1 2503 75 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 2 2174 20 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 3 6886 21 [ROLE OF EPIGENETIC MODIFICATION IN HIGHER BRAIN DYSFUNCTION AND AGING]. EPIGENETIC MECHANISMS TYPICALLY INVOLVE HERITABLE ALTERATIONS IN CHROMATIN STRUCTURE, WHICH, IN TURN, REGULATE GENE EXPRESSION. FUNDAMENTAL INSIGHTS ABOUT EPIGENETIC HERITABILITY HAVE COME FROM STUDIES OF CELL DIVISION AND DEVELOPMENT. HOWEVER, THERE IS INCREASING EVIDENCE THAT THE REGULATION OF CHROMATIN STRUCTURE THROUGH HISTONE MODIFICATIONS AND DNA METHYLATION MIGHT MEDIATE THE EXPRESSION OF KEY GENES INVOLVED IN ACQUIRED CHRONIC DISORDERS. THIS IDEA IS FASCINATING BECAUSE SIMILAR MECHANISMS ARE USED FOR TRIGGERING AND STORING LONG-TERM MEMORIES AT THE CELLULAR LEVEL DURING, FOR EXAMPLE, HIGHER-BRAIN DYSFUNCTION, STRESS DISEASE, DRUG DEPENDENCE, AGING, AND CHRONIC PAIN. THIS REVIEW WILL EXPLORE THE MOST CURRENT ISSUES IN THE FIELD OF EPIGENETICS, WITH A FOCUS ON NEXT LEVELS OF TRANSCRIPTIONAL MECHANISMS UNDERLYING AGING, ENRICHED ENVIRONMENT AND DRUG ADDICTION. EPIGENETIC MECHANISMS, WHICH ARE KEY CELLULAR AND MOLECULAR PROCESSES THAT INTEGRATE DIVERSE ENVIRONMENTAL STIMULI TO EXERT POTENT AND OFTEN LONG-LASTING CHANGES IN GENE EXPRESSION THROUGH THE REGULATION OF CHROMATIN STRUCTURE, CONTRIBUTE TO TRANSCRIPTIONAL AND BEHAVIORAL CHANGES. 2012 4 5817 23 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 5 2338 25 EPIGENETIC REGULATION OF INFLAMMATORY SIGNALING AND INFLAMMATION-INDUCED CANCER. EPIGENETICS COMPRISE A DIVERSE ARRAY OF REVERSIBLE AND DYNAMIC MODIFICATIONS TO THE CELL'S GENOME WITHOUT IMPLICATING ANY DNA SEQUENCE ALTERATIONS. BOTH THE EXTERNAL ENVIRONMENT SURROUNDING THE ORGANISM, AS WELL AS THE INTERNAL MICROENVIRONMENT OF CELLS AND TISSUES, CONTRIBUTE TO THESE EPIGENETIC PROCESSES THAT PLAY CRITICAL ROLES IN CELL FATE SPECIFICATION AND ORGANISMAL DEVELOPMENT. ON THE OTHER HAND, DYSREGULATION OF EPIGENETIC ACTIVITIES CAN INITIATE AND SUSTAIN CARCINOGENESIS, WHICH IS OFTEN AUGMENTED BY INFLAMMATION. CHRONIC INFLAMMATION, ONE OF THE MAJOR HALLMARKS OF CANCER, STEMS FROM PROINFLAMMATORY CYTOKINES THAT ARE SECRETED BY TUMOR AND TUMOR-ASSOCIATED CELLS IN THE TUMOR MICROENVIRONMENT. AT THE SAME TIME, INFLAMMATORY SIGNALING CAN ESTABLISH POSITIVE AND NEGATIVE FEEDBACK CIRCUITS WITH CHROMATIN TO MODULATE CHANGES IN THE GLOBAL EPIGENETIC LANDSCAPE. IN THIS REVIEW, WE PROVIDE AN IN-DEPTH DISCUSSION OF THE INTERCONNECTED CROSSTALK BETWEEN EPIGENETICS AND INFLAMMATION, SPECIFICALLY HOW EPIGENETIC MECHANISMS AT DIFFERENT HIERARCHICAL LEVELS OF THE GENOME CONTROL INFLAMMATORY GENE TRANSCRIPTION, WHICH IN TURN ENACT CHANGES WITHIN THE CELL'S EPIGENOMIC PROFILE, ESPECIALLY IN THE CONTEXT OF INFLAMMATION-INDUCED CANCER. 2022 6 5410 22 REGULATION OF ADAPTIVE IMMUNE CELLS BY SIRTUINS. IT IS NOW WELL-ESTABLISHED THAT THE PATHWAYS THAT CONTROL LYMPHOCYTE METABOLISM AND FUNCTION ARE INTIMATELY LINKED, AND CHANGES IN LYMPHOCYTE METABOLISM CAN INFLUENCE AND DIRECT CELLULAR FUNCTION. INTERESTINGLY, A NUMBER OF RECENT ADVANCES INDICATE THAT LYMPHOCYTE IDENTITY AND METABOLISM IS PARTIALLY CONTROLLED VIA EPIGENETIC REGULATION. EPIGENETIC MECHANISMS, SUCH AS CHANGES IN DNA METHYLATION OR HISTONE ACETYLATION, HAVE BEEN FOUND TO ALTER IMMUNE FUNCTION AND PLAY A ROLE IN NUMEROUS CHRONIC DISEASE STATES. THERE ARE SEVERAL ENZYMES THAT CAN MEDIATE EPIGENETIC CHANGES; OF PARTICULAR INTEREST ARE SIRTUINS, PROTEIN DEACETYLASES THAT MEDIATE ADAPTIVE RESPONSES TO A VARIETY OF STRESSES (INCLUDING CALORIE RESTRICTION AND METABOLIC STRESS) AND ARE NOW UNDERSTOOD TO PLAY A SIGNIFICANT ROLE IN IMMUNITY. THIS REVIEW WILL FOCUS ON RECENT ADVANCES IN THE UNDERSTANDING OF HOW SIRTUINS AFFECT THE ADAPTIVE IMMUNE SYSTEM. THESE PATHWAYS ARE OF SIGNIFICANT INTEREST AS THERAPEUTIC TARGETS FOR THE TREATMENT OF AUTOIMMUNITY, CANCER, AND TRANSPLANT TOLERANCE. 2019 7 1923 16 ENVIRONMENTAL EPIGENETIC MODIFICATIONS AND REPROGRAMMING-RECALCITRANT GENES. THE TERM "ENVIRONMENTAL EPIGENETIC MODIFICATIONS" REFERS TO ALTERATIONS IN PHENOTYPE TRIGGERED BY ENVIRONMENTAL STIMULI VIA EPIGENETIC MECHANISMS. EPIDEMIOLOGIC AND ANIMAL MODEL STUDIES SHOW THAT A SUBSET OF SUCH ENVIRONMENTAL EPIGENETIC MARKS MAY AFFECT SUSCEPTIBILITY TO CHRONIC DISEASES. A GROWING BODY OF EVIDENCE REGARDING INCOMPLETENESS OF REPROGRAMMING INDICATES THAT THE POTENTIAL RETENTION OF PATHOGENIC ENVIRONMENTAL EPIGENETICS IN HUMAN INDUCED PLURIPOTENT STEM CELLS (IPSCS) SHOULD BE SERIOUSLY CONSIDERED. GIVEN THIS POSSIBILITY, THE OPTIMIZATION OF METHODS FOR THE GENERATION OF HUMAN INDUC PLURIPOTENT STEM CELLS MAY REQUIRE THE IDENTIFICATION OF EPIGENETICALLY APPROPRIATE SOMATIC CELL SOURCES. SIMILARLY, TECHNIQUES FOR CONTROLLING EPIGENETIC MODIFICATION BY ENVIRONMENTAL FACTORS MAY ALSO PLAY A CRITICAL ROLE IN THE DEVELOPMENT OF EPIGENETICALLY STABLE SOURCES OF PLURIPOTENT STEM CELLS. 2010 8 3703 23 INFLAMMATORY SIGNALLING AS MEDIATOR OF EPIGENETIC MODULATION IN TISSUE-SPECIFIC CHRONIC INFLAMMATION. RECENT SUCCESSES OF THERAPEUTIC INTERVENTION IN CHRONIC INFLAMMATORY DISEASES USING EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASE INHIBITORS AND INHIBITORS OF DNA METHYLATION SUGGEST THAT EPIGENETIC REPROGRAMMING PLAYS A ROLE IN THE AETIOLOGY OF THESE DISEASES. THE EPIGENETIC SIGNATURE OF A GIVEN IMMUNE CELL IS REFLECTED IN THE HISTORY OF MODIFICATIONS FROM DIFFERENT SIGNALS THE CELL HAS BEEN SUBJECTED TO DURING DIFFERENTIATION. LIKE OTHER CELLS, DIFFERENTIATING IMMUNE CELLS ARE DEPENDENT ON A COMPLEX COMBINATION OF INTER- AND INTRACELL SIGNALLING AS WELL AS TRANSCRIPTION MACHINERIES TO MODULATE THEIR EPIGENOMES IN ORDER TO MEDIATE DIFFERENTIATION. DESPITE EXTENSIVE RESEARCH INTO THESE PROCESSES, THE LINK BETWEEN CELLULAR SIGNALLING AND EPIGENETIC MODULATION REMAINS POORLY UNDERSTOOD. HERE, WE REVIEW RECENT PROGRESS AND DISCUSS KEY FACTORS DRIVING EPIGENETIC MODULATION IN CHRONIC INFLAMMATION. 2009 9 389 17 AN INTEGRATIVE HYPOTHESIS LINKING CANCER, DIABETES AND ATHEROSCLEROSIS: THE ROLE OF MUTATIONS AND EPIGENETIC CHANGES. IT APPEARS THAT THE DISEASE STATES OF CANCER, ALTHEROSCLEROSIS AND DIABETES MIGHT SHARE A COMMON ETIOLOGY. THESE CHRONIC DISEASES APPEAR TO BE MULTI-STAGED IN THEIR PROGRESSION, WITH GENETIC, NUTRITIONAL, PSYCHO-SOCIAL, ENVIRONMENTAL AND VIRAL FACTORS INFLUENCING THEIR APPEARANCE. WE OFFERED A HYPOTHESIS (A "MUTATION THEORY OF DISEASE"), STATING THAT THESE DISEASES CAN BE DESCRIBED BY INITIATION AND PROMOTION PHASES; INITIATION BEING THE RESULT OF THE PRODUCTION OF MUTATED CELLS AFTER UNREPAIRED DAMAGED DNA IS REPLICATED; PROMOTION BEING THE SELECTIVE PROLIFERATION OF THE INITIATED CELLS TO FORM CLONES OF MUTATED CELLS. IT WAS FURTHER POSTULATED THAT PROMOTION AFFECTS CELL PROLIFERATION BY ALTERING A MEMBRANE-CA++ REGULATORY SYSTEM. DEPENDING ON THE NATURE OF THE MUTATION IN THE CLONE OF CELLS, SPECIFIC DISEASE STATES WOULD RESULT. THE ROLES OF RADIATIONS, CHEMICALS, VIRUSES, GENES, NUTRITION AND PSYCHO-SOCIAL STRESS WERE RELATED TO EITHER THE INITIATION (MUTATION PRODUCTION) OR THE PROMOTION (CELL PROLIFERATION) PHASE OF THESE DISEASES. 1980 10 2592 18 EPIGENETICS OF RENAL DEVELOPMENT AND DISEASE. AN UNDERSTANDING OF EPIGENETICS IS INDISPENSABLE TO OUR UNDERSTANDING OF GENE REGULATION UNDER NORMAL AND PATHOLOGICAL STATES. THIS KNOWLEDGE WILL HELP WITH DESIGNING BETTER THERAPEUTIC APPROACHES IN REGENERATIVE TISSUE MEDICINE. EPIGENETICS ALLOWS US TO PARSE OUT THE MECHANISMS BY WHICH TRANSCRIPTIONAL REGULATORS GAIN ACCESS TO SPECIFIC GENE LOCI THEREBY IMPRINTING EPIGENETIC INFORMATION AFFECTING CHROMATIN FUNCTION. THIS EPIGENETIC MEMORY FORMS THE BASIS OF CELL LINEAGE SPECIFICATION IN MULTICELLULAR ORGANISMS. POST-TRANSLATIONAL MODIFICATIONS TO DNA AND HISTONES IN THE NUCLEOSOME CORE FORM CHARACTERISTIC EPIGENETIC CODES WHICH ARE DISTINCT FOR SELF-RENEWING AND PRIMED PROGENITOR CELL POPULATIONS. STUDIES OF CHROMATIN MODIFIERS AND MODIFICATIONS IN RENAL DEVELOPMENT AND DISEASE HAVE BEEN GAINING MOMENTUM. BOTH CONGENITAL AND ADULT RENAL DISEASES HAVE A GENE-ENVIRONMENT COMPONENT, WHICH INVOLVES ALTERATIONS TO THE EPIGENETIC INFORMATION IMPRINTED DURING DEVELOPMENT. THIS EPIGENETIC MEMORY MUST BE CHARACTERIZED TO ESTABLISH OPTIMAL TREATMENT OF BOTH ACUTE AND CHRONIC RENAL DISEASES. 2016 11 2586 20 EPIGENETICS OF PAIN MEDIATORS. PURPOSE OF REVIEW: THE FIELD OF EPIGENETICS CONTINUES ITS INFLUENTIAL RISE AS A MEANS TO BETTER UNDERSTAND AN ORGANISM'S UNIQUE DEVELOPMENTAL IDENTITY OVER A LIFESPAN. WHEREAS A GENOME IS CONSTANT AND UNCHANGING, AN EPIGENOME IS DYNAMIC AND ALTERABLE. EPIGENETIC CHANGES ARE IN RESPONSE TO INNUMERABLE INTERNAL AND EXTERNAL INFLUENCES INCLUDING ENVIRONMENTAL CHANGES SUCH AS DIET, EXERCISE, DISEASE, TOXINS, AND STRESS. EPIGENETICS IS OF PARTICULAR INTEREST IN THE MEDICAL RESEARCH COMMUNITY BOTH FOR THE POTENTIAL TO CAUSE DISEASE AND AS A TARGET FOR THERAPEUTIC INTERVENTIONS. THIS ARTICLE PROVIDES A SUCCINCT EXPLANATION OF THE POTENTIAL FOR EPIGENETICS TO INFLUENCE THE UNDERSTANDING OF PAIN AS WELL AS A REVIEW OF RELEVANT RESEARCH ON THE TOPIC. RECENT FINDINGS: STUDIES ON EPIGENETICS AND PAIN REMAIN LARGELY PRECLINICAL AND INVESTIGATE THE THEORETICAL ABILITY OF EPIGENETICS TO ALTER THE NOCICEPTIVE PATHWAYS BOTH IN THE PERIPHERY AND CENTRALLY. SIGNIFICANT EVIDENCE NOW EXISTS FOR THE ABILITY OF EPIGENETICS TO MODIFY BROADLY CATEGORIZED PAIN TYPES, INCLUDING INFLAMMATORY, NEUROPATHIC, VISCERAL, AND CANCER RELATED. SUMMARY: BOTH PATIENTS AND PROVIDERS RECOGNIZE THAT NOVEL MEDICATIONS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC PAIN CONDITIONS ARE SORELY NEEDED. THE UNDERSTANDING OF EPIGENETICS AND ITS INFLUENCE ON NOCICEPTION REMAINS IN RELATIVE INFANCY BUT EARLY EVIDENCE IS STRONG FOR POTENTIAL THERAPEUTIC BENEFITS TO TREAT THESE CONDITIONS. 2018 12 6131 26 THE EPIGENETIC REGULATION OF WOUND HEALING. SIGNIFICANCE: EPIGENETIC REGULATORY MECHANISMS ARE ESSENTIAL FOR EPIDERMAL HOMEOSTASIS AND CONTRIBUTE TO THE PATHOGENESIS OF MANY SKIN DISEASES, INCLUDING SKIN CANCER AND PSORIASIS. HOWEVER, WHILE THE EPIGENETIC REGULATION OF EPIDERMAL HOMEOSTASIS IS NOW BECOMING ACTIVE AREA OF RESEARCH, THE EPIGENETIC MECHANISMS CONTROLLING THE WOUND HEALING RESPONSE REMAIN RELATIVELY UNTOUCHED. RECENT ADVANCES: SUBSTANTIAL PROGRESS ACHIEVED WITHIN THE LAST TWO DECADES IN UNDERSTANDING EPIGENETIC MECHANISMS CONTROLLING GENE EXPRESSION ALLOWED DEFINING SEVERAL LEVELS, INCLUDING COVALENT DNA AND HISTONE MODIFICATIONS, ATP-DEPENDENT AND HIGHER-ORDER CHROMATIN CHROMATIN REMODELING, AS WELL AS NONCODING RNA- AND MICRORNA-DEPENDENT REGULATION. RESEARCH PERTAINED OVER THE LAST FEW YEARS SUGGESTS THAT EPIGENETIC REGULATORY MECHANISMS PLAY A PIVOTAL ROLE IN THE REGULATION OF SKIN REGENERATION AND CONTROL AN EXECUTION OF REPARATIVE GENE EXPRESSION PROGRAMS IN BOTH SKIN EPITHELIUM AND MESENCHYME. CRITICAL ISSUES: EPIGENETIC REGULATORS APPEAR TO BE INHERENTLY INVOLVED IN THE PROCESSES OF SKIN REPAIR, AND ARE ABLE TO DYNAMICALLY REGULATE KERATINOCYTE PROLIFERATION, DIFFERENTIATION, AND MIGRATION, TOGETHER WITH INFLUENCING DERMAL REGENERATION AND NEOANGIOGENESIS. THIS IS ACHIEVED THROUGH A SERIES OF COMPLEX REGULATORY MECHANISMS THAT ARE ABLE TO BOTH STIMULATE AND REPRESS GENE ACTIVATION TO TRANSIENTLY ALTER CELLULAR PHENOTYPE AND BEHAVIOR, AND INTERACT WITH GROWTH FACTOR ACTIVITY. FUTURE DIRECTIONS: UNDERSTANDING THE MOLECULAR BASIS OF EPIGENETIC REGULATION IS A PRIORITY AS IT REPRESENTS POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC SKIN CONDITIONS. FUTURE RESEARCH IS, THEREFORE, IMPERATIVE TO HELP DISTINGUISH EPIGENETIC MODULATING DRUGS THAT CAN BE USED TO IMPROVE WOUND HEALING. 2014 13 4103 20 MECHANICAL CUES REGULATE HISTONE MODIFICATIONS AND CELL BEHAVIOR. CHANGE OF BIOPHYSICAL FACTORS IN TISSUE MICROENVIRONMENT IS AN IMPORTANT STEP IN A CHRONIC DISEASE DEVELOPMENT PROCESS. A MECHANICAL AND BIOCHEMICAL FACTOR FROM CELL LIVING MICRONICHE CAN REGULATE CELL EPIGENETIC DECORATION AND, THEREFORE, FURTHER INDUCE CHANGE OF GENE EXPRESSION. IN THIS REVIEW, WE WILL EMPHASIZE THE MECHANISM THAT BIOPHYSICAL MICROENVIRONMENT MANIPULATES CELL BEHAVIOR INCLUDING GENE EXPRESSION AND PROTEIN DECORATION, THROUGH MODIFYING HISTONE AMINO ACID RESIDUE MODIFICATION. THE INFLUENCE GIVEN BY DIFFERENT MECHANICAL FORCES, INCLUDING MECHANICAL STRETCH, SUBSTRATE SURFACE STIFFNESS, AND SHEAR STRESS, ON CELL FATE AND BEHAVIOR DURING CHRONIC DISEASE DEVELOPMENT INCLUDING TUMORIGENESIS WILL ALSO BE TEASED OUT. OVERALL, THE RECENT WORK SUMMARIZED IN THIS REVIEW CULMINATES ON THE HYPOTHESIS THAT A MECHANICAL FACTOR STIMULATES THE MODIFICATION ON HISTONE WHICH COULD FACILITATE DISEASE DETECTION AND POTENTIAL THERAPEUTIC TARGET. 2022 14 6213 18 THE INTESTINAL EPITHELIAL CELL CYCLE: UNCOVERING ITS 'CRYPTIC' NATURE. PURPOSE OF REVIEW: TO DISCUSS THE RECENT LANDMARK FINDINGS THAT HAVE INCREASED OUR UNDERSTANDING NOT ONLY OF THE ROLE OF THE EPITHELIAL CELL CYCLE IN THE HOMEOSTASIS OF THE SMALL INTESTINE, BUT ALSO ITS RELEVANCE TO INFLAMMATION AND CANCER. RECENT FINDINGS: RECENT DATA HAVE UNVEILED NOVEL INFORMATION ON PROTEIN INTERACTIONS DIRECTLY INVOLVED IN THE CELL CYCLE AS WELL AS IN THE PATHWAYS THAT TRANSDUCE EXTERNAL ENVIRONMENTAL SIGNALS TO THE CELL CYCLE. A GROWING BODY OF THE RECENT EVIDENCE CONFIRMS THE IMPORTANCE OF FOOD AS WELL AS HORMONAL REGULATION IN THE GUT ON CELL CYCLE. INFORMATION ON THE CONTRIBUTION OF THE EPITHELIAL MICROENVIRONMENT, INCLUDING THE MICROBIOTA, HAS GROWN SUBSTANTIALLY IN THE RECENT YEARS AS WELL AS ON THE GENE-ENVIRONMENT INTERACTIONS AND THE MULTIPLE EPIGENETIC MECHANISMS INVOLVED IN REGULATING CELL-CYCLE PROTEINS AND SIGNALLING. FINALLY, FURTHER STUDIES INVESTIGATING THE DYSREGULATION OF THE CELL CYCLE DURING INFLAMMATION AND PROLIFERATION HAVE INCREASED OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATORY DISEASES AND CANCER. SUMMARY: THIS REVIEW HIGHLIGHTS SOME OF THE MOST RECENT ADVANCES THAT FURTHER EMPHASIZE THE IMPORTANCE OF THE CELL CYCLE IN THE SMALL INTESTINE DURING HOMEOSTASIS AS WELL AS IN INFLAMMATION AND CANCER. 2015 15 4204 22 METABOLISM, EPIGENETICS, AND CAUSAL INFERENCE IN HEART FAILURE. EUKARYOTES MUST BALANCE THE METABOLIC AND CELL DEATH ACTIONS OF MITOCHONDRIA VIA CONTROL OF GENE EXPRESSION AND CELL FATE BY CHROMATIN, THEREBY FUNCTIONALLY BINDING THE METABOLOME AND EPIGENOME. THIS INTERACTION HAS FAR-REACHING IMPLICATIONS FOR CHRONIC DISEASES IN HUMANS, THE MOST COMMON OF WHICH ARE THOSE OF THE CARDIOVASCULAR SYSTEM. THE MOST DEVASTATING CONSEQUENCE OF CARDIOVASCULAR DISEASE, HEART FAILURE, IS NOT A SINGLE DISEASE, DIAGNOSIS, OR ENDPOINT. HUMAN AND ANIMAL STUDIES HAVE REVEALED THAT, REGARDLESS OF ETIOLOGY AND SYMPTOMS, HEART FAILURE IS UNIVERSALLY ASSOCIATED WITH ABNORMAL METABOLISM AND GENE EXPRESSION - TO FRAME THIS AS CAUSE OR CONSEQUENCE, HOWEVER, MAY BE TO WRONGFOOT THE QUESTION. THIS ESSAY AIMS TO CHALLENGE CURRENT THINKING ON METABOLIC-EPIGENETIC CROSSTALK IN HEART FAILURE, PRESENTING HYPOTHESES FOR HOW CHRONIC DISEASES ARISE, TAKE HOLD, AND PERSIST. WE UNPACK ASSUMPTIONS ABOUT THE ORDER OF OPERATIONS FOR GENE EXPRESSION AND METABOLISM, EXPLORING RECENT FINDINGS IN NONCARDIAC SYSTEMS THAT LINK METABOLIC INTERMEDIATES DIRECTLY TO CHROMATIN REMODELING. LASTLY, WE DISCUSS POTENTIAL MECHANISMS BY WHICH CHROMATIN MAY SERVE AS A SUBSTRATE FOR METABOLIC MEMORY, AND HOW CHANGES IN CELLULAR TRANSCRIPTOMES (AND HENCE IN CELLULAR BEHAVIOR) IN RESPONSE TO STRESS CORRESPOND TO GLOBAL CHANGES IN CHROMATIN ACCESSIBILITY AND STRUCTURE. 2020 16 2416 23 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 17 3123 22 GETTING AN INSIGHT INTO THE COMPLEXITY OF MAJOR CHRONIC INFLAMMATORY AND DEGENERATIVE DISEASES: A POTENTIAL NEW SYSTEMIC APPROACH TO THEIR TREATMENT. AS THE MODERN SOCIETY IS TROUBLED BY MULTI-FACTORIAL DISEASES, RESEARCH HAS BEEN CONDUCTED ON COMPLEX REALITIES INCLUDING CHRONIC INFLAMMATION, CANCER, OBESITY, HIV INFECTION, METABOLIC SYNDROME AND ITS DETRIMENTAL CARDIOVASCULAR COMPLICATIONS AS WELL AS DEPRESSION AND OTHER BRAIN DISORDERS. DETERIORATION OF CRUCIAL HOMEOSTATIC MECHANISMS IN SUCH DISEASES INVARIABLY RESULTS IN ACTIVATION OF INFLAMMATORY MEDIATORS, CHRONIC INFLAMMATION, LOSS IN IMMUNOLOGICAL FUNCTION, INCREASED SUSCEPTIBILITY TO DISEASES, ALTERATION OF METABOLISM, DECREASE OF ENERGY PRODUCTION AND NEURO-COGNITIVE DECLINE. REGULATION OF GENES EXPRESSION BY EPIGENETIC CODE IS THE DOMINANT MECHANISM FOR THE TRANSDUCTION OF ENVIRONMENTAL INPUTS, SUCH AS STRESS AND INFLAMMATION TO LASTING PHYSIOLOGICAL CHANGES. ACUTE AND CHRONIC STRESS DETERMINES DNA METHYLATION AND HISTONE MODIFICATIONS IN BRAIN REGIONS WHICH MAY CONTRIBUTE TO NEURO-DEGENERATIVE DISORDERS. NUCLEAR GLUCOCORTICOIDS RECEPTOR INTERACTS WITH THE EPIGENOMA RESULTING IN A CORTISOL RESISTANCE STATUS ASSOCIATED WITH A DETERIORATION OF THE METABOLIC AND IMMUNE FUNCTIONS. GONADAL STEROIDS RECEPTORS HAVE A SIMILAR CAPACITY TO PRODUCE EPIGENOMIC REORGANIZATION OF CHROMATINE STRUCTURE. EPIGENOMIC-INDUCED REDUCTION IN IMMUNE CELLS TELOMERES LENGTH HAS BEEN OBSERVED IN MANY DEGENERATIVE DISEASES, INCLUDING ALL TYPES OF CANCER. THE FINAL RESULT OF THESE EPIGENETIC ALTERATIONS IS A SERIOUS DAMAGE TO THE NEURO-ENDOCRINE-IMMUNE-METABOLIC ADAPTIVE SYSTEMS. IN THIS STUDY, WE PROPOSE A TREATMENT WITH STEM CELLS DIFFERENTIATION STAGE FACTORS TAKEN FROM ZEBRAFISH EMBRYOS WHICH ARE ABLE TO REGULATE THE GENES EXPRESSION OF NORMAL AND PATHOLOGICAL STEM CELLS IN A DIFFERENT SPECIFIC WAY. 2015 18 2049 15 EPIGENETIC CODE AND POTENTIAL EPIGENETIC-BASED THERAPIES AGAINST CHRONIC DISEASES IN DEVELOPMENTAL ORIGINS. ACCUMULATED FINDINGS HAVE DEMONSTRATED THAT THE EPIGENETIC CODE PROVIDES A POTENTIAL LINK BETWEEN PRENATAL STRESS AND CHANGES IN GENE EXPRESSION THAT COULD BE INVOLVED IN THE DEVELOPMENTAL PROGRAMMING OF VARIOUS CHRONIC DISEASES IN LATER LIFE. MEANWHILE, BASED ON THE FACT THAT EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND CAN BE MANIPULATED, THIS PROVIDES A UNIQUE CHANCE TO DEVELOP MULTIPLE NOVEL EPIGENETIC-BASED THERAPEUTIC STRATEGIES AGAINST MANY CHRONIC DISEASES IN EARLY DEVELOPMENTAL PERIODS. THIS ARTICLE WILL GIVE A SHORT REVIEW OF RECENT FINDINGS OF PRENATAL INSULT-INDUCED EPIGENETIC CHANGES IN DEVELOPMENTAL ORIGINS OF SEVERAL CHRONIC DISEASES, AND WILL ATTEMPT TO PROVIDE AN OVERVIEW OF THE CURRENT EPIGENETIC-BASED STRATEGIES APPLIED IN THE EARLY PREVENTION, DIAGNOSIS AND POSSIBLE THERAPIES FOR HUMAN CHRONIC DISEASES. 2014 19 4392 22 MODIFIABLE RISK FACTORS IN PERIODONTAL DISEASE: EPIGENETIC REGULATION OF GENE EXPRESSION IN THE INFLAMMATORY RESPONSE. EPIGENETICS AS A MODIFIABLE RISK FACTOR IN PERIODONTAL DISEASES HAS BEEN INVESTIGATED IN LIGHT OF THE CURRENT KNOWLEDGE OF HOW CHRONIC INFECTION AND INFLAMMATION CAN AFFECT GENE-SPECIFIC EPIGENETIC REPROGRAMMING IN PERIODONTAL TISSUES. EPIGENOMIC PROGRAMMING MIGHT BE PARTICULARLY SENSITIVE TO ENVIRONMENTAL INFLUENCES, AND A COMBINATION OF PHYSIOLOGICAL STRESSORS AND ENVIRONMENTAL EXPOSURES APPEARS TO AFFECT THE EPIGENOMIC PROGRAM ACQUIRED BY A CELL DURING DIFFERENTIATION AND THROUGHOUT THE CELLULAR LINEAGE LIFESPAN. VIRAL AND BACTERIAL INFECTIONS CAN ESTABLISH SEVERAL TYPES OF EPIGENETIC MODIFICATIONS, WHICH SOMETIMES ENGAGE IN A COMPLEX EPIGENETIC CROSSTALK ALSO REFLECTING IN THE ESTABLISHMENT AND PROGRESS OF PERIODONTAL DISEASES. THE INFLAMMATORY AND METABOLIC STATES OF THE PERIODONTAL TISSUES ARE DRIVEN BY THE INFECTIOUS STIMULI, AND THE MAGNITUDE OF THE CELLULAR AND MOLECULAR SIGNATURE RESPONSE IS FURTHER DICTATED BY THE HOST GENETIC AND EPIGENETIC TRAITS ASSOCIATED WITH VARIOUS SYSTEMIC EXPOSURES, INCLUDING SMOKING, OBESITY AND DIABETES/HYPERGLYCEMIA. THIS REVIEW DISCUSSES THE ADVANCES IN EPIGENETICS, FOCUSING ON THE ROLE OF DNA METHYLATION IN THE PATHOGENESIS OF PERIODONTAL DISEASE AND THE POTENTIAL OF EPIGENETIC THERAPY. 2014 20 4550 21 MUTATION-PROMOTING MOLECULAR NETWORKS OF UNCONTROLLED INFLAMMATION. MORE AND MORE STUDIES SHOW THAT CHRONIC INFLAMMATION CAN LEAD TO TUMOR FORMATION. THE COMPLEX INTERACTIONS OF INFLAMMATORY CELLS, STROMA AND TUMOR PARENCHYMAL CELL ARE CLOSELY RELATED TO TUMOR FORMATION. UNDER THE STATE OF CHRONIC INFLAMMATORY MICROENVIRONMENT, LONG-TERM INTERACTION OF INFLAMMATORY CELLS AND STROMAL CELLS AS WELL AS THE PARENCHYMAL CELLS MAKES SIGNALING PATHWAY IN PARENCHYMA CELLS DISORDERED. A SERIES OF GENE LEVEL EDITOR MODIFICATION, EPIGENETIC CHANGES, AND THE REGULATION OF TRANSCRIPTION AND TRANSLATION CHANGES WILL HAPPEN BASED ON SIGNALING PATHWAY DISORDER. THE CHANGES ULTIMATELY LEAD TO CELL MUTATIONS AND PHENOTYPIC TRANSFORMATION OCCURRED. RECENT FINDINGS PROVIDE AN OBJECTIVE BASIS FOR CANCER TREATMENT AND PREVENTION. HOWEVER, FURTHER DISCUSSES AT THE CORE OF THE POSSIBLE MOLECULAR IN TUMOR FORMATION PROVIDE A THEORETICAL FOUNDATION FOR FUTURE STUDY OF THE PATHOGENESIS AND MOLECULAR TARGETED THERAPY OF CANCER. THIS REVIEW SUMMARIZES THE RESEARCH IN THE FIELD OF CHRONIC INFLAMMATION AND CANCER IN RECENT YEARS, AND ANALYZE THE MOLECULES NETWORK IN THE PROCESS OF THE CARCINOGENIC INFLAMMATION COMPREHENSIVELY. BEYOND THAT, THIS REVIEW INTENDS TO DESCRIBE POSSIBLE CARCINOGENIC INFLAMMATION CORE MOLECULAR AND PROVIDES A THEORETICAL BASIS FOR FUTURE STUDY OF THE PATHOGENESIS, CHEMOPREVENTION AND MOLECULAR TARGETED THERAPY OF CANCER. 2017