1    24 136 8-OXOGUANINE DNA GLYCOSYLASE-1-DRIVEN DNA BASE EXCISION REPAIR: ROLE IN ASTHMA PATHOGENESIS. PURPOSE OF REVIEW: TO PROVIDE BOTH AN OVERVIEW AND EVIDENCE OF THE POTENTIAL CAUSE OF OXIDATIVE DNA BASE DAMAGE AND REPAIR SIGNALING IN CHRONIC INFLAMMATION AND HISTOLOGICAL CHANGES ASSOCIATED WITH ASTHMA. RECENT FINDINGS: ASTHMA IS INITIATED/MAINTAINED BY IMMUNOLOGICAL, GENETIC/EPIGENETIC, AND ENVIRONMENTAL FACTORS. IT IS A WORLD-WIDE HEALTH PROBLEM, AS CURRENT THERAPIES SUPPRESS SYMPTOMS RATHER THAN PREVENT/REVERSE THE DISEASE, LARGELY DUE TO GAPS IN UNDERSTANDING ITS MOLECULAR MECHANISMS. INFLAMMATION, OXIDATIVE STRESS, AND DNA DAMAGE ARE INSEPARABLE PHENOMENA, BUT THEIR MOLECULAR ROLES IN ASTHMA PATHOGENESIS ARE UNCLEAR. IT WAS FOUND THAT AMONG OXIDATIVELY MODIFIED DNA BASES, 8-OXOGUANINE (8-OXOG) IS ONE OF THE MOST ABUNDANT, AND ITS LEVELS IN DNA AND BODY FLUIDS ARE CONSIDERED A BIOMARKER OF ONGOING ASTHMATIC PROCESSES. FREE 8-OXOG FORMS A COMPLEX WITH 8-OXOG DNA GLYCOSYLASE-1 AND ACTIVATES RAS-FAMILY GTPASES THAT INDUCE GENE EXPRESSION TO MOBILIZE INNATE AND ADAPTIVE IMMUNE SYSTEMS, ALONG WITH GENES REGULATING AIRWAY HYPERPLASIA, HYPER-RESPONSIVENESS, AND LUNG REMODELING IN ATOPIC AND NONATOPIC ASTHMA. SUMMARY: DNA'S INTEGRITY MUST BE MAINTAINED TO PREVENT MUTATION, SO ITS CONTINUOUS REPAIR AND DOWNSTREAM SIGNALING 'FUEL' CHRONIC INFLAMMATORY PROCESSES IN ASTHMA AND FORM THE BASIC MECHANISM WHOSE ELUCIDATION WILL ALLOW THE DEVELOPMENT OF NEW DRUG TARGETS FOR THE PREVENTION/REVERSAL OF LUNG DISEASES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2  3989  34 LONGITUDINAL ANALYSIS OF BLOOD DNA METHYLATION IDENTIFIES MECHANISMS OF RESPONSE TO TUMOR NECROSIS FACTOR INHIBITOR THERAPY IN RHEUMATOID ARTHRITIS. BACKGROUND: RHEUMATOID ARTHRITIS (RA) IS A CHRONIC, IMMUNE-MEDIATED INFLAMMATORY DISEASE OF THE JOINTS THAT HAS BEEN ASSOCIATED WITH VARIATION IN THE PERIPHERAL BLOOD METHYLOME. IN THIS STUDY, WE AIM TO IDENTIFY EPIGENETIC VARIATION THAT IS ASSOCIATED WITH THE RESPONSE TO TUMOR NECROSIS FACTOR INHIBITOR (TNFI) THERAPY. METHODS: PERIPHERAL BLOOD GENOME-WIDE DNA METHYLATION PROFILES WERE ANALYZED IN A DISCOVERY COHORT OF 62 RA PATIENTS AT BASELINE AND AT WEEK 12 OF TNFI THERAPY. DNA METHYLATION OF INDIVIDUAL CPG SITES AND ENRICHMENT OF BIOLOGICAL PATHWAYS WERE EVALUATED FOR THEIR ASSOCIATION WITH DRUG RESPONSE. USING A NOVEL CELL DECONVOLUTION APPROACH, ALTERED DNA METHYLATION ASSOCIATED WITH TNFI RESPONSE WAS ALSO TESTED IN THE SIX MAIN IMMUNE CELL TYPES IN BLOOD. VALIDATION OF THE RESULTS WAS PERFORMED IN AN INDEPENDENT LONGITUDINAL COHORT OF 60 RA PATIENTS. FINDINGS: TREATMENT WITH TNFI WAS ASSOCIATED WITH SIGNIFICANT LONGITUDINAL PERIPHERAL BLOOD METHYLATION CHANGES IN BIOLOGICAL PATHWAYS RELATED TO RA (FDR<0.05). 139 BIOLOGICAL FUNCTIONS WERE MODIFIED BY THERAPY, WITH METHYLATION LEVELS CHANGING SYSTEMATICALLY TOWARDS A SIGNATURE SIMILAR TO THAT OF HEALTHY CONTROLS. DIFFERENCES IN THE METHYLATION PROFILE OF T CELL ACTIVATION AND DIFFERENTIATION, GTPASE-MEDIATED SIGNALING, AND ACTIN FILAMENT ORGANIZATION PATHWAYS WERE ASSOCIATED WITH THE CLINICAL RESPONSE TO THERAPY. CELL TYPE DECONVOLUTION ANALYSIS IDENTIFIED CPG SITES IN CD4+T, NK, NEUTROPHILS AND MONOCYTES THAT WERE SIGNIFICANTLY ASSOCIATED WITH THE RESPONSE TO TNFI. INTERPRETATION: OUR RESULTS SHOW THAT TREATMENT WITH TNFI RESTORES HOMEOSTATIC BLOOD METHYLATION IN RA. THE CLINICAL RESPONSE TO TNFI IS ASSOCIATED TO METHYLATION VARIATION IN SPECIFIC BIOLOGICAL PATHWAYS, AND IT INVOLVES CELLS FROM BOTH THE INNATE AND ADAPTIVE IMMUNE SYSTEMS. FUNDING: THE INSTITUTO DE SALUD CARLOS III.	2022	
                     
3  4507  36 MRTF: BASIC BIOLOGY AND ROLE IN KIDNEY DISEASE. A LESSER KNOWN BUT CRUCIALLY IMPORTANT DOWNSTREAM EFFECT OF RHO FAMILY GTPASES IS THE REGULATION OF GENE EXPRESSION. THIS MAJOR ROLE IS MEDIATED VIA THE CYTOSKELETON, THE ORGANIZATION OF WHICH DICTATES THE NUCLEOCYTOPLASMIC SHUTTLING OF A SET OF TRANSCRIPTION FACTORS. CENTRAL AMONG THESE IS MYOCARDIN-RELATED TRANSCRIPTION FACTOR (MRTF), WHICH UPON ACTIN POLYMERIZATION TRANSLOCATES TO THE NUCLEUS AND BINDS TO ITS COGNATE PARTNER, SERUM RESPONSE FACTOR (SRF). THE MRTF/SRF COMPLEX THEN DRIVES A LARGE COHORT OF GENES INVOLVED IN CYTOSKELETON REMODELING, CONTRACTILITY, EXTRACELLULAR MATRIX ORGANIZATION AND MANY OTHER PROCESSES. ACCORDINGLY, MRTF, ACTIVATED BY A VARIETY OF MECHANICAL AND CHEMICAL STIMULI, AFFECTS A PLETHORA OF FUNCTIONS WITH PHYSIOLOGICAL AND PATHOLOGICAL RELEVANCE. THESE INCLUDE CELL MOTILITY, DEVELOPMENT, METABOLISM AND THUS METASTASIS FORMATION, INFLAMMATORY RESPONSES AND-PREDOMINANTLY-ORGAN FIBROSIS. THE AIM OF THIS REVIEW IS TWOFOLD: TO PROVIDE AN UP-TO-DATE SUMMARY ABOUT THE BASIC BIOLOGY AND REGULATION OF THIS VERSATILE TRANSCRIPTIONAL COACTIVATOR; AND TO HIGHLIGHT ITS PRINCIPAL INVOLVEMENT IN THE PATHOBIOLOGY OF KIDNEY DISEASE. ACTING THROUGH BOTH DIRECT TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS, MRTF PLAYS A KEY (YET NOT FULLY APPRECIATED) ROLE IN THE INDUCTION OF A PROFIBROTIC EPITHELIAL PHENOTYPE (PEP) AS WELL AS IN FIBROBLAST-MYOFIBROBLAST TRANSITION, PRIME PATHOMECHANISMS IN CHRONIC KIDNEY DISEASE AND RENAL FIBROSIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4  5508  38 RHOA/RHO-KINASES IN ASTHMA: FROM PATHOGENESIS TO THERAPEUTIC TARGETS. ASTHMA IS A CHRONIC AND HETEROGENEOUS DISEASE CHARACTERISED BY AIRWAY INFLAMMATION AND INTERMITTENT AIRWAY NARROWING. THE KEY OBSTACLE IN THE PREVENTION AND TREATMENT OF ASTHMA HAS BEEN OUR INCOMPLETE UNDERSTANDING OF ITS AETIOLOGY AND BIOLOGICAL MECHANISMS. THE RAS HOMOLOG FAMILY MEMBER A (RHOA) OF THE RHO FAMILY GTPASES HAS BEEN CONSIDERED TO BE ONE OF THE MOST PROMISING AND NOVEL THERAPEUTIC TARGETS FOR ASTHMA. IT IS WELL KNOWN THAT RHOA/RHO-KINASES PLAY AN IMPORTANT ROLE IN THE PATHOPHYSIOLOGY OF ASTHMA, INCLUDING AIRWAY SMOOTH MUSCLE CONTRACTION, AIRWAY HYPER-RESPONSIVENESS, BETA-ADRENERGIC DESENSITISATION AND AIRWAY REMODELLING. HOWEVER, RECENT ADVANCES HAVE SUGGESTED NOVEL ROLES FOR RHOA IN REGULATING ALLERGIC AIRWAY INFLAMMATION. SPECIFICALLY, RHOA HAS BEEN SHOWN TO REGULATE ALLERGIC AIRWAY INFLAMMATION THROUGH CONTROLLING TH2 OR TH17 CELL DIFFERENTIATION AND TO REGULATE AIRWAY REMODELLING THROUGH REGULATING MESENCHYMAL STEM CELL (MSC) DIFFERENTIATION. IN THIS REVIEW, WE EVALUATE THE LITERATURE REGARDING THE RECENT ADVANCES IN THE ACTIVATION OF RHOA/RHO-KINASE, CYTOKINE AND EPIGENETIC REGULATION OF RHOA/RHO-KINASE, AND THE ROLE OF RHOA/RHO-KINASE IN REGULATING MAJOR FEATURES OF ASTHMA, SUCH AS AIRWAY HYPER-RESPONSIVENESS, REMODELLING AND INFLAMMATION. WE ALSO DISCUSS THE IMPORTANCE OF THE NEWLY IDENTIFIED ROLE OF RHOA/RHO-KINASE SIGNALLING IN MSC DIFFERENTIATION AND BRONCHIAL EPITHELIAL BARRIER DYSFUNCTION. THESE FINDINGS INDICATE THE FUNCTIONAL SIGNIFICANCE OF THE RHOA/RHO-KINASE PATHWAY IN THE PATHOPHYSIOLOGY OF ASTHMA AND SUGGEST THAT RHOA/RHO-KINASE SIGNALLING MAY BE A PROMISING THERAPEUTIC TARGET FOR THE TREATMENT OF ASTHMA.	2020	
                                                                                                                                                                                                                                                                                                                
5  5265  29 PROMISING THERAPEUTIC TARGETS FOR TREATMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A SYSTEMIC POLY-ARTICULAR CHRONIC AUTOIMMUNE JOINT DISEASE THAT MAINLY DAMAGES THE HANDS AND FEET, WHICH AFFECTS 0.5% TO 1.0% OF THE POPULATION WORLDWIDE. WITH THE SUSTAINED DEVELOPMENT OF DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS), SIGNIFICANT SUCCESS HAS BEEN ACHIEVED FOR PREVENTING AND RELIEVING DISEASE ACTIVITY IN RA PATIENTS. UNFORTUNATELY, SOME PATIENTS STILL SHOW LIMITED RESPONSE TO DMARDS, WHICH PUTS FORWARD NEW REQUIREMENTS FOR SPECIAL TARGETS AND NOVEL THERAPIES. UNDERSTANDING THE PATHOGENETIC ROLES OF THE VARIOUS MOLECULES IN RA COULD FACILITATE DISCOVERY OF POTENTIAL THERAPEUTIC TARGETS AND APPROACHES. IN THIS REVIEW, BOTH EXISTING AND EMERGING TARGETS, INCLUDING THE PROTEINS, SMALL MOLECULAR METABOLITES, AND EPIGENETIC REGULATORS RELATED TO RA, ARE DISCUSSED, WITH A FOCUS ON THE MECHANISMS THAT RESULT IN INFLAMMATION AND THE DEVELOPMENT OF NEW DRUGS FOR BLOCKING THE VARIOUS MODULATORS IN RA.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  2378  28 EPIGENETIC REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING IN ATHEROSCLEROTIC ARTERY REMODELING: A MINI-REVIEW. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY EXTENSIVE REMODELING OF MEDIUM AND LARGE-SIZED ARTERIES. INWARD REMODELING (=LUMEN SHRINKAGE) OF THE VASCULAR WALLS IS THE UNDERLYING CAUSE FOR ISCHEMIA IN TARGET ORGANS. THEREFORE, INWARD REMODELING CAN BE CONSIDERED THE PREDOMINANT FEATURE OF ATHEROSCLEROTIC PATHOLOGY. OUTWARD REMODELING (=LUMEN ENLARGEMENT) IS A PHYSIOLOGICAL RESPONSE COMPENSATING FOR LUMEN SHRINKAGE CAUSED BY NEOINTIMAL HYPERPLASIA, BUT AS A PATHOLOGICAL RESPONSE TO CHANGES IN BLOOD FLOW, OUTWARD REMODELING LEADS TO SUBSTANTIAL ARTERIAL WALL THINNING. THINNED VASCULAR WALLS ARE PRONE TO RUPTURE, AND SUBSEQUENT THROMBUS FORMATION ACCOUNTS FOR THE MAJORITY OF ACUTE CARDIOVASCULAR EVENTS. PATHOLOGICAL REMODELING IS DRIVEN BY INFLAMMATORY CELLS WHICH INDUCE VASCULAR SMOOTH MUSCLE CELLS TO SWITCH FROM QUIESCENT TO A PROLIFERATIVE AND MIGRATORY PHENOTYPE. AFTER DECADES OF INTENSIVE RESEARCH, THE MOLECULAR MECHANISMS OF ARTERIAL REMODELING ARE STARTING TO UNFOLD. IN THIS MINI-REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING FROM THE CONTRACTILE TO THE SYNTHETIC PHENOTYPE INVOLVED IN ARTERIAL REMODELING AND DISCUSS POTENTIAL THERAPEUTIC OPTIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7  5857  31 SUBSTRATE-SPECIFIC BINDING OF 8-OXOGUANINE DNA GLYCOSYLASE 1 (OGG1) REPROGRAMS MUCOSAL ADAPTATIONS TO CHRONIC AIRWAY INJURY. RECENT ADVANCES HAVE UNCOVERED THE NON-RANDOM DISTRIBUTION OF 7, 8-DIHYDRO-8-OXOGUANINE (8-OXOGUA) INDUCED BY REACTIVE OXYGEN SPECIES, WHICH IS BELIEVED TO HAVE EPIGENETIC EFFECTS. ITS COGNATE REPAIR PROTEIN, 8-OXOGUANINE DNA GLYCOSYLASE 1 (OGG1), READS OXIDATIVE SUBSTRATES AND PARTICIPATES IN TRANSCRIPTIONAL INITIATION. WHEN REDOX SIGNALING IS ACTIVATED IN SMALL AIRWAY EPITHELIAL CELLS, THE DNA REPAIR FUNCTION OF OGG1 IS REPURPOSED TO TRANSMIT ACUTE INFLAMMATORY SIGNALS ACCOMPANIED BY CELL STATE TRANSITIONS AND MODIFICATION OF THE EXTRACELLULAR MATRIX. EPITHELIAL-MESENCHYMAL AND EPITHELIAL-IMMUNE INTERACTIONS ACT COOPERATIVELY TO ESTABLISH A LOCAL NICHE THAT INSTRUCTS THE MUCOSAL IMMUNE LANDSCAPE. IF THE TRANSITIONAL CELL STATE GOVERNED BY OGG1 REMAINS RESPONSIVE TO INFLAMMATORY MEDIATORS INSTEAD OF DIFFERENTIATION, THE COLLATERAL DAMAGE PROVIDES POSITIVE FEEDBACK TO INFLAMMATION, ASCRIBING INFLAMMATORY REMODELING TO ONE OF THE DRIVERS IN CHRONIC PATHOLOGIES. IN THIS REVIEW, WE DISCUSS THE SUBSTRATE-SPECIFIC READ THROUGH OGG1 HAS EVOLVED IN REGULATING THE INNATE IMMUNE RESPONSE, CONTROLLING ADAPTATIONS OF THE AIRWAY TO ENVIRONMENTAL AND INFLAMMATORY INJURY, WITH A FOCUS ON THE READER FUNCTION OF OGG1 IN INITIATION AND PROGRESSION OF EPITHELIAL TO MESENCHYMAL TRANSITIONS IN CHRONIC PULMONARY DISEASE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8  6005  32 THE AIRWAY EPITHELIUM-A CENTRAL PLAYER IN ASTHMA PATHOGENESIS. ASTHMA IS A CHRONIC INFLAMMATORY AIRWAY DISEASE CHARACTERIZED BY VARIABLE AIRFLOW OBSTRUCTION IN RESPONSE TO A WIDE RANGE OF EXOGENOUS STIMULI. THE AIRWAY EPITHELIUM IS THE FIRST LINE OF DEFENSE AND PLAYS AN IMPORTANT ROLE IN INITIATING HOST DEFENSE AND CONTROLLING IMMUNE RESPONSES. INDEED, INCREASING EVIDENCE INDICATES A RANGE OF ABNORMALITIES IN VARIOUS ASPECTS OF EPITHELIAL BARRIER FUNCTION IN ASTHMA. A CENTRAL PART OF THIS IMPAIRMENT IS A DISRUPTION OF THE AIRWAY EPITHELIAL LAYER, ALLOWING INHALED SUBSTANCES TO PASS MORE EASILY INTO THE SUBMUCOSA WHERE THEY MAY INTERACT WITH IMMUNE CELLS. FURTHERMORE, MANY OF THE IDENTIFIED SUSCEPTIBILITY GENES FOR ASTHMA ARE EXPRESSED IN THE AIRWAY EPITHELIUM. THIS REVIEW FOCUSES ON THE BIOLOGY OF THE AIRWAY EPITHELIUM IN HEALTH AND ITS PATHOBIOLOGY IN ASTHMA. WE WILL SPECIFICALLY DISCUSS EXTERNAL TRIGGERS SUCH AS ALLERGENS, VIRUSES AND ALARMINS AND THE EFFECT OF TYPE 2 INFLAMMATORY RESPONSES ON AIRWAY EPITHELIAL FUNCTION IN ASTHMA. WE WILL ALSO DISCUSS EPIGENETIC MECHANISMS RESPONDING TO EXTERNAL STIMULI ON THE LEVEL OF TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION OF GENE EXPRESSION, AS WELL THE AIRWAY EPITHELIUM AS A POTENTIAL TREATMENT TARGET IN ASTHMA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9  5938  48 TARGETING INDUCIBLE EPIGENETIC REPROGRAMMING PATHWAYS IN CHRONIC AIRWAY REMODELING. ALLERGIC ASTHMA IS A CHRONIC INFLAMMATORY AIRWAY DISEASE WHOSE CLINICAL COURSE IS PUNCTUATED BY ACUTE EXACERBATIONS FROM AEROALLERGEN EXPOSURE OR RESPIRATORY VIRUS INFECTIONS. AEROALLERGENS AND RESPIRATORY VIRUSES STIMULATE TOLL-LIKE RECEPTOR (TLR) SIGNALING, PRODUCING OXIDATIVE INJURY AND INFLAMMATION. REPETITIVE EXACERBATIONS PRODUCE COMPLEX MUCOSAL ADAPTATIONS, CELL-STATE CHANGES, AND STRUCTURAL REMODELING. THESE STRUCTURAL CHANGES PRODUCE SUBSTANTIAL MORBIDITY, DECREASE LUNG CAPACITY, AND IMPAIR QUALITY OF LIFE. WE WILL REVIEW RECENT SYSTEMS-LEVEL STUDIES THAT PROVIDE FUNDAMENTAL NEW INSIGHTS INTO HOW REPETITIVE ACTIVATION OF INNATE SIGNALING PATHWAYS PRODUCE EPIGENETIC 'TRAINING' TO INDUCE ADAPTIVE EPITHELIAL RESPONSES. OXIDATIVE STRESS PRODUCED DOWNSTREAM OF TLR SIGNALING INDUCES TRANSIENT OXIDATION OF GUANINE BASES IN THE REGULATORY REGIONS OF INFLAMMATORY GENES. THE EPIGENETIC MARK 8-OXOG IS BOUND BY A PLEIOTROPIC DNA REPAIR ENZYME, 8-OXOGUANINE DNA GLYCOSYLASE (OGG1), WHICH INDUCES CONFORMATIONAL CHANGES IN ADJACENT DNA TO RECRUIT THE NFKAPPAB.BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) COMPLEX. THE NFKAPPAB.BRD4 COMPLEX NOT ONLY PLAYS A CENTRAL ROLE IN INFLAMMATION, BUT ALSO TRIGGERS MESENCHYMAL TRANSITION AND EXTRACELLULAR MATRIX REMODELING. SMALL MOLECULE INHIBITORS OF OGG1-8-OXOG BINDING AND BRD4-ACETYLATED HISTONE INTERACTION HAVE BEEN DEVELOPED. WE PRESENT STUDIES DEMONSTRATING EFFICACY OF THESE IN REDUCING AIRWAY INFLAMMATION IN PRECLINICAL MODELS. TARGETING INDUCIBLE EPIGENETIC REPROGRAMMING PATHWAY SHOWS PROMISE FOR THERAPEUTICS IN REVERSING AIRWAY REMODELING IN A VARIETY OF CHRONIC AIRWAY DISEASES.	2019	
                                                                                                                                                                                                                                                                                                                           
10  3711  31 INHALED DRUG DELIVERY FOR THE TARGETED TREATMENT OF ASTHMA. ASTHMA IS A CHRONIC LUNG DISEASE AFFECTING MILLIONS WORLDWIDE. WHILE CLASSICALLY ACKNOWLEDGED TO RESULT FROM ALLERGEN-DRIVEN TYPE 2 INFLAMMATORY RESPONSES LEADING TO IGE AND CYTOKINE PRODUCTION AND THE INFLUX OF IMMUNE CELLS SUCH AS MAST CELLS AND EOSINOPHILS, THE WIDE RANGE IN ASTHMATIC PATHOBIOLOGICAL SUBTYPES LEAD TO HIGHLY VARIABLE RESPONSES TO ANTI-INFLAMMATORY THERAPIES. THUS, THERE IS A NEED TO DEVELOP PATIENT-SPECIFIC THERAPIES CAPABLE OF ADDRESSING THE FULL SPECTRUM OF ASTHMATIC LUNG DISEASE. MOREOVER, DELIVERY OF TARGETED TREATMENTS FOR ASTHMA DIRECTLY TO THE LUNG MAY HELP TO MAXIMIZE THERAPEUTIC BENEFIT, BUT CHALLENGES REMAIN IN DESIGN OF EFFECTIVE FORMULATIONS FOR THE INHALED ROUTE. IN THIS REVIEW, WE DISCUSS THE CURRENT UNDERSTANDING OF ASTHMATIC DISEASE PROGRESSION AS WELL AS GENETIC AND EPIGENETIC DISEASE MODIFIERS ASSOCIATED WITH ASTHMA SEVERITY AND EXACERBATION OF DISEASE. WE ALSO OVERVIEW THE LIMITATIONS OF CLINICALLY AVAILABLE TREATMENTS FOR ASTHMA AND DISCUSS PRE-CLINICAL MODELS OF ASTHMA USED TO EVALUATE NEW THERAPIES. BASED ON THE SHORTCOMINGS OF EXISTING TREATMENTS, WE HIGHLIGHT RECENT ADVANCES AND NEW APPROACHES TO TREAT ASTHMA VIA INHALATION FOR MONOCLONAL ANTIBODY DELIVERY, MUCOLYTIC THERAPY TO TARGET AIRWAY MUCUS HYPERSECRETION AND GENE THERAPIES TO ADDRESS UNDERLYING DRIVERS OF DISEASE. FINALLY, WE CONCLUDE WITH DISCUSSION ON THE PROSPECTS FOR AN INHALED VACCINE TO PREVENT ASTHMA.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11  5573  34 ROLE OF MICRORNA IN SEVERE ASTHMA. THE VARIOUS ROLES OF MICRORNAS (MIRNAS) IN THE EPIGENETIC REGULATION OF HUMAN DISEASE ARE GAINING IMPORTANCE AS AREAS OF RESEARCH, AND A BETTER UNDERSTANDING OF THESE ROLES MAY IDENTIFY TARGETS FOR DEVELOPMENT OF NOVEL THERAPIES FOR SEVERE ASTHMA. MIRNAS, A CLASS OF SMALL NON-CODING RNAS THAT SERVE AS POST-TRANSCRIPTIONAL GENE REPRESSORS, ARE RECOGNIZED AS CRITICAL COMPONENTS IN REGULATING TISSUE HOMEOSTASIS. ALTERATION IN MIRNA EXPRESSION DISRUPTS HOMEOSTASIS AND IS AN UNDERLYING MECHANISM FOR DEVELOPMENT OF CHRONIC RESPIRATORY DISEASES, INCLUDING ASTHMA. DIFFERENTIAL PROFILES OF MIRNA EXPRESSION ARE INVOLVED IN INFLAMMATION AND REMODELING PATHOGENICITY VIA ACTIVATING AIRWAY STRUCTURAL CELLS AND IMMUNE CELLS AND INDUCING CYTOKINE RELEASES. MIRNA ACTION LEADS TO ASTHMA PROGRESSION FROM MILD TO SEVERE STAGES. HERE, CURRENT KNOWLEDGE OF THE HETEROGENEOUS ROLES OF MIRNAS IN SEVERE ASTHMA, INCLUDING BIOLOGICAL MECHANISMS UNDERLYING TH2 AND MACROPHAGE POLARIZATION, TYPE 2 INNATE LYMPHOID CELL (ILC2) BIOLOGY REGULATION, STEROID-RESISTANT ASTHMA PHENOTYPE, AIRWAY SMOOTH MUSCLE (ASM) DYSFUNCTION, AND IMPAIRED ANTI-VIRAL INNATE IMMUNE, ARE REVIEWED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12  4954  25 PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ENCOMPASSES A NUMBER OF INJURIOUS PROCESSES, INCLUDING AN ABNORMAL INFLAMMATORY RESPONSE IN THE LUNGS TO INHALED PARTICLES AND GASES. OTHER PROCESSES, SUCH AS FAILURE TO RESOLVE INFLAMMATION, ABNORMAL CELL REPAIR, APOPTOSIS, ABNORMAL CELLULAR MAINTENANCE PROGRAMS, EXTRACELLULAR MATRIX DESTRUCTION (PROTEASE/ANTIPROTEASE IMBALANCE), AND OXIDATIVE STRESS (OXIDANT/ANTIOXIDANT IMBALANCE) ALSO HAVE A ROLE. THE INFLAMMATORY RESPONSES TO THE INHALATION OF ACTIVE AND PASSIVE TOBACCO SMOKE AND URBAN AND RURAL AIR POLLUTION ARE MODIFIED BY GENETIC AND EPIGENETIC FACTORS. THE SUBSEQUENT CHRONIC INFLAMMATORY RESPONSES LEAD TO MUCUS HYPERSECRETION, AIRWAY REMODELING, AND ALVEOLAR DESTRUCTION. THIS ARTICLE PROVIDES AN UPDATE ON THE CELLULAR AND MOLECULAR MECHANISMS OF THESE PROCESSES IN THE PATHOGENESIS OF COPD.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13  4337  37 MICROTUBULES AS MAJOR REGULATORS OF ENDOTHELIAL FUNCTION: IMPLICATION FOR LUNG INJURY. ENDOTHELIAL DYSFUNCTION HAS BEEN ATTRIBUTED AS ONE OF THE MAJOR COMPLICATIONS IN COVID-19 PATIENTS, A GLOBAL PANDEMIC THAT HAS ALREADY CAUSED OVER 4 MILLION DEATHS WORLDWIDE. THE DYSFUNCTION OF ENDOTHELIAL BARRIER IS CHARACTERIZED BY AN INCREASE IN ENDOTHELIAL PERMEABILITY AND INFLAMMATORY RESPONSES, AND HAS EVEN BROADER IMPLICATIONS IN THE PATHOGENESIS OF ACUTE RESPIRATORY SYNDROMES SUCH AS ARDS, SEPSIS AND CHRONIC ILLNESSES REPRESENTED BY PULMONARY ARTERIAL HYPERTENSION AND INTERSTITIAL LUNG DISEASE. THE STRUCTURAL INTEGRITY OF ENDOTHELIAL BARRIER IS MAINTAINED BY CYTOSKELETON ELEMENTS, CELL-SUBSTRATE FOCAL ADHESION AND ADHESIVE CELL JUNCTIONS. AGONIST-MEDIATED CHANGES IN ENDOTHELIAL PERMEABILITY ARE DIRECTLY ASSOCIATED WITH REORGANIZATION OF ACTOMYOSIN CYTOSKELETON LEADING TO CELL CONTRACTION AND OPENING OF INTERCELLULAR GAPS OR ENHANCEMENT OF CORTICAL ACTIN CYTOSKELETON ASSOCIATED WITH STRENGTHENING OF ENDOTHELIAL BARRIER. THE ROLE OF ACTIN CYTOSKELETON REMODELING IN ENDOTHELIAL BARRIER REGULATION HAS TAKEN THE CENTRAL STAGE, BUT THE IMPACT OF MICROTUBULES IN THIS PROCESS REMAINS LESS EXPLORED AND UNDER-APPRECIATED. THIS REVIEW WILL SUMMARIZE THE CURRENT KNOWLEDGE ON THE CROSSTALK BETWEEN MICROTUBULES DYNAMICS AND ACTIN CYTOSKELETON REMODELING, DESCRIBE THE SIGNALING MECHANISMS MEDIATING THIS CROSSTALK, DISCUSS EPIGENETIC REGULATION OF MICROTUBULES STABILITY AND ITS NEXUS WITH ENDOTHELIAL BARRIER MAINTENANCE, AND OVERVIEW A ROLE OF MICROTUBULES IN TARGETED DELIVERY OF SIGNALING MOLECULES REGULATING ENDOTHELIAL PERMEABILITY AND INFLAMMATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                             
14  5372  33 RECENT ADVANCES IN UNDERSTANDING THE PATHOGENESIS OF RHEUMATOID ARTHRITIS: NEW TREATMENT STRATEGIES. RHEUMATOID ARTHRITIS (RA) IS CONSIDERED A CHRONIC SYSTEMIC, MULTI-FACTORIAL, INFLAMMATORY, AND PROGRESSIVE AUTOIMMUNE DISEASE AFFECTING MANY PEOPLE WORLDWIDE. WHILE PATIENTS SHOW VERY INDIVIDUAL COURSES OF DISEASE, WITH RA FOCUSING ON THE MUSCULOSKELETAL SYSTEM, JOINTS ARE OFTEN SEVERELY AFFECTED, LEADING TO LOCAL INFLAMMATION, CARTILAGE DESTRUCTION, AND BONE EROSION. TO PREVENT JOINT DAMAGE AND PHYSICAL DISABILITY AS ONE OF MANY SYMPTOMS OF RA, EARLY DIAGNOSIS IS CRITICAL. AUTO-ANTIBODIES PLAY A PIVOTAL CLINICAL ROLE IN PATIENTS WITH SYSTEMIC RA. AS BIOMARKERS, THEY COULD HELP TO MAKE A MORE EFFICIENT DIAGNOSIS, PROGNOSIS, AND TREATMENT DECISION. BESIDES AUTO-ANTIBODIES, SEVERAL OTHER FACTORS ARE INVOLVED IN THE PROGRESSION OF RA, SUCH AS EPIGENETIC ALTERATIONS, POST-TRANSLATIONAL MODIFICATIONS, GLYCOSYLATION, AUTOPHAGY, AND T-CELLS. UNDERSTANDING THE INTERPLAY BETWEEN THESE FACTORS WOULD CONTRIBUTE TO A DEEPER INSIGHT INTO THE CAUSES, MECHANISMS, PROGRESSION, AND TREATMENT OF THE DISEASE. IN THIS REVIEW, THE LATEST RA RESEARCH FINDINGS ARE DISCUSSED TO BETTER UNDERSTAND THE PATHOGENESIS, AND FINALLY, TREATMENT STRATEGIES FOR RA THERAPY ARE PRESENTED, INCLUDING BOTH CONVENTIONAL APPROACHES AND NEW METHODS THAT HAVE BEEN DEVELOPED IN RECENT YEARS OR ARE CURRENTLY UNDER INVESTIGATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15  5309  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16  2221  26 EPIGENETIC MODIFICATIONS IN RHEUMATOID ARTHRITIS, A REVIEW. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC JOINT INFLAMMATION AND PROGRESSIVE DESTRUCTION OF CARTILAGE AND BONE WHICH LEADS TO ULTIMATELY LOSS OF FUNCTION AND PAIN. ACTIVATED SYNOVIAL FIBROBLASTS ARE KEY EFFECTOR CELLS IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS. IN THE RECENT YEARS, EPIGENETIC CHANGES INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND OTHER HISTONE MODIFICATIONS WERE IDENTIFIED THAT ARE ASSOCIATED WITH AN INTRINSIC ACTIVATION AND THE AGGRESSIVE PHENOTYPE OF THESE CELLS. SO FAR, NO THERAPIES TARGETING RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS EXIST. THIS REVIEW COMPRISES RECENT RESEARCH EFFORTS THAT PROPOSE EPIGENETIC MECHANISMS BEHIND THE ACTIVATION OF RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS AND OTHER CELL TYPES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  6214  34 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	

18  2455  37 EPIGENETIC TARGETS FOR NOVEL THERAPIES OF LUNG DISEASES. IN SPITE OF SUBSTANTIAL ADVANCES IN DEFINING THE IMMUNOBIOLOGY AND FUNCTION OF STRUCTURAL CELLS IN LUNG DISEASES THERE IS STILL INSUFFICIENT KNOWLEDGE TO DEVELOP FUNDAMENTALLY NEW CLASSES OF DRUGS TO TREAT MANY LUNG DISEASES. FOR EXAMPLE, THERE IS A COMPELLING NEED FOR NEW THERAPEUTIC APPROACHES TO ADDRESS SEVERE PERSISTENT ASTHMA THAT IS INSENSITIVE TO INHALED CORTICOSTEROIDS. ALTHOUGH THE PREVALENCE OF STEROID-RESISTANT ASTHMA IS 5-10%, SEVERE ASTHMATICS REQUIRE A DISPROPORTIONATE LEVEL OF HEALTH CARE SPENDING AND CONSTITUTE A MAJORITY OF FATAL ASTHMA EPISODES. NONE OF THE ESTABLISHED DRUG THERAPIES INCLUDING LONG-ACTING BETA AGONISTS OR INHALED CORTICOSTEROIDS REVERSE ESTABLISHED AIRWAY REMODELING. OBSTRUCTIVE AIRWAYS REMODELING IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), RESTRICTIVE REMODELING IN IDIOPATHIC PULMONARY FIBROSIS (IPF) AND OCCLUSIVE VASCULAR REMODELING IN PULMONARY HYPERTENSION ARE SIMILARLY UNRESPONSIVE TO CURRENT DRUG THERAPY. THEREFORE, DRUGS ARE NEEDED TO ACHIEVE LONG-ACTING SUPPRESSION AND REVERSAL OF PATHOLOGICAL AIRWAY AND VASCULAR REMODELING. NOVEL DRUG CLASSES ARE EMERGING FROM ADVANCES IN EPIGENETICS. NOVEL MECHANISMS ARE EMERGING BY WHICH CELLS ADAPT TO ENVIRONMENTAL CUES, WHICH INCLUDE CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS AND REGULATION OF TRANSCRIPTION AND TRANSLATION BY NONCODING RNAS. IN THIS REVIEW WE WILL SUMMARIZE CURRENT EPIGENETIC APPROACHES BEING APPLIED TO PRECLINICAL DRUG DEVELOPMENT ADDRESSING IMPORTANT THERAPEUTIC CHALLENGES IN LUNG DISEASES. THESE CHALLENGES ARE BEING ADDRESSED BY ADVANCES IN LUNG DELIVERY OF OLIGONUCLEOTIDES AND SMALL MOLECULES THAT MODIFY THE HISTONE CODE, DNA METHYLATION PATTERNS AND MIRNA FUNCTION.	2015	
                                                                                                                                                                                                                                                                    
19  5138  36 POTENTIAL METABOLIC BIOMARKERS IN ADULT ASTHMATICS. ASTHMA IS THE MOST COMMON CHRONIC AIRWAY INFLAMMATION, WITH MULTIPLE PHENOTYPES CAUSED BY COMPLICATED INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. TO DATE, VARIOUS DETERMINANTS HAVE BEEN SUGGESTED FOR ASTHMA PATHOGENESIS BY A NEW TECHNOLOGY TERMED OMICS, INCLUDING GENOMICS, TRANSCRIPTOMICS, PROTEOMICS, AND METABOLOMICS. IN PARTICULAR, THE SYSTEMATIC ANALYSIS OF ALL METABOLITES IN A BIOLOGICAL SYSTEM, SUCH AS CARBOHYDRATES, AMINO ACIDS, AND LIPIDS, HAS HELPED IDENTIFY A NOVEL PATHWAY RELATED TO COMPLEX DISEASES. THESE METABOLITES ARE INVOLVED IN THE REGULATION OF HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTIONS IN THE PATHOGENESIS OF ASTHMA. AMONG THEM, LIPID METABOLISM HAS BEEN SUGGESTED TO BE RELATED TO LUNG DYSFUNCTION IN MILD-TO-MODERATE ASTHMA. SPHINGOLIPID METABOLITES ARE AN IMPORTANT MEDIATOR CONTRIBUTING TO AIRWAY INFLAMMATION IN OBESE ASTHMA AND ASPIRIN-EXACERBATED RESPIRATORY DISEASE. ALTHOUGH HOW THESE MOLECULAR VARIANTS IMPACT THE DISEASE HAS NOT BEEN COMPLETELY DETERMINED, IDENTIFICATION OF NEW CAUSATIVE FACTORS MAY POSSIBLY LEAD TO MORE-PERSONALIZED AND PRECISE PATHWAY-SPECIFIC APPROACHES FOR BETTER DIAGNOSIS AND TREATMENT OF ASTHMA. IN THIS REVIEW, PERSPECTIVES OF METABOLITES RELATED TO ASTHMA AND CLINICAL IMPLICATIONS HAVE BEEN HIGHLIGHTED ACCORDING TO VARIOUS PHENOTYPES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20  4097  27 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