1 2459 78 EPIGENETIC THERAPIES FOR NON-ONCOLOGY INDICATIONS. CHRONIC AND DEGENERATIVE DISORDERS ARE A MAJOR, AND GROWING, HUMAN HEALTH BURDEN, AND CURRENT TREATMENTS ARE IN MANY CASES INADEQUATE OR VERY EXPENSIVE. EPIGENETIC THERAPIES ARE ATTRACTIVE OPTIONS FOR TREATING SUCH DISORDERS BECAUSE THEY MANIPULATE THE PROCESSES THAT MAINTAIN CELLS IN AN ABNORMAL TRANSCRIPTIONAL STATE. THE CHALLENGES LIE IN IDENTIFYING THE MOST APPROPRIATE DISEASES AND THE ENZYMES THAT SHOULD BE TARGETED. THIS REVIEW DESCRIBES THE DIFFERENT APPROACHES THAT CAN BE USED TO ADDRESS THIS PROBLEM, FOCUSING PARTICULARLY ON CNS DISORDERS (ESPECIALLY MENTAL RETARDATION, NEURODEGENERATIVE DISEASE, PSYCHIATRIC DISORDERS AND DRUG ADDICTION), DIABETES AND DIABETIC COMPLICATIONS, AND AUTOIMMUNITY AND INFLAMMATORY DISEASES. 2010 2 5309 18 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 3 6101 16 THE EMERGING ROLE OF EPIGENETICS IN THE IMMUNE RESPONSE TO VACCINATION AND INFECTION: A SYSTEMATIC REVIEW. EXTENSIVE RESEARCH HAS HIGHLIGHTED THE ROLE OF INFECTION-INDUCED EPIGENETIC EVENTS IN THE DEVELOPMENT OF CANCER. MORE RECENTLY, ATTENTION HAS FOCUSED ON THE ABILITY OF NON-CARCINOGENIC INFECTIONS, AS WELL AS VACCINES, TO MODIFY THE HUMAN EPIGENOME AND MODULATE THE IMMUNE RESPONSE. THIS REVIEW EXPLORES THIS RAPIDLY EVOLVING AREA OF INVESTIGATION AND OUTLINES THE MANY AND VARIED WAYS IN WHICH VACCINATION AND NATURAL INFECTION CAN INFLUENCE THE HUMAN EPIGENOME FROM MODULATION OF THE INNATE AND ADAPTIVE IMMUNE RESPONSE, TO BIOLOGICAL AGEING AND MODIFICATION OF DISEASE RISK. THE IMPLICATIONS OF THESE EPIGENETIC CHANGES ON IMMUNE REGULATION AND THEIR POTENTIAL APPLICATION TO THE DIAGNOSIS AND TREATMENT OF CHRONIC INFECTION AND VACCINE DEVELOPMENT ARE ALSO DISCUSSED. 2020 4 4716 18 NON-GENETIC RATS MODELS FOR ATHEROSCLEROSIS RESEARCH: FROM PAST TO PRESENT. ATHEROSCLEROSIS IS AN INFLAMMATORY, PROGRESSIVE, AND CHRONIC ILLNESS THAT INVOLVES SEVERAL MOLECULAR AND EPIGENETIC FACTORS. DESPITE TREATMENT LIMITATIONS, CLINICAL AND THERAPEUTIC APPROACHES HAVE UNDENIABLY CHANGED RADICALLY IN RECENT DECADES THROUGH BETTER KNOWLEDGE OF THE PATHOPHYSIOLOGICAL BASIS OF THE DISEASE, WHICH HAS CONSIDERABLY IMPROVED PATIENTS' SURVIVAL AND QUALITY OF LIFE. SOME OF THESE ADVANCES ARE ATTRIBUTABLE TO BASIC BIOMEDICAL RESEARCH THAT PROVIDES INSIGHTS INTO A BETTER UNDERSTANDING AND IDENTIFICATION OF NEW MOLECULAR AND CELLULAR TARGETS FOR ATHEROSCLEROSIS TREATMENT. ALTHOUGH RODENT MODELS HAVE CONTRIBUTED SUBSTANTIALLY TO A BETTER UNDERSTANDING OF THE DEVELOPMENT OF ATHEROSCLEROSIS, THE ACCURACY OF THESE MODELS REMAINS CONTROVERSIAL. RESEARCH THAT UTILIZES GENETIC RODENT MODELS IS WELL ESTABLISHED, BUT THE USE OF SPECIFIC DIETS THAT ARE ASSOCIATED WITH OTHER RISK FACTORS (E.G., HYPERTENSION, HORMONE DEPRIVATION, AND PHARMACOLOGICAL TOOLS) IS STILL DEBATABLE. THE PRESENT REVIEW PROVIDES AN UPDATE ON NON-GENETIC RAT MODELS OF ATHEROSCLEROSIS AND AN OVERVIEW OF THE MAIN METHODOLOGIES THAT ARE CURRENTLY AVAILABLE. 2019 5 5024 15 PERSONALIZED EPIGENETIC MANAGEMENT OF DIABETES. THE NOVEL GENOME-WIDE ASSAYS OF EPIGENETIC MARKS HAVE RESULTED IN A GREATER UNDERSTANDING OF HOW GENETICS AND THE ENVIRONMENT INTERACT IN THE DEVELOPMENT AND INHERITANCE OF DIABETES. CHRONIC HYPERGLYCEMIA INDUCES EPIGENETIC CHANGES IN MULTIPLE ORGANS, CONTRIBUTING TO DIABETIC COMPLICATIONS. SPECIFIC EPIGENETIC-MODIFYING COMPOUNDS HAVE BEEN DEVELOPED TO ERASE THESE MODIFICATIONS, POSSIBLY SLOWING DOWN THE ONSET OF DIABETES-RELATED COMPLICATIONS. THE CURRENT REVIEW IS AN UPDATE OF THE PREVIOUSLY PUBLISHED PAPER, DESCRIBING THE MOST RECENT ADVANCES IN THE EPIGENETICS OF DIABETES. 2017 6 6913 21 [VARIOUS PATHWAYS LEADING TO THE PROGRESSION OF CHRONIC LIVER DISEASES]. AS THE RESULT OF VARIOUS EFFECTS (VIRUSES, METABOLIC DISEASES, NUTRITIONAL FACTORS, TOXIC AGENTS, AUTOIMMUNE PROCESSES) ABNORMAL LIVER FUNCTION, LIVER STEATOSIS AND CONNECTIVE TISSUE REMODELING MAY DEVELOP. PROGRESSION OF THIS PROCESS IS COMPLEX INCLUDING VARIOUS PATHWAYS AND A NUMBER OF FACTORS. THE AUTHORS SUMMARIZE THE FACTORS INVOLVED IN THE PROGRESSION OF CHRONIC LIVER DISEASE. THEY DESCRIBE THE ROLE OF CELLS AND THE PRODUCED INFLAMMATORY MEDIATORS AND CYTOKINES, AS WELL AS THE RELATIONSHIP BETWEEN THE DISEASE AND THE INTESTINAL FLORA. THEY EMPHASIZE THE ROLE OF OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION AND CELL DEATH IN DISEASE PROGRESSION. INSULIN RESISTANCE AND MICRO-ELEMENTS (IRON, COPPER) IN RELATION TO LIVER DAMAGE ARE ALSO DISCUSSED, AND GENETIC AND EPIGENETIC ASPECTS UNDERLYING DISEASE PROGRESSION ARE SUMMARIZED. DISCOVERY OF NOVEL TREATMENT OPTIONS, ASSESSMENT OF THE EFFECTIVENESS OF TREATMENT, AS WELL AS THE SUCCESS AND PROPER TIMING OF LIVER TRANSPLANTATION MAY DEPEND ON A BETTER UNDERSTANDING OF THE PROCESS OF DISEASE PROGRESSION. 2016 7 2932 22 GENES AND EPIGENETIC PROCESSES AS PROSPECTIVE PAIN TARGETS. CHRONIC PAIN AFFECTS APPROXIMATELY ONE IN FIVE ADULTS, RESULTING IN A GREATLY REDUCED QUALITY OF LIFE AND A HIGHER RISK OF DEVELOPING CO-MORBIDITIES SUCH AS DEPRESSION. AVAILABLE TREATMENTS OFTEN PROVIDE INADEQUATE PAIN RELIEF, BUT IT IS HOPED THAT THROUGH DEEPER UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING CHRONIC PAIN STATES WE CAN DISCOVER NEW AND IMPROVED THERAPIES. ALTHOUGH GENETIC RESEARCH HAS FLOURISHED OVER THE PAST DECADE AND HAS IDENTIFIED MANY KEY GENES IN PAIN PROCESSING, THE BUDDING FIELD OF EPIGENETICS PROMISES TO PROVIDE NEW INSIGHTS AND A MORE DYNAMIC VIEW OF PAIN REGULATION. THIS REVIEW GIVES AN OVERVIEW OF BASIC MECHANISMS AND CURRENT THERAPIES TO TREAT PAIN, AND DISCUSSES THE CLINICAL AND PRECLINICAL EVIDENCE FOR THE CONTRIBUTION OF GENETIC AND EPIGENETIC FACTORS, WITH A FOCUS ON HOW THIS KNOWLEDGE CAN AFFECT DRUG DEVELOPMENT. 2013 8 5829 18 STRESS, PSYCHIATRIC DISORDERS, MOLECULAR TARGETS, AND MORE. MENTAL HEALTH IS CENTRAL TO NORMAL HEALTH OUTCOMES. A WIDELY ACCEPTED THEORY IS THAT CHRONIC PERSISTENT STRESS DURING ADULTHOOD AS WELL AS DURING EARLY LIFE TRIGGERS ONSET OF NEUROPSYCHIATRIC AILMENTS. HOWEVER, QUESTIONS RELATED TO HOW THAT OCCURS, AND WHY ARE SOME INDIVIDUALS RESISTANT TO STRESS WHILE OTHERS ARE NOT, REMAIN UNANSWERED. AN INTEGRATED, MULTISYSTEMIC STRESS RESPONSE INVOLVING NEUROINFLAMMATORY, NEUROENDOCRINE, EPIGENETIC AND METABOLIC CASCADES HAVE BEEN SUGGESTED TO HAVE CAUSATIVE LINKS. SEVERAL THEORIES HAVE BEEN PROPOSED OVER THE YEARS TO CONCEPTUALIZE THIS LINK INCLUDING THE CYTOKINE HYPOTHESIS, THE ENDOCRINE HYPOTHESIS, THE OXIDATIVE STRESS HYPOTHESIS AND THE OXIDO-NEUROINFLAMMATION HYPOTHESIS. THE DATA DISCUSSED IN THIS REVIEW DESCRIBES POTENTIAL BIOCHEMICAL BASIS OF THE LINK BETWEEN STRESS, AND STRESS-INDUCED NEURONAL, BEHAVIORAL AND EMOTIONAL DEFICITS, PROVIDING INSIGHTS INTO POTENTIALLY NOVEL DRUG TARGETS. 2019 9 115 18 A STEM CELL AGING FRAMEWORK, FROM MECHANISMS TO INTERVENTIONS. STEM CELLS PLAY CENTRAL ROLES IN TISSUE DEVELOPMENT, HOMEOSTASIS, AND REGENERATION. DECADES OF SCIENTIFIC RESEARCH HAVE UNCOVERED PROCESSES OF STEM CELL DECLINE IN TISSUE AND ORGANISMAL AGING, AND MORE RECENTLY, PIONEERING TECHNOLOGIES PERMIT THE DISSECTION OF ITS UNDERLYING MECHANISMS AND INFORM THERAPEUTIC DEVELOPMENT FOR AGING AND AGING-ASSOCIATED DISORDERS. IN THIS REVIEW, WE ELUCIDATE AGING-RELATED FEATURES ACROSS DIFFERENT SOMATIC STEM CELL TYPES, WITH A SPECIFIC FOCUS ON EPIGENETIC CHANGES, LOSS OF PROTEIN HOMEOSTASIS, AND SYSTEMIC INFLUENCING FACTORS, INCLUDING CHRONIC INFLAMMATION, CIRCADIAN RHYTHM DYSREGULATION, AND METABOLIC DISORDER. OUR SURVEY OF ORGANISMAL STEM CELL AGING SUMMARIZES ITS UNDERLYING BIOLOGICAL IMPLICATIONS, POINTS TO POTENTIAL BIOMARKERS OF STEM CELL AGING, AND DISCUSSES STEM CELL-BASED THERAPEUTIC STRATEGIES WITH THE POTENTIAL FOR PROMOTING HEALTHY AGING AND COMBATING AGING AND AGE-RELATED DISEASES. 2022 10 3682 19 INFLAMMATION, FIBROSIS AND CANCER: MECHANISMS, THERAPEUTIC OPTIONS AND CHALLENGES. UNCONTROLLED INFLAMMATION IS A SALIENT FACTOR IN MULTIPLE CHRONIC INFLAMMATORY DISEASES AND CANCERS. IN THIS REVIEW, WE PROVIDED AN IN-DEPTH ANALYSIS OF THE RELATIONSHIPS AND DISTINCTIONS BETWEEN UNCONTROLLED INFLAMMATION, FIBROSIS AND CANCERS, WHILE EMPHASIZING THE CHALLENGES AND OPPORTUNITIES OF DEVELOPING NOVEL THERAPIES FOR THE TREATMENT AND/OR MANAGEMENT OF THESE DISEASES. WE DESCRIBED HOW DRUG DELIVERY SYSTEMS, COMBINATION THERAPY AND THE INTEGRATION OF TISSUE-TARGETED AND/OR PATHWAYS SELECTIVE STRATEGIES COULD OVERCOME THE CHALLENGES OF CURRENT AGENTS FOR MANAGING AND/OR TREATING CHRONIC INFLAMMATORY DISEASES AND CANCERS. WE ALSO RECOGNIZED THE VALUE OF THE RE-EVALUATION OF THE DISEASE-SPECIFIC ROLES OF MULTIPLE PATHWAYS IMPLICATED IN THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATORY DISEASES AND CANCERS-AS WELL AS THE APPLICATION OF DATA FROM SINGLE-CELL RNA SEQUENCING IN THE SUCCESS OF FUTURE DRUG DISCOVERY ENDEAVORS. 2022 11 3776 21 INTERACTIONS BETWEEN DYSLIPIDEMIA AND THE IMMUNE SYSTEM AND THEIR RELEVANCE AS PUTATIVE THERAPEUTIC TARGETS IN ATHEROSCLEROSIS. CARDIOVASCULAR DISEASE (CVD) CONTINUES TO BE A LEADING CAUSE OF DEATH WORLDWIDE WITH ATHEROSCLEROSIS BEING THE MAJOR UNDERLYING PATHOLOGY. THE INTERPLAY BETWEEN LIPIDS AND IMMUNE CELLS IS BELIEVED TO BE A DRIVING FORCE IN THE CHRONIC INFLAMMATION OF THE ARTERIAL WALL DURING ATHEROGENESIS. ATHEROSCLEROSIS IS INITIATED AS LIPID PARTICLES ACCUMULATE AND BECOME TRAPPED IN VESSEL WALLS. THE SUBSEQUENT IMMUNE RESPONSE, INVOLVING BOTH ADAPTIVE AND IMMUNE CELLS, PROGRESSES PLAQUE DEVELOPMENT, WHICH MAY BE EXACERBATED UNDER DYSLIPIDEMIC CONDITIONS. BROAD EVIDENCE, ESPECIALLY FROM ANIMAL MODELS, CLEARLY DEMONSTRATES THE EFFECT OF LIPIDS ON IMMUNE CELLS FROM THEIR DEVELOPMENT IN THE BONE MARROW TO THEIR PHENOTYPIC SWITCHING IN CIRCULATION. INTERESTINGLY, RECENT RESEARCH HAS ALSO SHOWN A LONG-LASTING EPIGENETIC SIGNATURE FROM LIPIDS ON IMMUNE CELLS. TRADITIONALLY, CARDIOVASCULAR THERAPIES HAVE APPROACHED ATHEROSCLEROSIS THROUGH LIPID-LOWERING MEDICATIONS BECAUSE, UNTIL RECENTLY, ANTI-INFLAMMATORY THERAPIES HAVE BEEN LARGELY UNSUCCESSFUL IN CLINICAL TRIALS. HOWEVER, THE RECENT CANAKINUMAB ANTIINFLAMMATORY THROMBOSIS OUTCOMES STUDY (CANTOS) PROVIDED PIVOTAL SUPPORT OF THE INFLAMMATORY HYPOTHESIS OF ATHEROSCLEROSIS IN MAN SPURRING ON ANTI-INFLAMMATORY STRATEGIES TO TREAT ATHEROSCLEROSIS. IN THIS REVIEW, WE DESCRIBE THE INTERACTIONS BETWEEN LIPIDS AND IMMUNE CELLS ALONG WITH THEIR SPECIFIC OUTCOMES AS WELL AS DISCUSS THEIR FUTURE PERSPECTIVE AS POTENTIAL CARDIOVASCULAR TARGETS. 2019 12 4844 22 ONE YEAR IN REVIEW 2019: PATHOGENESIS OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE INFLUENCED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. OVER THE LAST FEW YEARS, PARTICULAR ATTENTION HAS BEEN GIVEN TO NOVEL GENES AND TO THE CLOSE INTERACTION BETWEEN GENETIC FACTORS AND EPIGENETIC MECHANISMS. RESEARCH HAS ALSO FOCUSED ON THE INFLUENCE OF ENVIRONMENTAL FACTORS ON DISEASE DEVELOPMENT, AND ON NEW MECHANISMS OF THE INNATE AND ADAPTIVE IMMUNE SYSTEM THAT CAN INFLUENCE THE DIFFERENT STAGES OF RA. HOWEVER, THERE ARE STILL SEVERAL ASPECTS OF THE DISEASE THAT NEED FURTHER INVESTIGATION. SHEDDING SOME LIGHT ON THE DIFFERENT ASPECTS OF RA PATHOGENESIS WILL HELP TO IMPROVE THE CURRENT DIAGNOSTIC TOOLS AND TO IDENTIFY NEW TARGETS FOR THE DEVELOPMENT OF DISEASE-MODIFYING THERAPIES. THUS, IN THIS REVIEW WE SUMMARISE THE NEW INSIGHTS IN RA PATHOGENESIS, RESULTING FROM LITERATURE RESEARCH DATA PUBLISHED IN THE LAST YEAR. 2019 13 6276 23 THE PATHOGENIC ROLE OF DYSREGULATED EPIGENETIC MODIFICATIONS IN AUTOIMMUNE DISEASES. AUTOIMMUNE DISEASES CAN BE CHRONIC WITH RELAPSE OF INFLAMMATORY SYMPTOMS, BUT IT CAN BE ALSO ACUTE AND LIFE-THREATENING IF IMMUNE CELLS DESTROY LIFE-SUPPORTING ORGANS, SUCH AS LUPUS NEPHRITIS. THE ETIOPATHOGENESIS OF AUTOIMMUNE DISEASES HAS BEEN REVEALED AS THAT GENETICS AND ENVIRONMENTAL FACTORS-MEDIATED DYSREGULATED IMMUNE RESPONSES CONTRIBUTE TO THE INITIATION AND DEVELOPMENT OF AUTOIMMUNE DISORDERS. HOWEVER, THE CURRENT UNDERSTANDING OF PATHOGENESIS IS LIMITED AND THE UNDERLYING MECHANISM HAS NOT BEEN WELL DEFINED, WHICH LOWS THE DEVELOPMENT OF NOVEL BIOMARKERS AND NEW THERAPEUTIC STRATEGIES FOR AUTOIMMUNE DISEASES. TO IMPROVE THIS, BROADENING AND DEEPENING OUR UNDERSTANDING OF PATHOGENESIS IS AN UNMET NEED. AS GENETIC SUSCEPTIBILITY CANNOT EXPLAIN THE LOW ACCORDANCE RATE OF INCIDENCE IN HOMOZYGOUS TWINS, EPIGENETIC REGULATIONS MIGHT BE AN ADDITIONAL EXPLANATION. THEREFORE, THIS REVIEW WILL SUMMARIZE CURRENT PROGRESS OF STUDIES ON EPIGENETIC DYSREGULATIONS CONTRIBUTING TO AUTOIMMUNE DISEASES, INCLUDING SLE, RHEUMATOID ARTHRITIS (RA), PSORIASIS, TYPE 1 DIABETES (T1D), AND SYSTEMIC SCLEROSIS (SSC), HOPEFULLY PROVIDING OPINIONS ON ORIENTATION OF FUTURE RESEARCH, AS WELL AS DISCUSSING THE CLINICAL UTILIZATION OF POTENTIAL BIOMARKERS AND THERAPEUTIC STRATEGIES FOR THESE DISEASES. 2019 14 6860 26 [OBESITY EPIDEMIC: CURRENT EVIDENCE, CHALLENGES AND FUTURE DIRECTIONS]. THE OBESITY EPIDEMIC IS A PHENOMENON THAT HAS BEEN WIDELY STUDIED IN RECENT DECADES BUT IS STILL INCOMPLETELY UNDERSTOOD, AND ITS CONTROL IS FAR FROM THE DESIRABLE LEVEL IN VIEW OF THE INCREASING PREVALENCE FIGURES OBSERVED WORLDWIDE. THIS PAPER CONDUCTS A NARRATIVE REVIEW WITH THE AIM OF PROVIDING UPDATED EVIDENCE ON THE GLOBAL OBESITY EPIDEMIC, AND PARTICULARLY ON THE SITUATION IN LATIN AMERICA AND ARGENTINA, IDENTIFYING THE MAIN CHALLENGES AND FUTURE DIRECTIONS FOR ADDRESSING THIS PUBLIC HEALTH PROBLEM. IT FIRST DESCRIBES THE CURRENT BURDEN AND INCREASING TRENDS IN THE PREVALENCE OF OBESITY, IN THE OVERALL POPULATION AND BY POPULATION GROUPS, AND ITS POSSIBLE ASSOCIATION WITH GENETIC AND EPIGENETIC ASPECTS. IT ALSO SUMMARIZES THE DIRECT AND INDIRECT SOCIOECONOMIC CONSEQUENCES OF THIS EPIDEMIC, AS WELL AS RECENT STRATEGIES AND INITIATIVES FOCUSED ON OBESITY PREVENTION, WITH SPECIAL ATTENTION TO THOSE REPORTED AS THE MOST EFFICIENT IN THE LATIN AMERICAN CONTEXT. THIS REVIEW IDENTIFIED SOME PENDING CHALLENGES IN THE REGION, THE INTEGRATED APPROACH TO THE DOUBLE BURDEN OF MALNUTRITION AND THE GROWING CHILDHOOD OVERWEIGHT; AND IT POINTS OUT SOME EMERGING APPROACHES, SUCH AS THE SYNDEMIC APPROACH, AS POTENTIALLY USEFUL TO UNDERSTAND AND ADDRESS THIS COMPLEX PROBLEM IN THE CURRENT CONTEXT. IN CONCLUSION, IT HIGHLIGHTS THE IMPORTANCE OF IMPLEMENTING RENEWED, MORE EFFICIENT AND EVIDENCE-BASED STRATEGIES TO CONTROL THE GROWING PREVALENCE OF OBESITY, WHICH WOULD ALSO IMPACT ON THE BURDEN OF RELATED CHRONIC DISEASES, AND THUS ON THE ECONOMY AND WELL-BEING OF LATIN AMERICAN SOCIETIES. 2023 15 2525 21 EPIGENETICS AND TRAINED IMMUNITY. SIGNIFICANCE: A GROWING BODY OF CLINICAL AND EXPERIMENTAL EVIDENCE HAS CHALLENGED THE TRADITIONAL UNDERSTANDING THAT ONLY THE ADAPTIVE IMMUNE SYSTEM CAN MOUNT IMMUNOLOGICAL MEMORY. RECENT FINDINGS DESCRIBE THE ADAPTIVE CHARACTERISTICS OF THE INNATE IMMUNE SYSTEM, UNDERSCORED BY ITS ABILITY TO REMEMBER ANTECEDENT FOREIGN ENCOUNTERS AND RESPOND IN A NONSPECIFIC SENSITIZED MANNER TO REINFECTION. THIS HAS BEEN TERMED TRAINED INNATE IMMUNITY. ALTHOUGH BENEFICIAL IN THE CONTEXT OF RECURRENT INFECTIONS, THIS MIGHT ACTUALLY CONTRIBUTE TO CHRONIC IMMUNE-MEDIATED DISEASES, SUCH AS ATHEROSCLEROSIS. RECENT ADVANCES: IN LINE WITH ITS PROPOSED ROLE IN SUSTAINING CELLULAR MEMORIES, EPIGENETIC REPROGRAMMING HAS EMERGED AS A CRITICAL DETERMINANT OF TRAINED IMMUNITY. RECENT TECHNOLOGICAL AND COMPUTATIONAL ADVANCES THAT IMPROVE UNBIASED ACQUISITION OF EPIGENOMIC PROFILES HAVE SIGNIFICANTLY ENHANCED OUR APPRECIATION FOR THE COMPLEXITIES OF CHROMATIN ARCHITECTURE IN THE CONTEXTS OF DIVERSE IMMUNOLOGICAL CHALLENGES. CRITICAL ISSUES: KEY TO RESOLVING THE DISTINCT CHROMATIN SIGNATURES OF INNATE IMMUNE MEMORY IS A COMPREHENSIVE UNDERSTANDING OF THE PRECISE PHYSIOLOGICAL TARGETS OF REGULATORY PROTEINS THAT RECOGNIZE, DEPOSIT, AND REMOVE CHEMICAL MODIFICATIONS FROM CHROMATIN AS WELL AS OTHER GENE-REGULATING FACTORS. DRAWING FROM A RAPIDLY EXPANDING COMPENDIUM OF EXPERIMENTAL AND CLINICAL STUDIES, THIS REVIEW DETAILS A CURRENT PERSPECTIVE OF THE EPIGENETIC PATHWAYS THAT SUPPORT THE ADAPTED PHENOTYPES OF MONOCYTES AND MACROPHAGES. FUTURE DIRECTIONS: WE EXPLORE FUTURE STRATEGIES THAT ARE AIMED AT EXPLOITING THE MECHANISM OF TRAINED IMMUNITY TO IMPROVE THE PREVENTION AND TREATMENT OF INFECTIONS AND IMMUNE-MEDIATED CHRONIC DISORDERS. 2018 16 6054 27 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 17 5817 18 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 18 6843 18 [MEDICAL APPLICATIONS OF GENOME DISCOVERY]. THE DISCOVERY OF THE COMPLETE BASE SEQUENCE OF HUMAN GENOME UNVEILS SEVERAL PERSPECTIVES TO UNDERSTAND HUMAN DISEASES AND DEVELOP NEW THERAPIES. HUMAN GENOME CONTAINS APPROXIMATELY 39,000 GENES OF WHICH 26,000 CODE SPECIFIC PROTEINS THAT HAVE BEEN IDENTIFIED. THERE ARE APPROXIMATELY 1,500 DISEASES WITH IDENTIFIED MOLECULAR DISTURBANCES. GENES CAN MODIFY SIGNS AND SYMPTOMS OF COMMON DISEASES. THUS, THERE ARE NO PURE MONOGENIC DISEASES. CHRONIC DISEASES OF ADULTS ARE COMPLEX AND DEPENDENT ON MULTIPLE FACTORS. SEVERAL GENES THAT PREDISPOSE TO CHRONIC DEGENERATIVE DISEASES HAVE BEEN IDENTIFIED. THIS IS REVEALING THE COMPLEX NATURE AND THE INTERACTION OF THESE AILMENTS WITH THE ENVIRONMENT. THE DISCOVERY OF BACTERIAL AND VIRAL GENOMIC SEQUENCES WILL ALLOW THE MANUFACTURING OF NEW VACCINES AND SPECIFIC MOLECULAR ANTIMICROBIALS. THE NEW PHARMACOGENOMICS WILL DEVISE TREATMENTS FOR EACH SUBJECT ACCORDING TO HER SPECIFIC GENOMIC PROFILE. THE NEW APPLICATIONS OF GENOMIC TECHNOLOGY IS CREATING NEW PARADIGMS IN BIOMEDICAL RESEARCH SUCH AS FUNCTIONAL GENOMICS, PROTEONOMICS, EPIGENETIC REGULATION. GENE DIAGNOSIS AND THERAPY WILL CONSIDERABLY IMPROVE THE FUTURE OF MEDICINE. 2001 19 6180 20 THE HYGIENE HYPOTHESIS AND NEW PERSPECTIVES-CURRENT CHALLENGES MEETING AN OLD POSTULATE. DURING ITS 30 YEARS HISTORY, THE HYGIENE HYPOTHESIS HAS SHOWN ITSELF TO BE ADAPTABLE WHENEVER IT HAS BEEN CHALLENGED BY NEW SCIENTIFIC DEVELOPMENTS AND THIS IS A STILL A CONTINUOUSLY ONGOING PROCESS. IN THIS REGARD, THE MINI REVIEW AIMS TO DISCUSS SOME SELECTED NEW DEVELOPMENTS IN RELATION TO THEIR IMPACT ON FURTHER FINE-TUNING AND EXPANSION OF THE HYGIENE HYPOTHESIS. THIS WILL INCLUDE THE ROLE OF RECENTLY DISCOVERED CLASSES OF INNATE AND ADAPTIVE IMMUNE CELLS THAT CHALLENGES THE OLD TH1/TH2 PARADIGM, THE APPLICABILITY OF THE HYGIENE HYPOTHESIS TO NEWLY IDENTIFIED ALLERGY/ASTHMA PHENOTYPES WITH DIVERSE UNDERLYING PATHOMECHANISTIC ENDOTYPES, AND THE INCREASING KNOWLEDGE DERIVED FROM EPIGENETIC STUDIES THAT LEADS TO BETTER UNDERSTANDING OF MECHANISMS INVOLVED IN THE TRANSLATION OF ENVIRONMENTAL IMPACTS ON BIOLOGICAL SYSTEMS. FURTHER, WE DISCUSS IN BRIEF THE EXPANSION OF THE HYGIENE HYPOTHESIS TO OTHER DISEASE AREAS LIKE PSYCHIATRIC DISORDERS AND CANCER AND CONCLUDE THAT THE CONTINUOUSLY DEVELOPING HYGIENE HYPOTHESIS MAY PROVIDE A MORE GENERALIZED EXPLANATION FOR HEALTH BURDEN IN HIGHLY INDUSTRIALIZED COUNTRIES ALSO RELATION TO GLOBAL CHANGES. 2021 20 2503 16 EPIGENETICS AND METABOLISM AT THE CROSSROADS OF STRESS-INDUCED PLASTICITY, STEMNESS AND THERAPEUTIC RESISTANCE IN CANCER. DESPITE THE RECENT ADVANCES IN THE TREATMENT OF CANCERS, ACQUIRED DRUG RESISTANCE REMAINS A MAJOR CHALLENGE IN CANCER MANAGEMENT. WHILE EARLIER STUDIES SUGGEST DARWINIAN FACTORS DRIVING ACQUIRED DRUG RESISTANCE, RECENT STUDIES POINT TO A MORE DYNAMIC PROCESS INVOLVING PHENOTYPIC PLASTICITY AND TUMOR HETEROGENEITY IN THE EVOLUTION OF ACQUIRED DRUG RESISTANCE. CHRONIC STRESS AFTER DRUG TREATMENT INDUCES INTRINSIC CELLULAR REPROGRAMMING AND CANCER STEMNESS THROUGH A SLOW-CYCLING PERSISTER STATE, WHICH SUBSEQUENTLY DRIVES CANCER PROGRESSION. BOTH EPIGENETIC AND METABOLIC MECHANISMS PLAY AN IMPORTANT ROLE IN THIS DYNAMIC PROCESS. IN THIS REVIEW, WE DISCUSS HOW EPIGENETIC AND METABOLIC REPROGRAMMING LEADS TO STRESS-INDUCED PHENOTYPIC PLASTICITY AND ACQUIRED DRUG RESISTANCE, AND HOW THE TWO REPROGRAMMING MECHANISMS CROSSTALK WITH EACH OTHER. 2020