1 4348 156 MIR-146A DYSREGULATES ENERGY METABOLISM DURING NEUROINFLAMMATION. ALZHEIMER'S DISEASE (AD) AND OTHER NEURODEGENERATIVE DISEASES ARE CHARACTERIZED BY CHRONIC NEUROINFLAMMATION AND A REDUCTION IN BRAIN ENERGY METABOLISM. AN IMPORTANT ROLE HAS EMERGED FOR SMALL, NON-CODING RNA MOLECULES KNOWN AS MICRORNAS (MIRNAS) IN THE PATHOPHYSIOLOGY OF MANY NEURODEGENERATIVE DISORDERS. AS EPIGENETIC REGULATORS, MIRNAS POSSESS THE CAPACITY TO REGULATE AND FINE TUNE PROTEIN PRODUCTION BY INHIBITING TRANSLATION. SEVERAL MIRNAS, WHICH INCLUDE MIR-146A, ARE ELEVATED IN THE BRAIN, CSF, AND PLASMA OF AD PATIENTS. MIR-146A PARTICIPATES IN PATHWAYS THAT REGULATE IMMUNE ACTIVATION AND HAS SEVERAL MRNA TARGETS WHICH ENCODE FOR PROTEINS INVOLVED IN CELLULAR ENERGY METABOLISM. AN ADDITIONAL ROLE FOR EXTRACELLULAR VESICLES (EVS) HAS ALSO EMERGED IN THE PROGRESSION AD, AS EVS CAN TRANSFER FUNCTIONALLY ACTIVE PROTEINS AND RNAS FROM DISEASED TO HEALTHY CELLS. IN THE CURRENT STUDY, WE EXPOSED VARIOUS CELL TYPES PRESENT WITHIN THE CNS TO IMMUNOMODULATORY MOLECULES AND OBSERVED SIGNIFICANT UPREGULATION OF MIR-146A EXPRESSION, BOTH WITHIN CELLS AND WITHIN THEIR SECRETED EVS. FURTHER, WE ASSESSED THE EFFECTS OF MIR-146A OVEREXPRESSION ON BIOENERGETIC FUNCTION IN PRIMARY RAT GLIAL CELLS AND FOUND SIGNIFICANT REDUCTIONS IN OXIDATIVE PHOSPHORYLATION AND GLYCOLYSIS. LASTLY, WE CORRELATED MIR-146A EXPRESSION LEVELS WITHIN VARIOUS REGIONS OF THE AD BRAIN TO DISEASE STAGING AND FOUND SIGNIFICANT, POSITIVE CORRELATIONS. THESE NOVEL RESULTS DEMONSTRATE THAT THE MODULATION OF MIR-146A IN RESPONSE TO NEUROINFLAMMATORY STIMULI MAY MEDIATE THE LOSS OF MITOCHONDRIAL INTEGRITY AND FUNCTION IN CELLS, THEREBY CONTRIBUTING TO THE PROGRESSION OF BETA-AMYLOID AND TAU PATHOLOGY IN THE AD BRAIN. MULTIPLE INFLAMMATORY STIMULI CAN UPREGULATE MIRNA-146A EXPRESSION WITHIN NEURONS, MIXED GLIAL CELLS, AND BRAIN ENDOTHELIAL CELLS, WHICH IS EITHER RETAINED WITHIN THESE CELLS OR RELEASED FROM THEM AS EXTRACELLULAR VESICLE CARGO. THE UPREGULATION OF MIR-146A DISRUPTS CELLULAR BIOENERGETICS IN MIXED GLIAL CELLS. THIS MECHANISM MAY PLAY A CRITICAL ROLE IN THE NEUROINFLAMMATORY RESPONSE OBSERVED DURING ALZHEIMER'S DISEASE. 2022 2 6532 31 TRANSCRIPTIONAL REGULATION OF INFLAMMASOMES. INFLAMMASOMES ARE MULTIMOLECULAR COMPLEXES WITH POTENT INFLAMMATORY ACTIVITY. AS SUCH, THEIR ACTIVITY IS TIGHTLY REGULATED AT THE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL LEVELS. IN THIS REVIEW, WE PRESENT THE TRANSCRIPTIONAL REGULATION OF INFLAMMASOME GENES FROM SENSORS (E.G., NLRP3) TO SUBSTRATES (E.G., IL-1BETA). LINEAGE-DETERMINING TRANSCRIPTION FACTORS SHAPE INFLAMMASOME RESPONSES IN DIFFERENT CELL TYPES WITH PROFOUND CONSEQUENCES ON THE RESPONSIVENESS TO INFLAMMASOME-ACTIVATING STIMULI. PRO-INFLAMMATORY SIGNALS (STERILE OR MICROBIAL) HAVE A KEY TRANSCRIPTIONAL IMPACT ON INFLAMMASOME GENES, WHICH IS LARGELY MEDIATED BY NF-KAPPAB AND THAT TRANSLATES INTO HIGHER ANTIMICROBIAL IMMUNE RESPONSES. FURTHERMORE, DIVERSE INTRINSIC (E.G., CIRCADIAN CLOCK, METABOLITES) OR EXTRINSIC (E.G., XENOBIOTICS) SIGNALS ARE INTEGRATED BY SIGNAL-DEPENDENT TRANSCRIPTION FACTORS AND CHROMATIN STRUCTURE CHANGES TO MODULATE TRANSCRIPTIONALLY INFLAMMASOME RESPONSES. FINALLY, ANTI-INFLAMMATORY SIGNALS (E.G., IL-10) COUNTERBALANCE INFLAMMASOME GENES INDUCTION TO LIMIT DELETERIOUS INFLAMMATION. TRANSCRIPTIONAL REGULATIONS THUS APPEAR AS THE FIRST LINE OF INFLAMMASOME REGULATION TO RAISE THE DEFENSE LEVEL IN FRONT OF STRESS AND INFECTIONS BUT ALSO TO LIMIT EXCESSIVE OR CHRONIC INFLAMMATION. 2020 3 4311 29 MICRORNAS AND XENOBIOTIC TOXICITY: AN OVERVIEW. THE ADVENT OF NEW TECHNOLOGIES HAS PAVED THE RISE OF VARIOUS CHEMICALS THAT ARE BEING EMPLOYED IN INDUSTRIAL AS WELL AS CONSUMER PRODUCTS. THIS LEADS TO THE ACCUMULATION OF THESE XENOBIOTIC COMPOUNDS IN THE ENVIRONMENT WHERE THEY POSE A SERIOUS THREAT TO BOTH TARGET AND NON-TARGET SPECIES. MIRNAS ARE ONE OF THE KEY EPIGENETIC MECHANISMS THAT HAVE BEEN ASSOCIATED WITH TOXICITY BY MODULATING THE GENE EXPRESSION POST-TRANSCRIPTIONALLY. HERE, WE PROVIDE A COMPREHENSIVE VIEW ON MIRNA BIOGENESIS, THEIR MECHANISM OF ACTION AND, THEIR POSSIBLE ROLE IN XENOBIOTIC TOXICITY. FURTHER, WE REVIEW THE RECENT IN VITRO AND IN VIVO STUDIES INVOLVED IN XENOBIOTIC EXPOSURE INDUCED MIRNA ALTERATIONS AND THE MRNA-MIRNA INTERACTIONS. FINALLY, WE ADDRESS THE CHALLENGES ASSOCIATED WITH THE MIRNAS IN TOXICOLOGICAL STUDIES. 2020 4 6206 33 THE INFLUENCE OF TISSUE SPATIAL GEOMETRY AND FUNCTIONAL ORGANISATION ON LIVER REGENERATION. THE ADULT LIVER EXERTS CRUCIAL FUNCTIONS, INCLUDING NUTRIENT METABOLISM AND STORAGE, BILE PRODUCTION AND DRUG DETOXIFICATION. THESE COMPLEX FUNCTIONS EXPOSE THE LIVER TO CONSTANT DAMAGE INDUCED BY TOXINS, METABOLIC INTERMEDIATES AND OXIDATIVE STRESS. HOWEVER, THE ADULT LIVER EXHIBITS AN EXCEPTIONAL REGENERATIVE POTENTIAL, WHICH ALLOWS FAST AND EFFICIENT RESTORATION OF TISSUE ARCHITECTURE AND FUNCTION BOTH AFTER TISSUE RESECTION AND TOXIC DAMAGE. TO ACCOMPLISH ITS VITAL ROLE, THE LIVER SHOWS A PECULIAR TISSUE ARCHITECTURE INTO FUNCTIONAL UNITS, WHICH FOLLOW THE GRADIENT OF OXYGEN AND NUTRIENTS WITHIN THE PARENCHYMA. MUCH LESS IS KNOWN ABOUT THE INFLUENCE OF TISSUE SPATIAL GEOMETRY AND FUNCTIONAL ORGANISATION ON ADULT LIVER REGENERATION. HERE I EXAMINE THE EXPERIMENTAL EVIDENCE IN MOUSE MODELS SHOWING THAT THE SPATIAL ORGANISATION OF THE EPITHELIAL AND MESENCHYMAL COMPARTMENTS PLAYS A KEY ROLE IN LIVER REGENERATION AND FAVOURS THE ESTABLISHMENT OF REGENERATIVE ADULT LIVER PROGENITORS FOLLOWING LIVER INJURY. I ALSO DISCUSS THE ADVANTAGES AND LIMITATIONS OF HUMAN AND MOUSE 3D HEPATIC ORGANOID SYSTEMS, WHICH RECAPITULATE KEY ASPECTS OF LIVER FUNCTION AND ARCHITECTURE, AS MODELS OF LIVER REGENERATION AND DISEASE. FINALLY, I ANALYSE THE ROLE OF THE YAP/TAZ TRANSCRIPTIONAL CO-ACTIVATORS AS A CENTRAL HUB SENSING THE EXTRA-CELLULAR MATRIX (ECM), METABOLIC AND EPIGENETIC REMODELLING THAT REGULATE LIVER REGENERATION AND PROMOTE LIVER DISEASE, SUCH AS FIBROSIS, CHRONIC LIVER DISEASE AND LIVER CANCER. TOGETHER, THE FINDINGS SUMMARISED HERE DEMONSTRATE THAT LOCAL PHYSICAL AND FUNCTIONAL CELLULAR INTERACTIONS DETERMINED BY THE LIVER PECULIAR SPATIAL GEOMETRY, PLAY A CRUCIAL ROLE IN LIVER REGENERATION, AND THAT THEIR ALTERATIONS HAVE IMPORTANT IMPLICATIONS FOR HUMAN LIVER DISEASE. 2022 5 1382 45 DIABETES ALTERS ACTIVATION AND REPRESSION OF PRO- AND ANTI-INFLAMMATORY SIGNALING PATHWAYS IN THE VASCULATURE. A CENTRAL MECHANISM DRIVING VASCULAR DISEASE IN DIABETES IS IMMUNE CELL-MEDIATED INFLAMMATION. IN DIABETES, ENHANCED OXIDATION AND GLYCATION OF MACROMOLECULES, SUCH AS LIPOPROTEINS, INSULTS THE ENDOTHELIUM, AND ACTIVATES BOTH INNATE AND ADAPTIVE ARMS OF THE IMMUNE SYSTEM BY GENERATING NEW ANTIGENS FOR PRESENTATION TO ADAPTIVE IMMUNE CELLS. CHRONIC INFLAMMATION OF THE ENDOTHELIUM IN DIABETES LEADS TO CONTINUOUS INFILTRATION AND ACCUMULATION OF LEUKOCYTES AT SITES OF ENDOTHELIAL CELL INJURY. WE WILL DESCRIBE THE CENTRAL ROLE OF THE MACROPHAGE AS A SOURCE OF SIGNALING MOLECULES AND DAMAGING BY-PRODUCTS WHICH ACTIVATE INFILTRATING LYMPHOCYTES IN THE TISSUE AND CONTRIBUTE TO THE PRO-OXIDANT AND PRO-INFLAMMATORY MICROENVIRONMENT. AN IMPORTANT ASPECT TO BE CONSIDERED IS THE DIABETES-ASSOCIATED DEFECTS IN THE IMMUNE SYSTEM, SUCH AS FEWER OR DYSFUNCTIONAL ATHERO-PROTECTIVE LEUKOCYTE SUBSETS IN THE DIABETIC LESION COMPARED TO NON-DIABETIC LESIONS. THIS REVIEW WILL DISCUSS THE KEY PRO-INFLAMMATORY SIGNALING PATHWAYS RESPONSIBLE FOR LEUKOCYTE RECRUITMENT AND ACTIVATION IN THE INJURED VESSEL, WITH PARTICULAR FOCUS ON PRO- AND ANTI-INFLAMMATORY PATHWAYS ABERRANTLY ACTIVATED OR REPRESSED IN DIABETES. WE AIM TO DESCRIBE THE INTERACTION BETWEEN ADVANCED GLYCATION END PRODUCTS AND THEIR PRINCIPLE RECEPTOR RAGE, ANGIOTENSIN II, AND THE ANG II TYPE 1 RECEPTOR, IN ADDITION TO REACTIVE OXYGEN SPECIES (ROS) PRODUCTION BY NADPH-OXIDASE ENZYMES THAT ARE RELEVANT TO VASCULAR AND IMMUNE CELL FUNCTION IN THE CONTEXT OF DIABETIC VASCULOPATHY. FURTHERMORE, WE WILL TOUCH ON RECENT ADVANCES IN EPIGENETIC MEDICINE THAT HAVE REVEALED HIGH GLUCOSE-MEDIATED CHANGES IN THE TRANSCRIPTION OF GENES WITH KNOWN PRO-INFLAMMATORY DOWNSTREAM TARGETS. FINALLY, NOVEL ANTI-ATHEROSCLEROSIS STRATEGIES THAT TARGET THE VASCULAR IMMUNE INTERFACE WILL BE EXPLORED; SUCH AS VACCINATION AGAINST MODIFIED LOW-DENSITY LIPOPROTEIN AND PHARMACOLOGICAL INHIBITION OF ROS-PRODUCING ENZYMES. 2013 6 2313 44 EPIGENETIC REGULATION OF ENDOTHELIAL CELL FUNCTION BY NUCLEIC ACID METHYLATION IN CARDIAC HOMEOSTASIS AND DISEASE. PATHOLOGICAL REMODELLING OF THE MYOCARDIUM, INCLUDING INFLAMMATION, FIBROSIS AND HYPERTROPHY, IN RESPONSE TO ACUTE OR CHRONIC INJURY IS CENTRAL IN THE DEVELOPMENT AND PROGRESSION OF HEART FAILURE (HF). WHILE BOTH RESIDENT AND INFILTRATING CARDIAC CELLS ARE IMPLICATED IN THESE PATHOPHYSIOLOGICAL PROCESSES, RECENT EVIDENCE HAS SUGGESTED THAT ENDOTHELIAL CELLS (ECS) MAY BE THE PRINCIPAL CELL TYPE RESPONSIBLE FOR ORCHESTRATING PATHOLOGICAL CHANGES IN THE FAILING HEART. EPIGENETIC MODIFICATION OF NUCLEIC ACIDS, INCLUDING DNA, AND MORE RECENTLY RNA, BY METHYLATION IS ESSENTIAL FOR PHYSIOLOGICAL DEVELOPMENT DUE TO THEIR CRITICAL REGULATION OF CELLULAR GENE EXPRESSION. AS ACCUMULATING EVIDENCE HAS HIGHLIGHTED ALTERED PATTERNS OF DNA AND RNA METHYLATION IN HF AT BOTH THE GLOBAL AND INDIVIDUAL GENE LEVELS, MUCH EFFORT HAS BEEN DIRECTED TOWARDS DEFINING THE PRECISE ROLE OF SUCH CELL-SPECIFIC EPIGENETIC CHANGES IN THE CONTEXT OF HF. CONSIDERING THE INCREASINGLY APPARENT CRUCIAL ROLE THAT ECS PLAY IN CARDIAC HOMEOSTASIS AND DISEASE, THIS ARTICLE WILL SPECIFICALLY FOCUS ON NUCLEIC ACID METHYLATION (BOTH DNA AND RNA) IN THE FAILING HEART, EMPHASISING THE KEY INFLUENCE OF THESE EPIGENETIC MECHANISMS IN GOVERNING EC FUNCTION. THIS REVIEW SUMMARISES CURRENT UNDERSTANDING OF DNA AND RNA METHYLATION ALTERATIONS IN HF, ALONG WITH THEIR SPECIFIC ROLE IN REGULATING EC FUNCTION IN RESPONSE TO STRESS (E.G. HYPERGLYCAEMIA, HYPOXIA). IMPROVED APPRECIATION OF THIS IMPORTANT RESEARCH AREA WILL AID IN FURTHER IMPLICATING DYSFUNCTIONAL ECS IN HF PATHOGENESIS, WHILST INFORMING DEVELOPMENT OF EC-TARGETED STRATEGIES AND ADVANCING POTENTIAL TRANSLATION OF EPIGENETIC-BASED THERAPIES FOR SPECIFIC TARGETING OF PATHOLOGICAL CARDIAC REMODELLING IN HF. 2021 7 733 37 CANCER EPIGENETICS: LINKING BASIC BIOLOGY TO CLINICAL MEDICINE. CANCER EVOLUTION AT ALL STAGES IS DRIVEN BY BOTH EPIGENETIC ABNORMALITIES AS WELL AS GENETIC ALTERATIONS. DYSREGULATION OF EPIGENETIC CONTROL EVENTS MAY LEAD TO ABNORMAL PATTERNS OF DNA METHYLATION AND CHROMATIN CONFIGURATIONS, BOTH OF WHICH ARE CRITICAL CONTRIBUTORS TO THE PATHOGENESIS OF CANCER. THESE EPIGENETIC ABNORMALITIES ARE SET AND MAINTAINED BY MULTIPLE PROTEIN COMPLEXES AND THE INTERPLAY BETWEEN THEIR INDIVIDUAL COMPONENTS INCLUDING DNA METHYLATION MACHINERY, HISTONE MODIFIERS, PARTICULARLY, POLYCOMB (PCG) PROTEINS, AND CHROMATIN REMODELING PROTEINS. RECENT ADVANCES IN GENOME-WIDE TECHNOLOGY HAVE REVEALED THAT THE INVOLVEMENT OF THESE DYSREGULATED EPIGENETIC COMPONENTS APPEARS TO BE EXTENSIVE. MOREOVER, THERE IS A GROWING CONNECTION BETWEEN EPIGENETIC ABNORMALITIES IN CANCER AND CONCEPTS CONCERNING STEM-LIKE CELL SUBPOPULATIONS AS A DRIVING FORCE FOR CANCER. EMERGING DATA SUGGEST THAT ASPECTS OF THE EPIGENETIC LANDSCAPE INHERENT TO NORMAL EMBRYONIC AND ADULT STEM/PROGENITOR CELLS MAY HELP FOSTER, UNDER THE STRESS OF CHRONIC INFLAMMATION OR ACCUMULATING REACTIVE OXYGEN SPECIES, EVOLUTION OF MALIGNANT SUBPOPULATIONS. FINALLY, UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN INITIATION AND MAINTENANCE OF EPIGENETIC ABNORMALITIES IN ALL TYPES OF CANCER HAS GREAT POTENTIAL FOR TRANSLATIONAL PURPOSES. THIS IS ALREADY EVIDENT FOR EPIGENETIC BIOMARKER DEVELOPMENT, AND FOR PHARMACOLOGICAL TARGETING AIMED AT REVERSING CANCER-SPECIFIC EPIGENETIC ALTERATIONS. 2011 8 4575 35 MYOFIBROBLASTS. PURPOSE OF REVIEW: INTEREST IN THE MYOFIBROBLAST AS A KEY PLAYER IN PROPAGATION OF CHRONIC PROGRESSIVE FIBROSIS CONTINUES TO ELICIT MANY PUBLICATIONS, WITH FOCUS ON ITS CELLULAR ORIGINS AND THE MECHANISMS UNDERPINNING THEIR DIFFERENTIATION AND/OR TRANSITION. THE OBJECTIVE OF THE REVIEW IS TO HIGHLIGHT THIS RECENT PROGRESS. RECENT FINDINGS: THE EPITHELIAL ORIGIN OF THE MYOFIBROBLAST IN FIBROSIS HAS BEEN CHALLENGED BY RECENT STUDIES, WITH THE PERICYTE SUGGESTED AS A POSSIBLE PRECURSOR INSTEAD. ADDITIONAL SIGNALING PATHWAYS, INCLUDING NOTCH, WNT, AND HEDGEHOG, ARE IMPLICATED IN MYOFIBROBLAST DIFFERENTIATION. THE IMPORTANCE OF NADPH OXIDASE 4 WAS HIGHLIGHTED RECENTLY TO SUGGEST A POTENTIAL LINK BETWEEN CELLULAR/OXIDATIVE STRESS AND THE GENESIS OF THE MYOFIBROBLAST. RECENT OBSERVATIONS ON THE IMPORTANCE OF LYSOPHOSPHATIDIC ACID IN FIBROSIS SUGGEST THAT THIS MAY BE DUE, IN PART, TO ITS ABILITY TO REGULATE MYOFIBROBLAST DIFFERENTIATION. FINALLY, THERE IS INCREASING EVIDENCE FOR THE ROLE OF EPIGENETIC MECHANISMS IN REGULATING MYOFIBROBLAST DIFFERENTIATION, INCLUDING DNA METHYLATION AND MIRNA REGULATION OF GENE EXPRESSION. SUMMARY: THESE RECENT DISCOVERIES OPEN UP A WHOLE NEW ARRAY OF POTENTIAL TARGETS FOR NOVEL ANTIFIBROTIC THERAPIES. THIS IS OF SPECIAL IMPORTANCE GIVEN THE CURRENT BLEAK OUTLOOK FOR CHRONIC PROGRESSIVE FIBROTIC DISEASES, SUCH AS SCLERODERMA, DUE TO LACK OF EFFECTIVE THERAPIES. 2013 9 3961 43 LONG NON-CODING RNAS: THE NEW FRONTIER INTO UNDERSTANDING THE ETIOLOGY OF ALCOHOL USE DISORDER. ALCOHOL USE DISORDER (AUD) IS A COMPLEX, CHRONIC, DEBILITATING CONDITION IMPACTING MILLIONS WORLDWIDE. GENETIC, ENVIRONMENTAL, AND EPIGENETIC FACTORS ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF AUD. LONG NON-CODING RNAS (LNCRNAS) ARE A CLASS OF REGULATORY RNAS, COMMONLY REFERRED TO AS THE "DARK MATTER" OF THE GENOME, WITH LITTLE TO NO PROTEIN-CODING POTENTIAL. LNCRNAS HAVE BEEN IMPLICATED IN NUMEROUS PROCESSES CRITICAL FOR CELL SURVIVAL, SUGGESTING THAT THEY PLAY IMPORTANT FUNCTIONAL ROLES IN REGULATING DIFFERENT CELL PROCESSES. LNCRNAS WERE ALSO SHOWN TO DISPLAY HIGHER TISSUE SPECIFICITY THAN PROTEIN-CODING GENES AND HAVE A HIGHER ABUNDANCE IN THE BRAIN AND CENTRAL NERVOUS SYSTEM, DEMONSTRATING A POSSIBLE ROLE IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS. INDEED, GENETIC (E.G., GENOME-WIDE ASSOCIATION STUDIES (GWAS)), MOLECULAR (E.G., EXPRESSION QUANTITATIVE TRAIT LOCI (EQTL)) AND EPIGENETIC STUDIES FROM POSTMORTEM BRAIN TISSUES HAVE IDENTIFIED A GROWING LIST OF LNCRNAS ASSOCIATED WITH NEUROPSYCHIATRIC AND SUBSTANCE USE DISORDERS. GIVEN THAT THE EXPRESSION PATTERNS OF LNCRNAS HAVE BEEN ASSOCIATED WITH WIDESPREAD CHANGES IN THE TRANSCRIPTOME, INCLUDING METHYLATION, CHROMATIN ARCHITECTURE, AND ACTIVATION OR SUPPRESSION OF TRANSLATIONAL ACTIVITY, THE REGULATORY NATURE OF LNCRNAS MAY BE UBIQUITOUS AND AN INNATE COMPONENT OF GENE REGULATION. IN THIS REVIEW, WE PRESENT A SYNOPSIS OF THE FUNCTIONAL IMPACT THAT LNCRNAS MAY PLAY IN THE ETIOLOGY OF AUD. WE ALSO DISCUSS THE CLASSIFICATIONS OF LNCRNAS, THEIR KNOWN FUNCTIONAL ROLES, AND THERAPEUTIC ADVANCEMENTS IN THE FIELD OF LNCRNAS TO FURTHER CLARIFY THE FUNCTIONAL RELATIONSHIP BETWEEN LNCRNAS AND AUD. 2022 10 2906 30 GENE EDITING FOR INFLAMMATORY DISORDERS. TECHNOLOGY FOR PRECISE AND EFFICIENT GENETIC EDITING IS CONSTANTLY EVOLVING AND IS NOW CAPABLE OF HUMAN CLINICAL APPLICATIONS. AUTOIMMUNE AND INFLAMMATORY DISEASES ARE CHRONIC, DISABLING, SOMETIMES LIFE-THREATENING, CONDITIONS THAT FEATURE HERITABLE COMPONENTS. BOTH PRIMARY GENETIC LESIONS AND THE INFLAMMATORY PATHOBIOLOGY UNDERLYING THESE DISEASES REPRESENT FERTILE SOIL FOR NEW THERAPIES BASED ON THE CAPABILITIES OF GENE EDITING. THE ABILITY TO ORCHESTRATE PRECISE TARGETED MODIFICATIONS TO THE GENOME WILL LIKELY ENABLE CELL-BASED THERAPIES FOR INFLAMMATORY DISEASES SUCH AS MONOGENIC AUTOINFLAMMATORY DISEASE, ACQUIRED AUTOIMMUNE DISEASE AND FOR REGENERATIVE MEDICINE IN THE SETTING OF AN INFLAMMATORY ENVIRONMENT. HERE, WE DISCUSS RECENT ADVANCES IN GENOME EDITING AND THEIR EVOLVING APPLICATIONS IN IMMUNOINFLAMMATORY DISEASES. STRENGTHS AND LIMITATIONS OF OLDER GENETIC MODIFICATION TOOLS ARE COMPARED WITH CRISPR/CAS9, BASE EDITING, RNA EDITING, TARGETED ACTIVATORS AND REPRESSORS OF TRANSCRIPTION AND TARGETED EPIGENETIC MODIFIERS. COMMONLY EMPLOYED DELIVERY VEHICLES TO TARGET CELLS OR TISSUES OF INTEREST WITH GENETIC MODIFICATION MACHINERY, INCLUDING VIRAL, NON-VIRAL AND CELLULAR VECTORS, ARE DESCRIBED. FINALLY, APPLICATIONS IN ANIMAL AND HUMAN MODELS OF INFLAMMATORY DISEASES ARE DISCUSSED. USE OF CHIMERIC AUTOANTIGEN RECEPTOR T CELLS, CORRECTION OF MONOGENIC DISEASES WITH GENETICALLY EDITED HAEMATOPOIETIC STEM AND PROGENITOR CELLS, ENGINEERING OF INDUCED PLURIPOTENT STEM CELLS AND EX VIVO EXPANSION AND MODIFICATION OF REGULATORY T CELLS FOR A RANGE OF CHRONIC INFLAMMATORY DISEASES ARE REVIEWED. 2019 11 1712 45 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 5931 42 TARGETING EPIGENETIC MODIFIERS TO REPROGRAMME MACROPHAGES IN NON-RESOLVING INFLAMMATION-DRIVEN ATHEROSCLEROSIS. EPIGENOMIC AND EPIGENETIC RESEARCH HAS BEEN PROVIDING SEVERAL NEW INSIGHTS INTO A VARIETY OF DISEASES CAUSED BY NON-RESOLVING INFLAMMATION, INCLUDING CARDIOVASCULAR DISEASES. ATHEROSCLEROSIS (AS) HAS LONG BEEN RECOGNIZED AS A CHRONIC INFLAMMATORY DISEASE OF THE ARTERIAL WALLS, CHARACTERIZED BY LOCAL PERSISTENT AND STEPWISE ACCELERATING INFLAMMATION WITHOUT RESOLUTION, ALSO KNOWN AS UNCONTROLLED INFLAMMATION. THE PATHOGENESIS OF AS IS DRIVEN PRIMARILY BY HIGHLY PLASTIC MACROPHAGES VIA THEIR POLARIZATION TO PRO- OR ANTI-INFLAMMATORY PHENOTYPES AS WELL AS OTHER NOVEL SUBTYPES RECENTLY IDENTIFIED BY SINGLE-CELL SEQUENCING. ALTHOUGH EMERGING EVIDENCE HAS INDICATED THE KEY ROLE OF THE EPIGENETIC MACHINERY IN THE REGULATION OF MACROPHAGE PLASTICITY, THE INVESTIGATION OF EPIGENETIC ALTERATIONS AND MODIFIERS IN AS AND RELATED INFLAMMATION IS STILL IN ITS INFANCY. AN INCREASING NUMBER OF THE EPIGENETIC MODIFIERS (E.G. TET2, DNMT3A, HDAC3, HDAC9, JMJD3, KDM4A) HAVE BEEN IDENTIFIED IN EPIGENETIC REMODELLING OF MACROPHAGES THROUGH DNA METHYLATION OR HISTONE MODIFICATIONS (E.G. METHYLATION, ACETYLATION, AND RECENTLY LACTYLATION) IN INFLAMMATION. THESE OR MANY UNEXPLORED MODIFIERS FUNCTION TO DETERMINE OR SWITCH THE DIRECTION OF MACROPHAGE POLARIZATION VIA TRANSCRIPTIONAL REPROGRAMMING OF GENE EXPRESSION AND INTRACELLULAR METABOLIC REWIRING UPON MICROENVIRONMENTAL CUES, THEREBY REPRESENTING A PROMISING TARGET FOR ANTI-INFLAMMATORY THERAPY IN AS. HERE, WE REVIEW UP-TO-DATE FINDINGS INVOLVING THE EPIGENETIC REGULATION OF MACROPHAGES TO SHED LIGHT ON THE MECHANISM OF UNCONTROLLED INFLAMMATION DURING AS ONSET AND PROGRESSION. WE ALSO DISCUSS CURRENT CHALLENGES FOR DEVELOPING AN EFFECTIVE AND SAFE ANTI-AS THERAPY THAT TARGETS THE EPIGENETIC MODIFIERS AND PROPOSE A POTENTIAL ANTI-INFLAMMATORY STRATEGY THAT REPOLARIZES MACROPHAGES FROM PRO- TO ANTI-INFLAMMATORY PHENOTYPES. 2021 13 2460 31 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 14 5798 39 STEM CELLS AND LUNG REGENERATION. THE ABILITY TO REPLACE DEFECTIVE CELLS IN AN AIRWAY WITH CELLS THAT CAN ENGRAFT, INTEGRATE, AND RESTORE A FUNCTIONAL EPITHELIUM COULD POTENTIALLY CURE A NUMBER OF LUNG DISEASES. PROGRESS TOWARD THE DEVELOPMENT OF STRATEGIES TO REGENERATE THE ADULT LUNG BY EITHER IN VIVO OR EX VIVO TARGETING OF ENDOGENOUS STEM CELLS OR PLURIPOTENT STEM CELL DERIVATIVES IS LIMITED BY OUR FUNDAMENTAL LACK OF UNDERSTANDING OF THE MECHANISMS CONTROLLING HUMAN LUNG DEVELOPMENT, THE PRECISE IDENTITY AND FUNCTION OF HUMAN LUNG STEM AND PROGENITOR CELL TYPES, AND THE GENETIC AND EPIGENETIC CONTROL OF HUMAN LUNG FATE. IN THIS REVIEW, WE INTEND TO DISCUSS THE KNOWN STEM/PROGENITOR CELL POPULATIONS, THEIR RELATIVE DIFFERENCES BETWEEN RODENTS AND HUMANS, THEIR ROLES IN CHRONIC LUNG DISEASE, AND THEIR THERAPEUTIC PROSPECTS. ADDITIONALLY, WE HIGHLIGHT THE RECENT BREAKTHROUGHS THAT HAVE INCREASED OUR UNDERSTANDING OF THESE CELL TYPES. THESE ADVANCEMENTS INCLUDE NOVEL LINEAGE-TRACED ANIMAL MODELS AND SINGLE-CELL RNA SEQUENCING OF HUMAN AIRWAY CELLS, WHICH HAVE PROVIDED CRITICAL INFORMATION ON THE STEM CELL SUBTYPES, TRANSITION STATES, IDENTIFYING CELL MARKERS, AND INTRICATE PATHWAYS THAT COMMIT A STEM CELL TO DIFFERENTIATE OR TO MAINTAIN PLASTICITY. AS OUR CAPACITY TO MODEL THE HUMAN LUNG EVOLVES, SO WILL OUR UNDERSTANDING OF LUNG REGENERATION AND OUR ABILITY TO TARGET ENDOGENOUS STEM CELLS AS A THERAPEUTIC APPROACH FOR LUNG DISEASE. 2020 15 2073 25 EPIGENETIC CROSSTALK IN CHRONIC INFECTION WITH HIV-1. HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV-1) REPLICATES THROUGH THE INTEGRATION OF ITS VIRAL DNA INTO THE GENOME OF HUMAN IMMUNE TARGET CELLS. CHRONICALLY INFECTED INDIVIDUALS THUS CARRY A GENOMIC BURDEN OF VIRUS-DERIVED SEQUENCES THAT PERSISTS THROUGH ANTIRETROVIRAL THERAPY. THIS BURDEN CONSISTS OF A SMALL FRACTION OF INTACT, BUT TRANSCRIPTIONALLY SILENCED, I.E. LATENT, VIRAL GENOMES AND A DOMINANT FRACTION OF DEFECTIVE SEQUENCES. REMARKABLY, ALL VIRAL-DERIVED SEQUENCES ARE SUBJECT TO INTERACTION WITH HOST CELLULAR PHYSIOLOGY AT VARIOUS LEVELS. IN THIS REVIEW, WE FOCUS ON EPIGENETIC ASPECTS OF THIS INTERACTION. WE PROVIDE A COMPREHENSIVE OVERVIEW OF HOW EPIGENETIC MECHANISMS CONTRIBUTE TO ESTABLISHMENT AND MAINTENANCE OF HIV-1 GENE REPRESSION DURING LATENCY. WE FURTHERMORE SUMMARIZE FINDINGS INDICATING THAT HIV-1 INFECTION LEADS TO CHANGES IN THE EPIGENOME OF TARGET AND BYSTANDER IMMUNE CELLS. FINALLY, WE DISCUSS HOW AN IMPROVED UNDERSTANDING OF EPIGENETIC FEATURES AND MECHANISMS INVOLVED IN HIV-1 INFECTION COULD BE EXPLOITED FOR CLINICAL USE. 2020 16 1894 41 ENDOTHELIAL CELL SENESCENCE AND INFLAMMAGING: MICRORNAS AS BIOMARKERS AND INNOVATIVE THERAPEUTIC TOOLS. AGING IS ACCOMPANIED BY A PROGRESSIVE DECLINE OF ENDOTHELIAL FUNCTION AND A PROGRESSIVE DRIFT TOWARD A SYSTEMIC PRO-INFLAMMATORY STATUS THAT HAS BEEN DESIGNATED "INFLAMMAGING". BOTH PHENOMENA ARE ACCELERATED AND EXACERBATED IN PATIENTS WITH THE MOST COMMON AGE-RELATED DISEASES (ARDS), INCLUDING CANCER. THE FINDING THAT CHRONIC CELL STRESS ACTIVATES A PRO-INFLAMMATORY PROGRAM LEADING TO ACQUISITION OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) AND TO THE PROPAGATION OF SENESCENCE TO SURROUNDING CELLS THROUGH THE SECRETOME, SUGGESTS THAT CELL SENESCENCE MAY HAVE A ROLE IN BOTH PROCESSES. HERE WE: I) DESCRIBE THE ROLE OF CELL SENESCENCE IN ENDOTHELIAL DYSFUNCTION, II) EMPHASIZE THE CONTRIBUTION OF THE ENDOTHELIAL CELL SASP TO INFLAMMAGING, AND III) SUGGEST THAT SELECTIVE REMOVAL OF SENESCENT ENDOTHELIAL CELLS MAY NOT ONLY HINDER SUCH HARMFUL PROCESSES, BUT ALSO REDUCE THE RISK OF DEVELOPING ARDS AND THEIR COMPLICATIONS. ALTHOUGH IN VIVO DETECTION AND TARGETING OF SENESCENT ENDOTHELIAL CELLS ARE STILL BEING INVESTIGATED, IT IS LIKELY THAT THERAPEUTIC STRATEGIES BASED ON ANTIOXIDANT AND ANTI-INFLAMMATORY COMPOUNDS WOULD INVOLVE GENERALIZED ANTI-AGING EFFECTS ALSO BENEFITING ENDOTHELIAL CELLS. MICRORNA (MIRNAS) - SINGLE-STRANDED, NON-CODING RNAS EXPRESSED BY ALL LIVING CELLS AND INVOLVED IN THE EPIGENETIC MODULATION OF ALL TRANSCRIPTIONAL PROGRAMS - MAY CONSTITUTE AN INNOVATIVE, VALUABLE TOOL TO DETECT AND TARGET SENESCENT ENDOTHELIAL CELLS AND TO DEVISE TREATMENTS THAT CAN SLOW DOWN THE PRO-INFLAMMATORY PROGRAM ACTIVATED IN SENESCENT ENDOTHELIAL CELLS. 2016 17 6054 31 THE CURRENT STATE AND FUTURE OF T-CELL EXHAUSTION RESEARCH. 'EXHAUSTION' IS A TERM USED TO DESCRIBE A STATE OF NATIVE AND REDIRECTED T-CELL HYPO-RESPONSIVENESS RESULTING FROM PERSISTENT ANTIGEN EXPOSURE DURING CHRONIC VIRAL INFECTIONS OR CANCER. ALTHOUGH A WELL-ESTABLISHED PHENOTYPE ACROSS MICE AND HUMANS, EXHAUSTION AT THE MOLECULAR LEVEL REMAINS POORLY DEFINED AND INCONSISTENT ACROSS THE LITERATURE. THIS IS, IN PART, DUE TO AN OVERRELIANCE ON SURFACE RECEPTORS TO DEFINE THESE CELLS AND EXPLAIN EXHAUSTIVE BEHAVIOURS, AN INCOMPLETE UNDERSTANDING OF HOW EXHAUSTION ARISES, AND A LACK OF CLARITY OVER WHETHER EXHAUSTION IS THE SAME ACROSS CONTEXTS, E.G. CHRONIC VIRAL INFECTIONS VERSUS CANCER. WITH THE DEVELOPMENT OF SYSTEMS-BASED GENETIC APPROACHES SUCH AS SINGLE-CELL RNA-SEQ AND CRISPR SCREENS APPLIED TO IN VIVO DATA, WE ARE MOVING CLOSER TO A CONSENSUS VIEW OF EXHAUSTION, ALTHOUGH UNDERSTANDING HOW IT ARISES REMAINS CHALLENGING GIVEN THE DIFFICULTY IN MANIPULATING THE IN VIVO SETTING. ACCORDINGLY, PRODUCING AND STUDYING EXHAUSTED T-CELLS EX VIVO ARE BURGEONING, ALLOWING EXPERIMENTS TO BE CONDUCTED AT SCALE UP AND WITH HIGH THROUGHPUT. HERE, WE FIRST REVIEW WHAT IS CURRENTLY KNOWN ABOUT T-CELL EXHAUSTION AND HOW IT'S BEING STUDIED. WE THEN DISCUSS HOW IMPROVEMENTS IN THEIR METHOD OF ISOLATION/PRODUCTION AND EXAMINING THE IMPACT OF DIFFERENT MICROENVIRONMENTAL SIGNALS AND CELL INTERACTIONS HAVE NOW BECOME AN ACTIVE AREA OF RESEARCH. FINALLY, WE DISCUSS WHAT THE FUTURE HOLDS FOR THE ANALYSIS OF THIS PHYSIOLOGICAL CONDITION AND, GIVEN THE DIVERSITY OF WAYS IN WHICH EXHAUSTED CELLS ARE NOW BEING GENERATED, PROPOSE THE ADOPTION OF A UNIFIED APPROACH TO CLEARLY DEFINING EXHAUSTION USING A SET OF METABOLIC-, EPIGENETIC-, TRANSCRIPTIONAL-, AND ACTIVATION-BASED PHENOTYPIC MARKERS, THAT WE CALL 'M.E.T.A'. 2023 18 3703 31 INFLAMMATORY SIGNALLING AS MEDIATOR OF EPIGENETIC MODULATION IN TISSUE-SPECIFIC CHRONIC INFLAMMATION. RECENT SUCCESSES OF THERAPEUTIC INTERVENTION IN CHRONIC INFLAMMATORY DISEASES USING EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASE INHIBITORS AND INHIBITORS OF DNA METHYLATION SUGGEST THAT EPIGENETIC REPROGRAMMING PLAYS A ROLE IN THE AETIOLOGY OF THESE DISEASES. THE EPIGENETIC SIGNATURE OF A GIVEN IMMUNE CELL IS REFLECTED IN THE HISTORY OF MODIFICATIONS FROM DIFFERENT SIGNALS THE CELL HAS BEEN SUBJECTED TO DURING DIFFERENTIATION. LIKE OTHER CELLS, DIFFERENTIATING IMMUNE CELLS ARE DEPENDENT ON A COMPLEX COMBINATION OF INTER- AND INTRACELL SIGNALLING AS WELL AS TRANSCRIPTION MACHINERIES TO MODULATE THEIR EPIGENOMES IN ORDER TO MEDIATE DIFFERENTIATION. DESPITE EXTENSIVE RESEARCH INTO THESE PROCESSES, THE LINK BETWEEN CELLULAR SIGNALLING AND EPIGENETIC MODULATION REMAINS POORLY UNDERSTOOD. HERE, WE REVIEW RECENT PROGRESS AND DISCUSS KEY FACTORS DRIVING EPIGENETIC MODULATION IN CHRONIC INFLAMMATION. 2009 19 4434 22 MOLECULAR DISSECTION OF CD8(+) T-CELL DYSFUNCTION. CHRONIC VIRAL INFECTIONS AND CANCER OFTEN LEAD TO THE EMERGENCE OF DYSFUNCTIONAL OR 'EXHAUSTED' CD8(+) T CELLS, AND THE RESTORATION OF THEIR FUNCTIONS IS CURRENTLY THE FOCUS OF THERAPEUTIC INTERVENTIONS. IN THIS REVIEW, WE DETAIL RECENT ADVANCES IN THE ANNOTATION OF THE GENE MODULES AND THE EPIGENETIC LANDSCAPE ASSOCIATED WITH T-CELL DYSFUNCTION. TOGETHER WITH ANALYSIS OF SINGLE-CELL TRANSCRIPTOMES, THESE FINDINGS HAVE ENABLED A DEEPER AND MORE PRECISE UNDERSTANDING OF THE TRANSCRIPTIONAL MECHANISMS THAT INDUCE AND MAINTAIN THE DYSFUNCTIONAL STATE AND HIGHLIGHT THE HETEROGENEITY OF CD8(+) T-CELL PHENOTYPES PRESENT IN CHRONICALLY INFLAMED TISSUE. WE DISCUSS THE RELEVANCE OF THESE FINDINGS FOR UNDERSTANDING THE TRANSCRIPTIONAL AND SPATIAL REGULATION OF DYSFUNCTIONAL T CELLS AND FOR THE DESIGN OF THERAPEUTICS. 2017 20 4372 50 MIRNAS, OXIDATIVE STRESS, AND CANCER: A COMPREHENSIVE AND UPDATED REVIEW. OXIDATIVE STRESS REFERS TO ELEVATED LEVELS OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS). ROS HOMEOSTASIS FUNCTIONS AS A SIGNALING PATHWAY FOR NORMAL CELL SURVIVAL AND APPROPRIATE CELL SIGNALING. CHRONIC INFLAMMATION INDUCED BY IMBALANCED LEVELS OF ROS CONTRIBUTES TO MANY DISEASES AND DIFFERENT TYPES OF CANCER. ROS CAN ALTER THE EXPRESSION OF ONCOGENES AND TUMOR SUPPRESSOR GENES THROUGH EPIGENETIC MODIFICATIONS, TRANSCRIPTION FACTORS, AND NON-CODING RNAS. MICRORNAS (MIRNAS) ARE SMALL NON-CODING RNAS THAT PLAY A KEY ROLE IN MOST BIOLOGICAL PATHWAYS. EACH MIRNA REGULATES HUNDREDS OF TARGET GENES BY INHIBITING PROTEIN TRANSLATION AND/OR PROMOTING MESSENGER RNA DEGRADATION. IN NORMAL CONDITIONS, MIRNAS PLAY A PHYSIOLOGICAL ROLE IN CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. HOWEVER, DIFFERENT FACTORS THAT CAN DYSREGULATE CELL SIGNALING AND CELLULAR HOMEOSTASIS CAN ALSO AFFECT MIRNA EXPRESSION. THE ALTERATION OF MIRNA EXPRESSION CAN WORK AGAINST DISTURBING FACTORS OR MEDIATE THEIR EFFECTS. OXIDATIVE STRESS IS ONE OF THESE FACTORS. CONSIDERING THE COMPLEX INTERPLAY BETWEEN ROS LEVEL AND MIRNA REGULATION AND BOTH OF THESE WITH CANCER DEVELOPMENT, WE REVIEW THE ROLE OF MIRNAS IN CANCER, FOCUSING ON THEIR FUNCTION IN OXIDATIVE STRESS. 2020