACCUMULATING EVIDENCE HAS SUGGESTED THE CRITICAL ROLES OF HISTONE DEACETYLASES (HDACS) IN REGULATING VASCULAR CELL HOMEOSTASIS AND AS. THE PURPOSE OF THIS REVIEW IS TO PRESENT AN UPDATED VIEW ON THE ROLES OF HDACS (CLASS I, CLASS II, CLASS IV) AND HDAC INHIBITORS IN VASCULAR DYSFUNCTION AND AS. WE ALSO ELABORATE ON THE NOVEL THERAPEUTIC TARGETS AND AGENTS IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASES. 2020 16 5390 30 REDOX-FIBROSIS: IMPACT OF TGFBETA1 ON ROS GENERATORS, MEDIATORS AND FUNCTIONAL CONSEQUENCES. FIBROSIS IS ONE OF THE MOST PREVALENT FEATURES OF AGE-RELATED DISEASES LIKE OBESITY, DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, CHRONIC KIDNEY DISEASE, OR CARDIOMYOPATHY AND AFFECTS MILLIONS OF PEOPLE IN ALL COUNTRIES. ALTHOUGH THE UNDERSTANDING ABOUT THE PATHOPHYSIOLOGY OF FIBROSIS HAS IMPROVED A LOT DURING THE RECENT YEARS, A NUMBER OF MECHANISMS STILL REMAIN UNKNOWN. ALTHOUGH TGF-BETA1 SIGNALING, LOSS OF METABOLIC HOMEOSTASIS AND CHRONIC LOW-GRADE INFLAMMATION APPEAR TO PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF FIBROSIS, RECENT EVIDENCE INDICATES THAT OXIDATIVE STRESS AND THE ANTIOXIDANT SYSTEM MAY ALSO BE CRUCIAL FOR FIBROSIS DEVELOPMENT AND PERSISTENCE. THESE FINDINGS POINT TO A CONCEPT OF A REDOX-FIBROSIS WHERE THE CELLULAR OXIDANT AND ANTIOXIDANT SYSTEM COULD BE POTENTIAL THERAPEUTIC TARGETS. THE CURRENT REVIEW AIMS TO SUMMARIZE THE EXISTING LINKS BETWEEN TGF-BETA1 SIGNALING, GENERATION AND ACTION OF REACTIVE OXYGEN SPECIES, EXPRESSION OF ANTIOXIDATIVE ENZYMES, AND FUNCTIONAL CONSEQUENCES INCLUDING EPIGENETIC REDOX-MEDIATED RESPONSES DURING FIBROSIS. 2015 17 2460 30 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 18 3674 34 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 19 6214 30 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 20 3800 34 INTERPLAY OF INFLAMMATORY MEDIATORS WITH EPIGENETICS AND CARTILAGE MODIFICATIONS IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA), A DEGENERATIVE DISEASE OF DIARTHRODIAL JOINTS, IS INFLUENCED BY MECHANICAL AND INFLAMMATORY FACTORS WITH AGING, OBESITY, CHRONIC INJURIES, AND SECONDARY DISEASES THOUGHT TO BE MAJOR FACTORS DRIVING THE PROCESS OF ARTICULAR CARTILAGE DEGENERATION. CHONDROCYTES, THE CELLULAR COMPONENT OF CARTILAGE, RESIDE IN AN AVASCULAR ENVIRONMENT AND NORMALLY HAVE LIMITED POTENTIAL TO REPLICATE. HOWEVER, EXTRINSIC FACTORS SUCH AS INJURY TO THE JOINT OR INTRINSIC ALTERATIONS TO THE CHONDROCYTES THEMSELVES CAN LEAD TO AN ALTERED PHENOTYPE AND DEVELOPMENT OF OA. SYNOVIAL INFLAMMATION IS ALSO A PIVOTAL ELEMENT OF THE OSTEOARTHRITIC, DEGENERATIVE PROCESS: INFLUX OF PRO-INFLAMMATORY CYTOKINES AND PRODUCTION OF MATRIX METALLOPROTEINASES ACCELERATE ADVANCED CELLULAR PROCESSES SUCH AS SYNOVITIS AND CARTILAGE DAMAGE. AS WELL AS A GENETIC INPUT, RECENT DATA HAVE HIGHLIGHTED EPIGENETIC FACTORS AS CONTRIBUTING TO DISEASE. STUDIES CONDUCTED OVER THE LAST DECADE HAVE FOCUSED ON THREE KEY ASPECTS IN OA; INFLAMMATION AND THE IMMUNE RESPONSE, GENOME-WIDE ASSOCIATION STUDIES THAT HAVE IDENTIFIED IMPORTANT GENES UNDERGOING EPIGENETIC MODIFICATIONS, AND FINALLY HOW CHONDROCYTES TRANSFORM IN THEIR FUNCTION DURING DEVELOPMENT AND DISEASE. DATA HIGHLIGHTED HERE HAVE IDENTIFIED CRITICAL INFLAMMATORY GENES INVOLVED IN OA AND HOW THESE FACTORS IMPACT CHONDROCYTE HYPERTROPHY IN THE DISEASE. THIS REVIEW ALSO ADDRESSES KEY INFLAMMATORY FACTORS IN SYNOVIAL INFLAMMATION, EPIGENETICS, AND CHONDROCYTE FATE, AND HOW AGENTS THAT INHIBIT EPIGENETIC MECHANISMS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS COULD AID IN DEVELOPMENT OF LONG-TERM TREATMENT STRATEGIES FOR THE DISEASE. 2018