1 5817 76 STRESS AND THE EPIGENETIC LANDSCAPE: A LINK TO THE PATHOBIOLOGY OF HUMAN DISEASES? ACCUMULATING EVIDENCE POINTS TO A MAJOR ROLE FOR CHRONIC STRESS OF CELL RENEWAL SYSTEMS IN THE PATHOGENESIS OF IMPORTANT HUMAN DISEASES, INCLUDING CANCER, ATHEROSCLEROSIS AND DIABETES. HERE WE DISCUSS EMERGING EVIDENCE THAT EPIGENETIC ABNORMALITIES MAY MAKE SUBSTANTIAL CONTRIBUTIONS TO THESE STRESS-INDUCED PATHOLOGIES. ALTHOUGH THE MECHANISMS REMAIN TO BE FULLY ELUCIDATED, WE SUGGEST THAT CHRONIC STRESS CAN ELICIT HERITABLE CHANGES IN THE CHROMATIN LANDSCAPE THAT 'LOCK' CELLS IN ABNORMAL STATES, WHICH THEN LEAD TO DISEASE. WE EMPHASIZE THE NEED TO INVESTIGATE EPIGENETIC STATES IN DISEASE AND LINKS TO STRESS AND TO CONSIDER HOW THE KNOWLEDGE GAINED THROUGH THESE STUDIES MAY FOSTER NEW MEANS OF DISEASE PREVENTION AND MANAGEMENT. 2010 2 2933 25 GENESIS OF THE MYOFIBROBLAST IN LUNG INJURY AND FIBROSIS. TISSUE INJURY INCITES A REPAIR RESPONSE WITH A KEY MESENCHYMAL COMPONENT THAT PROVIDES THE ESSENTIAL CONNECTIVE TISSUE FOR SUBSEQUENT REGENERATION OR PATHOLOGICAL FIBROSIS. THE FIBROBLAST IS THE MAJOR MESENCHYMAL CELL TYPE TO BE IMPLICATED IN THIS CONNECTIVE TISSUE RESPONSE, AND IT IS IN ITS ACTIVATED OR DIFFERENTIATED FORM THAT IT PARTICIPATES IN THE REPAIR PROCESS. THE MYOFIBROBLAST REPRESENTS SUCH AN ACTIVATED MESENCHYMAL CELL AND IS A KEY SOURCE OF EXTRACELLULAR MATRIX AND INFLAMMATORY/FIBROGENIC CYTOKINES AS WELL AS PARTICIPATING IN WOUND CONTRACTION. ALTHOUGH SUCCESSFUL HEALING RESULTS IN GRADUAL DISAPPEARANCE OF MYOFIBROBLASTS, THEIR PERSISTENCE IS ASSOCIATED WITH CHRONIC AND PROGRESSIVE FIBROSIS. THUS, ELUCIDATION OF THE MECHANISM INVOLVED IN THE GENESIS OF THE MYOFIBROBLAST SHOULD PROVIDE INSIGHT INTO BOTH PATHOGENESIS OF CHRONIC FIBROTIC DISEASES AND THERAPEUTIC STRATEGIES FOR THEIR MANAGEMENT AND CONTROL. ALTHOUGH THE FIBROBLAST IS A WELL-DOCUMENTED PROGENITOR CELL FOR THE MYOFIBROBLAST, RECENT STUDIES HAVE SUGGESTED ADDITIONAL PRECURSOR CELLS THAT HAVE THE POTENTIAL TO GIVE RISE TO THE MYOFIBROBLAST. MANY OF THE STUDIES FOCUSED ON MECHANISMS AND FACTORS THAT REGULATE INDUCTION OF ALPHA-SMOOTH MUSCLE ACTIN EXPRESSION, A KEY AND COMMONLY USED MARKER OF THE MYOFIBROBLAST. THESE REVEAL COMPLEX AND MULTIFACTORIAL MECHANISMS INVOLVING TRANSCRIPTIONAL AND EPIGENETIC REGULATION AND IMPLICATING DIVERSE CELL-SIGNALING PATHWAYS, INCLUDING THOSE ACTIVATED BY THE POTENT FIBROGENIC CYTOKINE TRANSFORMING GROWTH FACTOR BETA. DESPITE THESE EXTENSIVE STUDIES, MANY ASPECTS REMAIN POORLY UNDERSTOOD, WITH THE SUGGESTION THAT ADDITIONAL NOVEL MECHANISMS REMAIN TO BE DISCOVERED. FUTURE STUDIES WITH THE HELP OF NEWLY DEVELOPED TECHNICAL ADVANCEMENTS SHOULD EXPEDITE DISCOVERY IN THIS DIRECTION. 2012 3 4191 27 METABOLIC LANDSCAPE IN CARDIAC AGING: INSIGHTS INTO MOLECULAR BIOLOGY AND THERAPEUTIC IMPLICATIONS. CARDIAC AGING IS EVIDENT BY A REDUCTION IN FUNCTION WHICH SUBSEQUENTLY CONTRIBUTES TO HEART FAILURE. THE METABOLIC MICROENVIRONMENT HAS BEEN IDENTIFIED AS A HALLMARK OF MALIGNANCY, BUT RECENT STUDIES HAVE SHED LIGHT ON ITS ROLE IN CARDIOVASCULAR DISEASES (CVDS). VARIOUS METABOLIC PATHWAYS IN CARDIOMYOCYTES AND NONCARDIOMYOCYTES DETERMINE CELLULAR SENESCENCE IN THE AGING HEART. METABOLIC ALTERATION IS A COMMON PROCESS THROUGHOUT CARDIAC DEGENERATION. IMPORTANTLY, THE INVOLVEMENT OF CELLULAR SENESCENCE IN CARDIAC INJURIES, INCLUDING HEART FAILURE AND MYOCARDIAL ISCHEMIA AND INFARCTION, HAS BEEN REPORTED. HOWEVER, METABOLIC COMPLEXITY AMONG HUMAN AGING HEARTS HINDERS THE DEVELOPMENT OF STRATEGIES THAT TARGETS METABOLIC SUSCEPTIBILITY. ADVANCES OVER THE PAST DECADE HAVE LINKED CELLULAR SENESCENCE AND FUNCTION WITH THEIR METABOLIC REPROGRAMMING PATHWAY IN CARDIAC AGING, INCLUDING AUTOPHAGY, OXIDATIVE STRESS, EPIGENETIC MODIFICATIONS, CHRONIC INFLAMMATION, AND MYOCYTE SYSTOLIC PHENOTYPE REGULATION. IN ADDITION, METABOLIC STATUS IS INVOLVED IN CRUCIAL ASPECTS OF MYOCARDIAL BIOLOGY, FROM FIBROSIS TO HYPERTROPHY AND CHRONIC INFLAMMATION. HOWEVER, FURTHER ELUCIDATION OF THE METABOLISM INVOLVEMENT IN CARDIAC DEGENERATION IS STILL NEEDED. THUS, DECIPHERING THE MECHANISMS UNDERLYING HOW METABOLIC REPROGRAMMING IMPACTS CARDIAC AGING IS THOUGHT TO CONTRIBUTE TO THE NOVEL INTERVENTIONS TO PROTECT OR EVEN RESTORE CARDIAC FUNCTION IN AGING HEARTS. HERE, WE SUMMARIZE EMERGING CONCEPTS ABOUT METABOLIC LANDSCAPES OF CARDIAC AGING, WITH SPECIFIC FOCUSES ON WHY METABOLIC PROFILE ALTERS DURING CARDIAC DEGENERATION AND HOW WE COULD UTILIZE THE CURRENT KNOWLEDGE TO IMPROVE THE MANAGEMENT OF CARDIAC AGING. 2023 4 1041 23 CLINICAL AND MOLECULAR ASPECTS OF LEAD TOXICITY: AN UPDATE. LEAD TOXICITY IS A MAJOR PUBLIC HEALTH ISSUE IN DEVELOPED AND DEVELOPING COUNTRIES. BOTH ACUTE AND CHRONIC LEAD EXPOSURE HAS THE POTENTIAL TO CAUSE MANY DELETERIOUS SYSTEMATIC EFFECTS INCLUDING HYPERTENSION, FRANK ANEMIA, COGNITIVE DEFICITS, INFERTILITY, IMMUNE IMBALANCES, DELAYED SKELETAL AND DECIDUOUS DENTAL DEVELOPMENT, VITAMIN D DEFICIENCY, AND GASTROINTESTINAL EFFECTS. THE UNDERLYING MECHANISMS FOR ALL THESE SYSTEMIC EFFECTS HAVE NOT BEEN ELUCIDATED COMPLETELY. HOWEVER, THE MOST PLAUSIBLE CAUSE IS FREE RADICAL DAMAGE. IN ADDITION TO THIS, LEAD BEING A DIVALENT CATION CAN SURROGATE FOR CALCIUM AT MULTIPLE LEVELS AFFECTING VARIOUS CELL SIGNALING PATHWAYS. THE MOLECULAR BASIS OF LEAD EXPOSURE RESULTING IN VARIOUS SYSTEMIC EFFECTS IS BEING EXTENSIVELY EXPLORED. THE REPORTS INCLUDE SINGLE NUCLEOTIDE POLYMORPHISMS, EPIGENETIC MODIFICATIONS IN SUSCEPTIBLE INDIVIDUALS, AND THE MOST RECENT REPORTS ALSO FEATURE REGULATORY RNA MOLECULES - MIRNAS. HOWEVER, MANY GENETIC TARGETS ARE IDENTIFIED, BUT THEIR POSSIBLE MECHANISMS ARE STILL AN AREA TO BE EXPLORED. ADDITIONAL STUDIES ARE NEEDED IN DIFFERENT POPULATION GROUPS TO VALIDATE THE EXISTING FINDINGS, AS WELL AS TO FIND NEWER TARGETS THAT MAY HELP IN BETTER UNDERSTANDING THE MOLECULAR MECHANISMS CONTRIBUTING TO LEAD TOXICITY. FURTHERMORE, NEWER STRATEGIES FOR LEAD RISK ASSESSMENT BECOMES NECESSARY AS THE PREVIOUSLY RECOGNIZED "SAFE" LEVEL OF LEAD IS ALSO BEING FOUND TO BE ASSOCIATED WITH NEGATIVE HEALTH OUTCOMES. 2017 5 2232 21 EPIGENETIC MODIFICATIONS OF MIRNAS IN OSTEOARTHRITIS: A SYSTEMATIC REVIEW ON THEIR METHYLATION LEVELS AND EFFECTS ON CHONDROCYTES, EXTRACELLULAR MATRIX AND JOINT INFLAMMATION. OSTEOARTHRITIS (OA) IS A JOINT DISORDER CHARACTERIZED BY PROGRESSIVE DEGENERATION OF CARTILAGE EXTRACELLULAR MATRIX (ECM), CHONDROCYTE HYPERTROPHY AND APOPTOSIS AND INFLAMMATION. THE CURRENT TREATMENTS MAINLY CONCERN PAIN CONTROL AND REDUCTION OF INFLAMMATION, BUT NO THERAPEUTIC STRATEGY HAS BEEN IDENTIFIED AS A DISEASE-MODIFYING TREATMENT. THEREFORE, IDENTIFYING SPECIFIC BIOMARKERS USEFUL TO PREVENT, TREAT OR DISTINGUISH THE STAGES OF OA DISEASE HAS BECOME AN IMMEDIATE NEED OF CLINICAL PRACTICE. THE ROLE OF MICRORNAS (MIRNAS) IN OA HAS BEEN INVESTIGATED IN THE LAST DECADE, AND INCREASING EVIDENCE HAS EMERGED THAT THE INFLUENCE OF THE ENVIRONMENT ON GENE EXPRESSION THROUGH EPIGENETIC PROCESSES CONTRIBUTES TO THE DEVELOPMENT, PROGRESSION AND AGGRESSIVENESS OF OA, IN PARTICULAR ACTING ON THE MICROENVIRONMENT MODULATIONS. THE EFFECTS OF EPIGENETIC REGULATION, PARTICULARLY DIFFERENT MIRNA METHYLATION DURING OA DISEASE, WERE HIGHLIGHTED IN THE PRESENT SYSTEMATIC REVIEW. THE EVIDENCE ARISING FROM THIS STUDY OF THE LITERATURE CONDUCTED IN THREE DATABASES (PUBMED, SCOPUS, WEB OF SCIENCE) SUGGESTED THAT MIRNA METHYLATION STATE ALREADY STRONGLY IMPACTS OA PROGRESSION, DRIVING CHONDROCYTES AND SYNOVIOCYTE PROLIFERATION, APOPTOSIS, INFLAMMATION AND ECM DEPOSITION. HOWEVER, THE POSSIBILITY OF UNDERSTANDING THE MECHANISM BY WHICH DIFFERENT EPIGENETIC MODIFICATIONS OF MIRNA OR PRE-MIRNA SEQUENCES DRIVE THE AGGRESSIVENESS OF OA COULD BE THE NEW FOCUS OF FUTURE INVESTIGATIONS. 2023 6 2416 22 EPIGENETIC SIGNALING OF CANCER STEM CELLS DURING INFLAMMATION. MALIGNANT TUMORS POSE A GREAT CHALLENGE TO HUMAN HEALTH, WHICH HAS LED TO MANY STUDIES INCREASINGLY ELUCIDATING THE TUMORIGENIC PROCESS. CANCER STEM CELLS (CSCS) HAVE PROFOUND IMPACTS ON TUMORIGENESIS AND DEVELOPMENT OF DRUG RESISTANCE. RECENTLY, THERE HAS BEEN INCREASED INTEREST IN THE RELATIONSHIP BETWEEN INFLAMMATION AND CSCS BUT THE MECHANISM UNDERLYING THIS RELATIONSHIP HAS NOT BEEN FULLY ELUCIDATED. INFLAMMATORY CYTOKINES PRODUCED DURING CHRONIC INFLAMMATION ACTIVATE SIGNALING PATHWAYS THAT REGULATE THE GENERATION OF CSCS THROUGH EPIGENETIC MECHANISMS. IN THIS REVIEW, WE FOCUS ON THE EFFECTS OF INFLAMMATION ON CANCER STEM CELLS, PARTICULARLY THE ROLE OF SIGNALING PATHWAYS SUCH AS NF-KAPPAB PATHWAY, STAT3 PATHWAY AND SMAD PATHWAY INVOLVED IN REGULATING EPIGENETIC CHANGES. WE HOPE TO PROVIDE A NOVEL PERSPECTIVE FOR IMPROVING STRATEGIES FOR TUMOR TREATMENT. 2021 7 2174 18 EPIGENETIC MECHANISMS INVOLVED IN MODULATION OF INFLAMMATORY DISEASES. PURPOSE OF REVIEW: THE ACTIVATION OF INFLAMMATORY RESPONSE IS DEPENDENT UPON GENETIC FACTORS AND EPIGENETIC CONTROL MECHANISMS. THIS OVERVIEW WILL HIGHLIGHT RECENT ADVANCES IN THE UNDERSTANDING OF EPIGENETIC DYNAMICS DURING CELLULAR INFLAMMATION. RECENT FINDINGS: THERE IS A GROWING BODY OF EVIDENCE INDICATING THAT ALTERATIONS OF THE CHROMATIN STATE ASSOCIATE WITH AN INCREASED RISK OF CHRONIC DISEASE DEVELOPMENT AND INFLAMMATION. EPIGENETIC ALTERATIONS RESPOND RAPIDLY TO ENVIRONMENTAL CHANGES AND HAVE A PROFOUND EFFECT ON GENE REGULATORY CROSS-WIRINGS AND TRANSCRIPTIONAL REGULATION. SUMMARY: SYSTEMATIC DISSECTION OF THE MECHANISMS UNDERLYING EPIGENETIC EFFECTS DURING INFLAMMATORY RESPONSE IS A CRITICAL STEP TOWARD ELUCIDATION OF THE CELL'S MOLECULAR PROCESSES AND HOLDS POTENTIAL FOR THE DEVELOPMENT OF NOVEL THERAPIES FOR THE TREATMENT OF CHRONIC DISEASES. 2016 8 874 24 CHRONIC ALLERGY SIGNALING: IS IT ALL STRESSED-OUT MITOCHONDRIA? ALLERGIC DISEASES IN GENERAL, AND CHRONIC ALLERGIC INFLAMMATION IN PARTICULAR, ARE ON THE RISE IN THE UNITED STATES AND OTHER DEVELOPED COUNTRIES. THE IDEA OF CHRONIC ALLERGIC DISEASE AS A CHRONIC TYPE 2 IMMUNE RESPONSE HAS BEEN AROUND FOR SEVERAL DECADES. HOWEVER, DATA SUGGEST THAT OTHER MECHANISMS MAY BE IMPORTANT IN CHRONIC DISEASE. THEREFORE, WE BELIEVE IT IS TIME FOR A PARADIGM SHIFT IN UNDERSTANDING THE MECHANISTIC CAUSES OF DISEASE SYMPTOMS IN THESE DISEASES. IN THIS REVIEW, WE HAVE AVOIDED THE CLASSIC CANONICAL PATHWAYS AND FOCUSED ON THE EMERGING IDEA THAT OXIDATIVE STRESS, CHANGES IN IMMUNO-METABOLISM, MITOCHONDRIAL DYSFUNCTION, AND EPIGENETIC CHANGES (PARTICULARLY MICRORNA PROFILE) MAY BE WORKING CONCURRENTLY OR SYNERGISTICALLY TO POTENTIATE ALLERGIC DISEASE SYMPTOMS. FURTHERMORE, WE HAVE ADDRESSED HOW THE EPIDEMIC OF OBESITY EXACERBATES ALLERGIC DISEASE VIA THE DYSREGULATION OF THE AFOREMENTIONED FACTORS. 2022 9 2413 21 EPIGENETIC SIGNALING AND RNA REGULATION IN CARDIOVASCULAR DISEASES. RNA EPIGENETICS IS PERHAPS THE MOST RECENT FIELD OF INTEREST FOR TRANSLATIONAL EPIGENETICISTS. RNA MODIFICATIONS CREATE SUCH AN EXTENSIVE NETWORK OF EPIGENETICALLY DRIVEN COMBINATIONS WHOSE ROLE IN PHYSIOLOGY AND PATHOPHYSIOLOGY IS STILL FAR FROM BEING ELUCIDATED. NOT SURPRISINGLY, SOME OF THE PLAYERS DETERMINING CHANGES IN RNA STRUCTURE ARE IN COMMON WITH THOSE INVOLVED IN DNA AND CHROMATIN STRUCTURE REGULATION, WHILE OTHER MOLECULES SEEM VERY SPECIFIC TO RNA. IT IS ENVISAGED, THEN, THAT NEW SMALL MOLECULES, ACTING SELECTIVELY ON RNA EPIGENETIC CHANGES, WILL BE REPORTED SOON, OPENING NEW THERAPEUTIC INTERVENTIONS BASED ON THE CORRECTION OF THE RNA EPIGENETIC LANDSCAPE. IN THIS REVIEW, WE SHALL SUMMARIZE SOME ASPECTS OF RNA EPIGENETICS LIMITED TO THOSE IN WHICH THE POTENTIAL CLINICAL TRANSLATABILITY TO CARDIOVASCULAR DISEASE IS EMERGING. 2020 10 4317 25 MICRORNAS AS REGULATORS OF AIRBORNE POLLUTION-INDUCED LUNG INFLAMMATION AND CARCINOGENESIS. THE INCREASING INCIDENCE OF PULMONARY INFLAMMATION AND LUNG CANCER, AS WELL AS EXACERBATION OF PRE-EXISTING CHRONIC LUNG DISEASES BY EXPOSURE TO AIRBORNE POLLUTANTS, E.G., PARTICULATE MATTER AND CIGARETTE SMOKE, IS BECOMING A MAJOR PUBLIC HEALTH CONCERN IN THE WORLD. HOWEVER, THE EXACT MECHANISMS OF PULMONARY INJURY FROM EXPOSURE TO THESE AIRBORNE INSULTS HAVE NOT BEEN FULLY ELUCIDATED. NEVERTHELESS, ACCUMULATING EVIDENCE SUGGESTS THAT MICRORNAS (MIRNAS) MAY PLAY A UNIQUE ROLE IN THE REGULATION OF AIRBORNE AGENT-INDUCED LUNG INFLAMMATION AND CARCINOGENESIS. SINCE EPIGENETIC MODIFICATIONS ARE HERITABLE AND REVERSIBLE, THIS MAY PROVIDE A NEW INSIGHT INTO THE RELATIONSHIP OF MIRNAS AND ENVIRONMENTAL POLLUTION-RELATED LUNG DISORDERS. THE AIM OF THIS REVIEW WAS TO UPDATE OUR EXISTING KNOWLEDGE REGARDING THE MECHANISMS BY WHICH AIRBORNE POLLUTANTS ALTERING MIRNA PROFILES IN THE LUNG, SPECIFICALLY FOR CIGARETTE SMOKE AND AIRBORNE PARTICULATE MATTER, AND THE POTENTIAL BIOLOGICAL ROLES OF MIRNAS IN THE INITIATION OF PULMONARY INFLAMMATION AND LUNG CANCER, AS WELL AS THE REGULATION OF UNDERLYING GENETIC SUSCEPTIBILITY TO THESE ENVIRONMENTAL STRESSORS. 2015 11 1712 35 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 3674 21 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 13 6223 23 THE LEADING ROLE OF EPITHELIAL CELLS IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A RELENTLESSLY PROGRESSIVE AND DEVASTATING INTERSTITIAL LUNG DISEASE OF UNKNOWN ETIOLOGY, WHERE THE NORMAL LUNG ARCHITECTURE IS LOST AND REPLACED BY FIBROTIC TISSUE LEADING TO AN IRREVERSIBLE AND PROGRESSIVE RESPIRATORY INSUFFICIENCY. HISTORICALLY, IPF WAS CONSIDERED A CHRONIC INFLAMMATORY DISORDER, WHICH GRADUALLY PROGRESSED TO ESTABLISHED FIBROSIS. HOWEVER, STRONG CLINICAL AND EXPERIMENTAL EVIDENCE INDICATES THAT THE DISEASE REPRESENTS AN EPITHELIAL-DRIVEN DISORDER WHICH RESULTS FROM A COMPLEX INTERPLAY OF GENETIC AND ENVIRONMENTAL RISK FACTORS, AGING-ASSOCIATED PROCESSES AND A PROFIBROTIC EPIGENETIC REPROGRAMMING. THE CONVERGENCE OF THESE FACTORS RESULTS IN THE ABERRANT ACTIVATION OF EPITHELIAL CELLS THAT INITIATE THE DEVELOPMENT OF THE DISEASE, PRODUCING VIRTUALLY ALL THE MEDIATORS THAT PARTICIPATE IN THE MIGRATION, PROLIFERATION AND ACTIVATION OF FIBROBLASTS, THEIR DIFFERENTIATION TO MYOFIBROBLASTS AND THE EXCESSIVE AND CHAOTIC SECRETION OF EXTRACELLULAR MATRIX PROTEINS. ALTHOUGH PROGRESS HAS BEEN MADE IN UNDERSTANDING THE CAUSES AND CONSEQUENCES OF THIS ABNORMAL BEHAVIOR OF DISTAL AIRWAYS AND ALVEOLAR EPITHELIUM, THE MECHANISMS THAT INITIATE AND PERPETUATE THE VICIOUS CIRCLE OF MULTIDIRECTIONAL ABNORMAL COMMUNICATIONS BETWEEN THE EPITHELIUM AND FIBROBLASTS AND OTHER RESIDENT CELLS HAVE NOT BEEN ELUCIDATED. IN THIS REVIEW, WE DISCUSS THE ROLE OF EPITHELIAL CELLS AND THE MECHANISMS UNDERLYING THE FIBROTIC RESPONSE IN IPF, AND HIGHLIGHT SOME PROMISING THERAPEUTIC TARGETS FOR THESE CELLS. 2020 14 3640 22 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 15 5805 28 STRATEGIES TO PREVENT AND REVERSE LIVER FIBROSIS IN HUMANS AND LABORATORY ANIMALS. LIVER FIBROSIS RESULTS FROM CHRONIC DAMAGE TO THE LIVER IN CONJUNCTION WITH VARIOUS PATHWAYS AND IS MEDIATED BY A COMPLEX MICROENVIRONMENT. BASED ON CLINICAL OBSERVATIONS, IT IS NOW EVIDENT THAT FIBROSIS IS A DYNAMIC, BIDIRECTIONAL PROCESS WITH AN INHERENT CAPACITY FOR RECOVERY AND REMODELING. THE MAJOR MECHANISMS INVOLVED IN LIVER FIBROSIS INCLUDE THE REPETITIVE INJURY OF HEPATOCYTES, THE ACTIVATION OF THE INFLAMMATORY RESPONSE AFTER INJURY STIMULATION, AND THE ACTIVATION AND PROLIFERATION OF HEPATIC STELLATE CELLS (HSCS), WHICH REPRESENTS THE MAJOR EXTRACELLULAR MATRIX (ECM)-PRODUCING CELLS, STIMULATED BY HEPATOCYTE INJURY AND INFLAMMATION. THE MICROENVIRONMENT IN THE LIVER IS SYNERGISTICALLY REGULATED ABNORMAL ECM DEPOSITION, SCAR FORMATION, ANGIOGENESIS, AND FIBROGENESIS. MOREOVER, RECENT STUDIES HAVE CLARIFIED NOVEL MECHANISM IN FIBROSIS SUCH AS EPIGENETIC REGULATION OF HSCS, THE LEPTIN AND PPARGAMMA PATHWAYS, THE COAGULATION SYSTEM, AND EVEN AUTOPHAGY. UNCOVERING THE MECHANISMS OF LIVER FIBROGENESIS PROVIDES A BASIS TO DEVELOP POTENTIAL THERAPIES TO REVERSE AND TREAT THE FIBROTIC RESPONSE, THEREBY IMPROVING THE OUTCOMES OF PATIENTS WITH CHRONIC LIVER DISEASE. ALTHOUGH BOTH SCIENTIFIC AND CLINICAL CHALLENGES REMAIN, EMERGING STUDIES ATTEMPT TO REVEAL THE IDEAL ANTI-FIBROTIC DRUG THAT COULD BE EASILY DELIVERED TO THE LIVER WITH HIGH SPECIFICITY AND LOW TOXICITY. THIS REVIEW HIGHLIGHTS THE MECHANISMS, INCLUDING NOVEL PATHWAYS UNDERLYING FIBROGENESIS THAT MAY BE TRANSLATED INTO PREVENTIVE AND TREATMENT STRATEGIES, REVIEWS BOTH CURRENT AND NOVEL AGENTS THAT TARGET SPECIFIC PATHWAYS OR MULTIPLE TARGETS, AND DISCUSSES NOVEL DRUG DELIVERY SYSTEMS SUCH AS NANOTECHNOLOGY THAT CAN BE APPLIED IN THE TREATMENT OF LIVER FIBROSIS. IN ADDITION, WE ALSO DISCUSS SOME CURRENT TREATMENT STRATEGIES THAT ARE BEING APPLIED IN ANIMAL MODELS AND IN CLINICAL TRIALS. 2015 16 5071 22 PHYSICAL EXERCISE AND EPIGENETIC ADAPTATIONS OF THE CARDIOVASCULAR SYSTEM. DURING THE LAST DECADE, EPIGENETICS BECAME ONE OF THE FASTEST GROWING RESEARCH FIELDS IN NUMEROUS CLINICAL AND BASIC SCIENCE DISCIPLINES. EVIDENCE SUGGESTS THAT CHROMATIN MODIFICATIONS (E.G., HISTONE MODIFICATIONS AND DNA METHYLATION) AS WELL AS THE EXPRESSION OF MICRO-RNA MOLECULES PLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF SEVERAL CARDIOVASCULAR DISEASES. ON THE ONE HAND, THEY ARE INVOLVED IN THE DEVELOPMENT OF GENERAL RISK FACTORS LIKE CHRONIC INFLAMMATION, BUT ON THE OTHER HAND, EPIGENETIC MODIFICATIONS ARE CONDUCIVE TO SMOOTH MUSCLE CELL, CARDIOMYOCYTE, AND ENDOTHELIAL PROGENITOR CELL PROLIFERATION/DIFFERENTIATION AS WELL AS TO EXTRACELLULAR MATRIX PROCESSING AND ENDOTHELIAL FUNCTION (E.G., ENDOTHELIAL NITRIC OXIDE SYNTHASE REGULATION). THEREFORE, EPIGENETIC MEDICAL DRUGS HAVE GAINED INCREASED ATTENTION AND PROVIDED THE FIRST PROMISING RESULTS IN THE CONTEXT OF CARDIOVASCULAR MALIGNANCIES. BESIDE OTHER LIFESTYLE FACTORS, PHYSICAL ACTIVITY AND SPORTS ESSENTIALLY CONTRIBUTE TO CARDIOVASCULAR HEALTH AND REGENERATION. IN THIS REVIEW WE FOCUS ON RECENT RESEARCH PROPOSING PHYSICAL ACTIVITY AS A POTENT EPIGENETIC REGULATOR THAT HAS THE POTENTIAL TO COUNTERACT PATHOPHYSIOLOGICAL ALTERATIONS IN ALMOST ALL THE AFOREMENTIONED CARDIOVASCULAR CELLS AND TISSUES. AS WITH EPIGENETIC MEDICAL DRUGS, MORE KNOWLEDGE ABOUT THE MOLECULAR MECHANISMS AND DOSE-RESPONSE RELATIONSHIPS OF EXERCISE IS NEEDED TO OPTIMIZE THE OUTCOME OF PREVENTIVE AND REHABILITATIVE EXERCISE PROGRAMS AND RECOMMENDATIONS. 2015 17 2180 28 EPIGENETIC MECHANISMS OF PANCREATOBILIARY FIBROSIS. PURPOSE OF REVIEW: THE GOAL OF THIS MANUSCRIPT IS TO REVIEW THE CURRENT LITERATURE RELATED TO FIBROGENESIS IN THE PANCREATOBILIARY SYSTEM AND HOW THIS PROCESS CONTRIBUTES TO PANCREATIC AND BILIARY DISEASES. IN PARTICULAR, WE SEEK TO DEFINE THE CURRENT STATE OF KNOWLEDGE REGARDING THE EPIGENETIC MECHANISMS THAT GOVERN AND REGULATE TISSUE FIBROSIS IN THESE ORGANS. A BETTER UNDERSTANDING OF THESE UNDERLYING MOLECULAR EVENTS WILL SET THE STAGE FOR FUTURE EPIGENETIC THERAPEUTICS. RECENT FINDINGS: WE HIGHLIGHT THE SIGNIFICANT ADVANCES THAT HAVE BEEN MADE IN DEFINING THE PATHOGENESIS OF PANCREATOBILIARY FIBROSIS AS IT RELATES TO CHRONIC PANCREATITIS, PANCREATIC CANCER, AND THE FIBRO-OBLITERATIVE CHOLANGIOPATHIES. WE ALSO REVIEW THE CELL TYPES INVOLVED AS WELL AS CONCEPTS RELATED TO EPITHELIAL-MESENCHYMAL CROSSTALK. FURTHERMORE, WE OUTLINE IMPORTANT SIGNALING PATHWAYS (E.G., TGFBETA) AND DIVERSE EPIGENETIC PROCESSES (I.E., DNA METHYLATION, NON-CODING RNAS, HISTONE MODIFICATIONS, AND 3D CHROMATIN REMODELING) THAT REGULATE FIBROGENIC GENE NETWORKS IN THESE CONDITIONS. WE REVIEW A GROWING BODY OF SCIENTIFIC EVIDENCE LINKING EPIGENETIC REGULATORY EVENTS TO FIBROTIC DISEASE STATES IN THE PANCREAS AND BILIARY SYSTEM. ADVANCES IN THIS UNDERSTUDIED AREA WILL BE CRITICAL TOWARD DEVELOPING EPIGENETIC PHARMACOLOGICAL APPROACHES THAT MAY LEAD TO MORE EFFECTIVE TREATMENTS FOR THESE DEVASTATING AND DIFFICULT TO TREAT DISORDERS. 2019 18 3404 28 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 19 554 25 AUTOPHAGY IN HUMAN HEALTH AND DISEASE: NOVEL THERAPEUTIC OPPORTUNITIES. SIGNIFICANCE: IN EUKARYOTES, AUTOPHAGY REPRESENTS A HIGHLY EVOLUTIONARY CONSERVED PROCESS, THROUGH WHICH MACROMOLECULES AND CYTOPLASMIC MATERIAL ARE DEGRADED INTO LYSOSOMES AND RECYCLED FOR BIOSYNTHETIC OR ENERGETIC PURPOSES. DYSFUNCTION OF THE AUTOPHAGIC PROCESS HAS BEEN ASSOCIATED WITH THE ONSET AND DEVELOPMENT OF MANY HUMAN CHRONIC PATHOLOGIES, SUCH AS CARDIOVASCULAR, METABOLIC, AND NEURODEGENERATIVE DISEASES AS WELL AS CANCER. RECENT ADVANCES: CURRENTLY, COMPREHENSIVE RESEARCH IS BEING CARRIED OUT TO DISCOVER NEW THERAPEUTIC AGENTS THAT ARE ABLE TO MODULATE THE AUTOPHAGIC PROCESS IN VIVO. RECENT EVIDENCE HAS SHOWN THAT A LARGE NUMBER OF NATURAL BIOACTIVE COMPOUNDS ARE INVOLVED IN THE REGULATION OF AUTOPHAGY BY MODULATING SEVERAL TRANSCRIPTIONAL FACTORS AND SIGNALING PATHWAYS. CRITICAL ISSUES: CRITICAL ISSUES THAT DESERVE PARTICULAR ATTENTION ARE THE INADEQUATE UNDERSTANDING OF THE COMPLEX ROLE OF AUTOPHAGY IN DISEASE PATHOGENESIS, THE LIMITED AVAILABILITY OF THERAPEUTIC DRUGS, AND THE LACK OF CLINICAL TRIALS. IN THIS CONTEXT, THE EFFECTS THAT NATURAL BIOACTIVE COMPOUNDS EXERT ON AUTOPHAGIC MODULATION SHOULD BE CLEARLY HIGHLIGHTED, SINCE THEY DEPEND ON THE TYPE AND STAGE OF THE PATHOLOGICAL CONDITIONS OF DISEASES. FUTURE DIRECTIONS: RESEARCH EFFORTS SHOULD NOW FOCUS ON UNDERSTANDING THE SURVIVAL-SUPPORTING AND DEATH-PROMOTING ROLES OF AUTOPHAGY, HOW NATURAL COMPOUNDS INTERACT EXACTLY WITH THE AUTOPHAGIC TARGETS SO AS TO INDUCE OR INHIBIT AUTOPHAGY AND ON THE EVALUATION OF THEIR PHARMACOLOGICAL EFFECTS IN A MORE IN-DEPTH AND MECHANISTIC WAY. IN ADDITION, CLINICAL STUDIES ON AUTOPHAGY-INDUCING NATURAL PRODUCTS ARE STRONGLY ENCOURAGED, ALSO TO HIGHLIGHT SOME FUNDAMENTAL ASPECTS, SUCH AS THE DOSE, THE DURATION, AND THE POSSIBLE SYNERGISTIC ACTION OF THESE COMPOUNDS WITH CONVENTIONAL THERAPY. 2019 20 3800 23 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