1 2303 129 EPIGENETIC REGULATION OF CANNABINOID-MEDIATED ATTENUATION OF INFLAMMATION AND ITS IMPACT ON THE USE OF CANNABINOIDS TO TREAT AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION IS CONSIDERED TO BE A SILENT KILLER BECAUSE IT IS THE UNDERLYING CAUSE OF A WIDE RANGE OF CLINICAL DISORDERS, FROM CARDIOVASCULAR TO NEUROLOGICAL DISEASES, AND FROM CANCER TO OBESITY. IN ADDITION, THERE ARE OVER 80 DIFFERENT TYPES OF DEBILITATING AUTOIMMUNE DISEASES FOR WHICH THERE ARE NO CURE. CURRENTLY, THE DRUGS THAT ARE AVAILABLE TO SUPPRESS CHRONIC INFLAMMATION ARE EITHER INEFFECTIVE OR OVERTLY SUPPRESS THE INFLAMMATION, THEREBY CAUSING INCREASED SUSCEPTIBILITY TO INFECTIONS AND CANCER. THUS, THE DEVELOPMENT OF A NEW CLASS OF DRUGS THAT CAN SUPPRESS CHRONIC INFLAMMATION IS IMPERATIVE. CANNABINOIDS ARE A GROUP OF COMPOUNDS PRODUCED IN THE BODY (ENDOCANNABINOIDS) OR FOUND IN CANNABIS (PHYTOCANNABINOIDS) THAT ACT THROUGH CANNABINOID RECEPTORS AND VARIOUS OTHER RECEPTORS EXPRESSED WIDELY IN THE BRAIN AND IMMUNE SYSTEM. IN THE LAST DECADE, CANNABINOIDS HAVE BEEN WELL ESTABLISHED EXPERIMENTALLY TO MEDIATE ANTI-INFLAMMATORY PROPERTIES. RESEARCH HAS SHOWN THAT THEY SUPPRESS INFLAMMATION THROUGH MULTIPLE PATHWAYS, INCLUDING APOPTOSIS AND INDUCING IMMUNOSUPPRESSIVE T REGULATORY CELLS (TREGS) AND MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS). INTERESTINGLY, CANNABINOIDS ALSO MEDIATE EPIGENETIC ALTERATIONS IN GENES THAT REGULATE INFLAMMATION. IN THE CURRENT REVIEW, WE HIGHLIGHT HOW THE EPIGENETIC MODULATIONS CAUSED BY CANNABINOIDS LEAD TO THE SUPPRESSION OF INFLAMMATION AND HELP IDENTIFY NOVEL PATHWAYS THAT CAN BE USED TO TARGET AUTOIMMUNE DISEASES. 2021 2 6715 37 VITAMIN A AND THE EPIGENOME. THE EPIGENETIC PHENOMENA REFER TO HERITABLE CHANGES IN GENE EXPRESSION OTHER THAN THOSE IN THE DNA SEQUENCE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS. MAJOR RESEARCH PROGRESS IN THE LAST FEW YEARS HAS PROVIDED FURTHER PROOF THAT ENVIRONMENTAL FACTORS, INCLUDING DIET AND NUTRITION, CAN INFLUENCE PHYSIOLOGIC AND PATHOLOGIC PROCESSES THROUGH EPIGENETIC ALTERATIONS, WHICH IN TURN INFLUENCE GENE EXPRESSION. THIS INFLUENCE IS TERMED NUTRITIONAL EPIGENETICS, AND ONE PROMINENT EXAMPLE IS THE REGULATION OF GENE TRANSCRIPTION BY VITAMIN A THROUGH INTERACTION TO ITS NUCLEAR RECEPTOR. VITAMIN A IS CRITICAL THROUGHOUT LIFE. TOGETHER WITH ITS DERIVATIVES, IT REGULATES DIVERSE PROCESSES INCLUDING REPRODUCTION, EMBRYOGENESIS, VISION, GROWTH, CELLULAR DIFFERENTIATION AND PROLIFERATION, MAINTENANCE OF EPITHELIAL CELLULAR INTEGRITY AND IMMUNE FUNCTION. HERE WE REVIEW THE EPIGENETIC ROLE OF VITAMIN A IN CANCER, STEM CELLS DIFFERENTIATION, PROLIFERATION, AND IMMUNITY. THE DATA PRESENTED HERE SHOW THAT RETINOIC ACID IS A POTENT AGENT CAPABLE OF INDUCING ALTERATIONS IN EPIGENETIC MODIFICATIONS THAT PRODUCE VARIOUS EFFECTS ON THE PHENOTYPE. MEDICAL BENEFITS OF VITAMIN A AS AN EPIGENETIC MODULATOR, ESPECIALLY WITH RESPECT TO ITS CHRONIC USE AS NUTRITIONAL SUPPLEMENT, SHOULD RELY ON OUR FURTHER UNDERSTANDING OF ITS EPIGENETIC EFFECTS DURING HEALTH AND DISEASE, AS WELL AS THROUGH DIFFERENT GENERATIONS. 2017 3 1300 32 DEDIFFERENTIATION AND IN VIVO REPROGRAMMING OF COMMITTED CELLS IN WOUND REPAIR (REVIEW). ACCUMULATING EVIDENCE HAS SHOWN THAT CELL DEDIFFERENTIATION OR REPROGRAMMING IS A PIVOTAL PROCEDURE FOR ANIMALS TO DEAL WITH INJURY AND PROMOTE ENDOGENOUS TISSUE REPAIR. TISSUE DAMAGE IS A CRITICAL FACTOR THAT TRIGGERS CELL DEDIFFERENTIATION OR REPROGRAMMING IN VIVO. BY CONTRAST, MICROENVIRONMENTAL CHANGES, INCLUDING THE LOSS OF STEM CELLS, HYPOXIA, CELL SENESCENCE, INFLAMMATION AND IMMUNITY, CAUSED BY TISSUE DAMAGE CAN RETURN CELLS TO AN UNSTABLE STATE. IF THE WOUND PERSISTS IN THE LONG?TERM DUE TO CHRONIC DAMAGE, THEN DEDIFFERENTIATION OR REPROGRAMMING OF THE SURROUNDING CELLS MAY LEAD TO CARCINOGENESIS. IN RECENT YEARS, EXTENSIVE RESEARCH HAS BEEN PERFORMED INVESTIGATING CELL DEDIFFERENTIATION OR REPROGRAMMING IN VIVO, WHICH CAN HAVE SIGNIFICANT IMPLICATIONS FOR WOUND REPAIR, TREATMENT AND PREVENTION OF CANCER IN THE FUTURE. THE CURRENT REVIEW SUMMARIZES THE MOLECULAR EVENTS THAT ARE KNOWN TO DRIVE CELL DEDIFFERENTIATION DIRECTLY FOLLOWING TISSUE INJURY AND THE EFFECTS OF EPIGENETIC MODIFICATION ON DEDIFFERENTIATION OR REPROGRAMMING IN VIVO. IN ADDITION, THE PRESENT REVIEW EXPLORES THE INTRACELLULAR MECHANISM OF ENDOGENOUS TISSUE REPAIR AND ITS RELATIONSHIP WITH CANCER, WHICH IS ESSENTIAL FOR BALANCING THE RISK BETWEEN TISSUE REPAIR AND MALIGNANT TRANSFORMATION AFTER INJURY. 2022 4 6257 22 THE MOLECULAR BASIS OF TOLERANCE. TOLERANCE IS DEFINED AS THE DIMINISHED RESPONSE TO ALCOHOL OR OTHER DRUGS OVER THE COURSE OF REPEATED OR PROLONGED EXPOSURE. THIS MECHANISM ALLOWS PHYSIOLOGICAL PROCESSES TO ACHIEVE STABILITY IN A CONSTANTLY CHANGING ENVIRONMENT. THE ONSET OF TOLERANCE MAY OCCUR WITHIN MINUTES, DURING A SINGLE EXPOSURE TO ALCOHOL (I.E., ACUTE TOLERANCE), OR OVER LONGER TIMEFRAMES AND WITH PROLONGED EXPOSURE TO ALCOHOL (I.E., RAPID OR CHRONIC TOLERANCE). CHANGES IN TOLERANCE INDUCED BY ALCOHOL MAY AFFECT SEVERAL PROCESSES AT THE MOLECULAR, CELLULAR, OR BEHAVIORAL LEVEL. THESE EFFECTS OFTEN ARE INTERRELATED AND MAY BE DIFFICULT TO SEPARATE. THIS ARTICLE DESCRIBES CHANGES AT THE MOLECULAR LEVEL THAT ARE RELATED TO THE ONSET OF ACUTE, RAPID, OR CHRONIC TOLERANCE. IT FOCUSES ON NEURONAL MEMBRANE-BOUND CHANNELS AND THE FACTORS THAT AFFECT THEIR FUNCTION AND PRODUCTION, SUCH AS MODIFICATION OF PROTEIN SYNTHESIS AND ACTIVITY, INTERACTION WITH THE MEMBRANE LIPID MICROENVIRONMENT, EPIGENETIC EFFECTS ON CYTOPLASMIC REGULATION, AND GENE TRANSCRIPTION. ALSO CONSIDERED IS THE GENETICS OF TOLERANCE. 2008 5 3571 30 IMPACT OF LOCAL ANESTHETICS ON EPIGENETICS IN CANCER. DEFECTIVE SILENCING OF TUMOR SUPPRESSOR GENES THROUGH EPIGENETIC ALTERATIONS CONTRIBUTES TO ONCOGENESIS BY PERTURBING CELL CYCLE REGULATION, DNA REPAIR OR CELL DEATH MECHANISMS. REVERSAL OF SUCH EPIGENETIC CHANGES INCLUDING DNA HYPERMETHYLATION PROVIDES A PROMISING ANTICANCER STRATEGY. UNTIL NOW, THE NUCLEOSIDE DERIVATIVES 5-AZACYTIDINE AND DECITABINE ARE THE SOLE DNA METHYLTRANSFERASE (DNMT) INHIBITORS APPROVED BY THE FDA FOR THE TREATMENT OF SPECIFIC HEMATOLOGICAL CANCERS. NEVERTHELESS, DUE TO THEIR NUCLEOSIDE STRUCTURE, THESE INHIBITORS DIRECTLY INCORPORATE INTO DNA, WHICH LEADS TO SEVERE SIDE EFFECTS AND COMPROMISES GENOMIC STABILITY. MUCH EMPHASIS HAS BEEN PLACED ON THE DEVELOPMENT OF LESS TOXIC EPIGENETIC MODIFIERS. RECENTLY, SEVERAL PRECLINICAL STUDIES DEMONSTRATED THE POTENT EPIGENETIC EFFECTS OF LOCAL ANESTHETICS, WHICH ARE ROUTINELY USED DURING PRIMARY TUMOR RESECTION TO RELIEF SURGICAL PAIN. THESE NON-NUCLEOSIDE MOLECULES INHIBIT DNMT ACTIVITY, AFFECT THE EXPRESSION OF MICRO-RNAS AND REPRESS HISTONE ACETYLATION, THUS EXERTING CYTOTOXIC EFFECTS ON MALIGNANT CELLS. THE IN-DEPTH MECHANISTIC COMPREHENSION OF THESE EPIGENETIC EFFECTS MIGHT PROMOTE THE USE OF LOCAL ANESTHETICS AS ANTICANCER DRUGS. 2022 6 3697 28 INFLAMMATORY MARKERS IN CANCER: POTENTIAL RESOURCES. CANCER IS A LEADING CAUSE OF DEATH WORLDWIDE AND A MAJOR BURDEN ON DEVELOPING AND LESS DEVELOPED COUNTRIES OF THE WORLD WITH LIMITED RESOURCES FOR PREVENTION AND EFFECTIVE TREATMENT OF CANCER. ALTHOUGH CANCER IS MULTIFACTORIAL IN ORIGIN, VARIOUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES SUGGEST THAT CHRONIC INFLAMMATION HAS AN IMPORTANT ROLE IN ALL STAGES OF CANCER, FROM INITIATION TO PROGRESSION AND EVEN SURVIVAL OF THE PATIENT. INFLAMMATORY PRODUCTS LIKE CYTOKINES, CHEMOKINES, LEUCOCYTES, PROSTAGLANDINS, CYCLOOXYGENASE, REACTIVE OXYGEN AND NITROGEN SPECIES, METALLOPROTEINASE INDUCE GENETIC AND EPIGENETIC CHANGES IN NORMAL CELLS DAMAGING ITS DNA, INHIBITING ITS REPAIR, ALTERING TRANSCRIPTION FACTORS, PREVENTING APOPTOSIS, AND STIMULATING ANGIOGENESIS, AND THUS RESULTING IN CARCINOGENESIS. THUS, THESE INFLAMMATORY MEDIATORS HAVE A POTENTIAL ROLE TO BECOME CANCER BIOMARKERS FOR ALL STAGES OF CANCER AS MANY OF THEM CAN BE MEASURED IN A COST-EFFECTIVE MANNER. HOWEVER, LARGE SCALE PROSPECTIVE TRIALS ARE REQUIRED TO VALIDATE THESE POTENTIAL CANCER BIOMARKERS. NONETHELESS, A TRANSITION FROM POTENTIAL TO PRACTICAL UTILIZATION OF THESE MARKERS WILL BE AN EFFECTIVE TOOL FOR THE AMELIORATION OF CANCER BURDEN AND MORTALITY IN A RESOURCE LIMITED SETTING. 2020 7 5581 31 ROLE OF NF-KAPPAB IN AGEING AND AGE-RELATED DISEASES: LESSONS FROM GENETICALLY MODIFIED MOUSE MODELS. AGEING IS A COMPLEX PROCESS, INDUCED BY MULTIFACETED INTERACTION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. IT IS MANIFESTED BY A DECLINE IN THE PHYSIOLOGICAL FUNCTIONS OF ORGANISMS AND ASSOCIATED TO THE DEVELOPMENT OF AGE-RELATED CHRONIC DISEASES AND CANCER DEVELOPMENT. IT IS CONSIDERED THAT AGEING FOLLOWS A STRICTLY-REGULATED PROGRAM, IN WHICH SOME SIGNALING PATHWAYS CRITICALLY CONTRIBUTE TO THE ESTABLISHMENT AND MAINTENANCE OF THE AGED STATE. CHRONIC INFLAMMATION IS A MAJOR MECHANISM THAT PROMOTES THE BIOLOGICAL AGEING PROCESS AND COMORBIDITY, WITH THE TRANSCRIPTION FACTOR NF-KAPPAB (NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS) AS A CRUCIAL MEDIATOR OF INFLAMMATORY RESPONSES. THIS, TOGETHER WITH THE FINDING THAT THE ACTIVATION OR INHIBITION OF NF-KAPPAB CAN INDUCE OR REVERSE RESPECTIVELY THE MAIN FEATURES OF AGED ORGANISMS, HAS BROUGHT IT UNDER CONSIDERATION AS A KEY TRANSCRIPTION FACTOR THAT ACTS AS A DRIVER OF AGEING. IN THIS REVIEW, WE FOCUSED ON THE DATA OBTAINED ENTIRELY THROUGH THE GENERATION OF KNOCKOUT AND TRANSGENIC MOUSE MODELS OF EITHER PROTEIN INVOLVED IN THE NF-KAPPAB SIGNALING PATHWAY THAT HAVE PROVIDED RELEVANT INFORMATION ABOUT THE INTRICATE PROCESSES OR MOLECULAR MECHANISMS THAT CONTROL AGEING. WE HAVE REVIEWED THE RELATIONSHIP OF NF-KAPPAB AND PREMATURE AGEING; THE DEVELOPMENT OF CANCER ASSOCIATED WITH AGEING AND THE IMPLICATION OF NF-KAPPAB ACTIVATION IN THE DEVELOPMENT OF AGE-RELATED DISEASES, SOME OF WHICH GREATLY INCREASE THE RISK OF DEVELOPING CANCER. 2021 8 6520 42 TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF MONOCYTE AND MACROPHAGE DYSFUNCTION BY CHRONIC ALCOHOL CONSUMPTION. DRINKING ALCOHOL, EVEN IN MODERATION, CAN AFFECT THE IMMUNE SYSTEM. STUDIES HAVE SHOWN DISPROPORTIONATE EFFECTS OF ALCOHOL ON CIRCULATING AND TISSUE-RESIDENT MYELOID CELLS (GRANULOCYTES, MONOCYTES, MACROPHAGES, DENDRITIC CELLS). THESE CELLS ORCHESTRATE THE BODY'S FIRST LINE OF DEFENSE AGAINST MICROBIAL CHALLENGES AS WELL AS MAINTAIN TISSUE HOMEOSTASIS AND REPAIR. ALCOHOL'S EFFECTS ON THESE CELLS ARE DEPENDENT ON EXPOSURE PATTERN, WITH ACUTE DRINKING DAMPENING BUT CHRONIC DRINKING ENHANCING PRODUCTION OF INFLAMMATORY MEDIATORS. ALTHOUGH CHRONIC DRINKING IS ASSOCIATED WITH HEIGHTENED SYSTEMIC INFLAMMATION, STUDIES ON TISSUE RESIDENT MACROPHAGE POPULATIONS IN SEVERAL ORGANS INCLUDING THE SPLEEN, LIVER, BRAIN, AND LUNG HAVE ALSO SHOWN COMPROMISED FUNCTIONAL AND METABOLIC CAPACITIES OF THESE CELLS. MANY OF THESE EFFECTS ARE THOUGHT TO BE MEDIATED BY OXIDATIVE STRESS CAUSED BY ALCOHOL AND ITS METABOLITES WHICH CAN DIRECTLY IMPACT THE CELLULAR EPIGENETIC LANDSCAPES. IN ADDITION, SINCE MYELOID CELLS ARE RELATIVELY SHORT-LIVED IN CIRCULATION AND ARE UNDER CONSTANT REPOPULATION FROM THE BONE MARROW COMPARTMENT, ALCOHOL'S EFFECTS ON BONE MARROW PROGENITORS AND HEMATOPOIESIS ARE IMPORTANT FOR UNDERSTANDING THE IMPACT OF ALCOHOL SYSTEMICALLY ON THESE MYELOID POPULATIONS. ALCOHOL-INDUCED DISRUPTION OF PROGENITOR, CIRCULATING, AND TISSUE RESIDENT MYELOID POPULATIONS CONTRIBUTE TO THE INCREASED SUSCEPTIBILITY OF PATIENTS WITH ALCOHOL USE DISORDERS TO VIRAL AND BACTERIAL INFECTIONS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE IMPACT OF CHRONIC ALCOHOL CONSUMPTION ON THE FUNCTION OF MONOCYTES AND MACROPHAGES IN HOST DEFENSE, TISSUE REPAIR AND INFLAMMATION. WE THEN SUMMARIZE OUR CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING ALCOHOL-INDUCED DISRUPTION AND EXAMINE CHANGES IN TRANSCRIPTOME AND EPIGENOME OF MONOCYTES AND MCROPHAGES. OVERALL, CHRONIC ALCOHOL CONSUMPTION LEADS TO HYPER-INFLAMMATION CONCOMITANT WITH DECREASED MICROBIAL AND WOUND HEALING RESPONSES BY MONOCYTES/MACROPHAGES DUE TO A REWIRING OF THE EPIGENTIC AND TRANSCRIPTIONAL LANDSCAPE. HOWEVER, IN ADVANCED ALCOHOLIC LIVER DISEASE, MYELOID CELLS BECOME IMMUNOSUPPRESSED AS A RESPONSE TO THE SURROUNDING HYPER-INFLAMMATORY MILIEU. THEREFORE, THE EFFECT OF CHRONIC ALCOHOL ON THE INFLAMMATORY RESPONSE DEPENDS ON DISEASE STATE AND THE IMMUNE CELL POPULATION. 2022 9 5550 38 ROLE OF EPIGENETICS IN INFLAMMATION-ASSOCIATED DISEASES. THERE IS CONSIDERABLE EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS MAY MEDIATE DEVELOPMENT OF CHRONIC INFLAMMATION BY MODULATING THE EXPRESSION OF PRO-INFLAMMATORY CYTOKINE TNF-ALPHA, INTERLEUKINS, TUMOR SUPPRESSOR GENES, ONCOGENES AND AUTOCRINE AND PARACRINE ACTIVATION OF THE TRANSCRIPTION FACTOR NF-KAPPAB. THESE MOLECULES ARE CONSTITUTIVELY PRODUCED BY A VARIETY OF CELLS UNDER CHRONIC INFLAMMATORY CONDITIONS, WHICH IN TURN LEADS TO THE DEVELOPMENT OF MAJOR DISEASES SUCH AS AUTOIMMUNE DISORDERS, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEURODEGENERATIVE DISEASES AND CANCER. DISTINCT OR GLOBAL CHANGES IN THE EPIGENETIC LANDSCAPE ARE HALLMARKS OF CHRONIC INFLAMMATION DRIVEN DISEASES. EPIGENETICS INCLUDE CHANGES TO DISTINCT MARKERS ON THE GENOME AND ASSOCIATED CELLULAR TRANSCRIPTIONAL MACHINERY THAT ARE COPIED DURING CELL DIVISION (MITOSIS AND MEIOSIS). THESE CHANGES APPEAR FOR A SHORT SPAN OF TIME AND THEY NECESSARILY DO NOT MAKE PERMANENT CHANGES TO THE PRIMARY DNA SEQUENCE ITSELF. HOWEVER, THE MOST FREQUENTLY OBSERVED EPIGENETIC CHANGES INCLUDE ABERRANT DNA METHYLATION, AND HISTONE ACETYLATION AND DEACETYLATION. IN THIS CHAPTER, WE FOCUS ON PRO-INFLAMMATORY MOLECULES THAT ARE REGULATED BY ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS ARGININE AND LYSINE METHYL TRANSFERASES, DNA METHYLTRANSFERASE, HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASES AND THEIR ROLE IN INFLAMMATION DRIVEN DISEASES. AGENTS THAT MODULATE OR INHIBIT THESE EPIGENETIC MODIFICATIONS, SUCH AS HAT OR HDAC INHIBITORS HAVE SHOWN GREAT POTENTIAL IN INHIBITING THE PROGRESSION OF THESE DISEASES. GIVEN THE PLASTICITY OF THESE EPIGENETIC CHANGES AND THEIR READINESS TO RESPOND TO INTERVENTION BY SMALL MOLECULE INHIBITORS, THERE IS A TREMENDOUS POTENTIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS THAT WILL SERVE AS DIRECT OR ADJUVANT THERAPEUTIC COMPOUNDS IN THE TREATMENT OF THESE DISEASES. 2013 10 2950 22 GENETIC AND EPIGENETIC DAMAGE INDUCED BY REACTIVE NITROGEN SPECIES: IMPLICATIONS IN CARCINOGENESIS. CHRONIC INFECTION AND INFLAMMATION ARE RECOGNIZED RISK FACTORS FOR HUMAN CANCER AT VARIOUS SITES. INFECTION AND INFLAMMATION CAN ACTIVATE AND INDUCE A VARIETY OF OXIDANT-GENERATING ENZYMES, INCLUDING NADPH OXIDASE AND INDUCIBLE NITRIC OXIDE SYNTHASE. REACTIVE OXYGEN AND NITROGEN SPECIES PRODUCED BY SUCH ENZYMES REACT WITH EACH OTHER TO GENERATE NEW AND MORE POTENT REACTIVE SPECIES. THESE OXIDANTS NOT ONLY CAN DAMAGE DNA AND INDUCE MUTATIONS, BUT ALSO CAN ACTIVATE ONCOGENE PRODUCTS AND/OR INACTIVATE TUMOR-SUPPRESSOR PROTEINS, THUS CONTRIBUTING TO MOST PROCESSES OF CARCINOGENESIS. APPROPRIATE TREATMENT OF INFLAMMATION SHOULD BE FURTHER EXPLORED FOR CHEMOPREVENTION OF HUMAN CANCERS, ESPECIALLY THOSE ASSOCIATED WITH CHRONIC INFLAMMATION. 2003 11 733 31 CANCER EPIGENETICS: LINKING BASIC BIOLOGY TO CLINICAL MEDICINE. CANCER EVOLUTION AT ALL STAGES IS DRIVEN BY BOTH EPIGENETIC ABNORMALITIES AS WELL AS GENETIC ALTERATIONS. DYSREGULATION OF EPIGENETIC CONTROL EVENTS MAY LEAD TO ABNORMAL PATTERNS OF DNA METHYLATION AND CHROMATIN CONFIGURATIONS, BOTH OF WHICH ARE CRITICAL CONTRIBUTORS TO THE PATHOGENESIS OF CANCER. THESE EPIGENETIC ABNORMALITIES ARE SET AND MAINTAINED BY MULTIPLE PROTEIN COMPLEXES AND THE INTERPLAY BETWEEN THEIR INDIVIDUAL COMPONENTS INCLUDING DNA METHYLATION MACHINERY, HISTONE MODIFIERS, PARTICULARLY, POLYCOMB (PCG) PROTEINS, AND CHROMATIN REMODELING PROTEINS. RECENT ADVANCES IN GENOME-WIDE TECHNOLOGY HAVE REVEALED THAT THE INVOLVEMENT OF THESE DYSREGULATED EPIGENETIC COMPONENTS APPEARS TO BE EXTENSIVE. MOREOVER, THERE IS A GROWING CONNECTION BETWEEN EPIGENETIC ABNORMALITIES IN CANCER AND CONCEPTS CONCERNING STEM-LIKE CELL SUBPOPULATIONS AS A DRIVING FORCE FOR CANCER. EMERGING DATA SUGGEST THAT ASPECTS OF THE EPIGENETIC LANDSCAPE INHERENT TO NORMAL EMBRYONIC AND ADULT STEM/PROGENITOR CELLS MAY HELP FOSTER, UNDER THE STRESS OF CHRONIC INFLAMMATION OR ACCUMULATING REACTIVE OXYGEN SPECIES, EVOLUTION OF MALIGNANT SUBPOPULATIONS. FINALLY, UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN INITIATION AND MAINTENANCE OF EPIGENETIC ABNORMALITIES IN ALL TYPES OF CANCER HAS GREAT POTENTIAL FOR TRANSLATIONAL PURPOSES. THIS IS ALREADY EVIDENT FOR EPIGENETIC BIOMARKER DEVELOPMENT, AND FOR PHARMACOLOGICAL TARGETING AIMED AT REVERSING CANCER-SPECIFIC EPIGENETIC ALTERATIONS. 2011 12 4974 27 PATHOPHYSIOLOGICAL MECHANISMS LEADING TO MUSCLE LOSS IN CHRONIC KIDNEY DISEASE. LOSS OF MUSCLE PROTEINS IS A DELETERIOUS CONSEQUENCE OF CHRONIC KIDNEY DISEASE (CKD) THAT CAUSES A DECREASE IN MUSCLE STRENGTH AND FUNCTION, AND CAN LEAD TO A REDUCTION IN QUALITY OF LIFE AND INCREASED RISK OF MORBIDITY AND MORTALITY. THE EFFECTIVENESS OF CURRENT TREATMENT STRATEGIES IN PREVENTING OR REVERSING MUSCLE PROTEIN LOSSES IS LIMITED. THE LIMITATIONS LARGELY STEM FROM THE SYSTEMIC NATURE OF DISEASES SUCH AS CKD, WHICH STIMULATE SKELETAL MUSCLE PROTEIN DEGRADATION PATHWAYS WHILE SIMULTANEOUSLY ACTIVATING MECHANISMS THAT IMPAIR MUSCLE PROTEIN SYNTHESIS AND REPAIR. STIMULI THAT INITIATE MUSCLE PROTEIN LOSS INCLUDE METABOLIC ACIDOSIS, INSULIN AND IGF1 RESISTANCE, CHANGES IN HORMONES, CYTOKINES, INFLAMMATORY PROCESSES AND DECREASED APPETITE. A GROWING BODY OF EVIDENCE SUGGESTS THAT SIGNALLING MOLECULES SECRETED FROM MUSCLE CAN ENTER THE CIRCULATION AND SUBSEQUENTLY INTERACT WITH RECIPIENT ORGANS, INCLUDING THE KIDNEYS, WHILE CONVERSELY, PATHOLOGICAL EVENTS IN THE KIDNEY CAN ADVERSELY INFLUENCE PROTEIN METABOLISM IN SKELETAL MUSCLE, DEMONSTRATING THE EXISTENCE OF CROSSTALK BETWEEN KIDNEY AND MUSCLE. TOGETHER, THESE SIGNALS, WHETHER DIRECT OR INDIRECT, INDUCE CHANGES IN THE LEVELS OF REGULATORY AND EFFECTOR PROTEINS VIA ALTERATIONS IN MRNAS, MICRORNAS AND CHROMATIN EPIGENETIC RESPONSES. ADVANCES IN OUR UNDERSTANDING OF THE SIGNALS AND PROCESSES THAT MEDIATE MUSCLE LOSS IN CKD AND OTHER MUSCLE WASTING CONDITIONS WILL SUPPORT THE FUTURE DEVELOPMENT OF THERAPEUTIC STRATEGIES TO REDUCE MUSCLE LOSS. 2022 13 3921 33 LINKING INFLAMMATION TO CELL CYCLE PROGRESSION. RISK OF GASTROINTESTINAL CANCERS IS CLOSELY RELATED TO INCREASED LEVELS OF OXIDANTS IN THE BALANCE BETWEEN OXIDANT AND ANTI-OXIDANT AGENTS. A POSSIBLE EXPLANATION OF THIS EPIDEMIOLOGICAL OBSERVATION IS THE LOCAL LOSS OF THE EPITHELIAL BARRIER FUNCTION WITH A FOCAL INFLAMMATORY RESPONSE. ACCORDINGLY, CHRONIC INFLAMMATORY DISEASES REPRESENT WELL-KNOWN RISK FACTORS FOR CANCER AND, ON THE OTHER HAND, IT IS KNOWN THAT ANTI-INFLAMMATORY AGENTS, DEMULCENTS AND ANTIOXIDANTS MARKEDLY INHIBIT THE DEVELOPMENT OF COLON CANCER IN ANIMAL MODELS AS WELL IN HUMANS. AT MOLECULAR LEVEL A KEY ROLE IN THE PROCESS THAT LINK INFLAMMATION TO CELLULAR TRANSFORMATION SEEMS TO BE PLAYED BY ACTIVATION OF CYCLOOXYGENASE-2 (COX-2) TOGETHER WITH PRODUCTION OF REACTIVE OXYGEN INTERMEDIATE (ROI). BOTH THESE EVENTS HAVE BEEN STRICTLY LINKED WITH CELL PROLIFERATION AND TRANSFORMATION, ALTHOUGH THE INTRACELLULAR PATHWAYS INVOLVED IN THESE PROCESSES ARE STILL NOT COMPLETELY UNDERSTOOD. THE UNCONTROLLED PROLIFERATION, WHICH IS A LANDMARK OF CELLULAR TRANSFORMATION, IS ACCOMPANIED BY THE DEREGULATION OF PROTEINS INVOLVED IN THE CONTROL OF CELL CYCLE CHECKPOINTS. ALTERED EXPRESSION AND FUNCTION OF CYCLOOXYGENASE AND NITRIC OXIDE SYNTHASE SEEM TO INFLUENCE, AMONG OTHERS, THE EXPRESSION OF PROTEINS INVOLVED IN THE REGULATION OF CELL CYCLE PROGRESSION. SIMILARLY, ANTI-INFLAMMATORY AND ANTIOXIDANT AGENTS MAY ALSO ACT ON THE EXPRESSION AND FUNCTION OF SEVERAL CELL CYCLE REGULATING PROTEINS. UNDERSTANDING THE MECHANISMS BY WHICH CHRONIC INFLAMMATION CONTRIBUTES TO GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE REGULATION OF CRITICAL CELL CYCLE CHECKPOINTS MAY HELP TO DEVELOP MORE AND MORE SPECIFIC TREATMENT STRATEGIES FOR REDUCING MALIGNANT TRANSFORMATION OF THESE INFLAMMATORY DISEASES. 2004 14 6449 40 THERAPEUTIC TARGETING OF TELOMERASE. TELOMERE LENGTH AND CELL FUNCTION CAN BE PRESERVED BY THE HUMAN REVERSE TRANSCRIPTASE TELOMERASE (HTERT), WHICH SYNTHESIZES THE NEW TELOMERIC DNA FROM A RNA TEMPLATE, BUT IS NORMALLY RESTRICTED TO CELLS NEEDING A HIGH PROLIFERATIVE CAPACITY, SUCH AS STEM CELLS. CONSEQUENTLY, TELOMERASE-BASED THERAPIES TO ELONGATE SHORT TELOMERES ARE DEVELOPED, SOME OF WHICH HAVE SUCCESSFULLY REACHED THE STAGE I IN CLINICAL TRIALS. TELOMERASE IS ALSO PERMISSIVE FOR TUMORIGENESIS AND 90% OF ALL MALIGNANT TUMORS USE TELOMERASE TO OBTAIN IMMORTALITY. THUS, REVERSAL OF TELOMERASE UPREGULATION IN TUMOR CELLS IS A POTENTIAL STRATEGY TO TREAT CANCER. NATURAL AND SMALL-MOLECULE TELOMERASE INHIBITORS, IMMUNOTHERAPEUTIC APPROACHES, OLIGONUCLEOTIDE INHIBITORS, AND TELOMERASE-DIRECTED GENE THERAPY ARE USEFUL TREATMENT STRATEGIES. TELOMERASE IS MORE WIDELY EXPRESSED THAN ANY OTHER TUMOR MARKER. THE LOW EXPRESSION IN NORMAL TISSUES, TOGETHER WITH THE LONGER TELOMERES IN NORMAL STEM CELLS VERSUS CANCER CELLS, PROVIDES SOME DEGREE OF SPECIFICITY WITH LOW RISK OF TOXICITY. HOWEVER, LONG TERM TELOMERASE INHIBITION MAY ELICIT NEGATIVE EFFECTS IN HIGHLY-PROLIFERATIVE CELLS WHICH NEED TELOMERASE FOR SURVIVAL, AND IT MAY INTERFERE WITH TELOMERE-INDEPENDENT PHYSIOLOGICAL FUNCTIONS. MOREOVER, ONLY A FEW HTERT MOLECULES ARE REQUIRED TO OVERCOME SENESCENCE IN CANCER CELLS, AND TELOMERASE INHIBITION REQUIRES PROLIFERATING CELLS OVER A SUFFICIENT NUMBER OF POPULATION DOUBLINGS TO INDUCE TUMOR SUPPRESSIVE SENESCENCE. THESE LIMITATIONS MAY EXPLAIN THE MODERATE SUCCESS RATES IN MANY CLINICAL STUDIES. DESPITE EXTENSIVE STUDIES, ONLY ONE VACCINE AND ONE TELOMERASE ANTAGONIST ARE ROUTINELY USED IN CLINICAL WORK. FOR COMPLETE ERADICATION OF ALL SUBPOPULATIONS OF CANCER CELLS A SIMULTANEOUS TARGETING OF SEVERAL MECHANISMS WILL LIKELY BE NEEDED. POSSIBLE TECHNICAL IMPROVEMENTS HAVE BEEN PROPOSED INCLUDING THE DEVELOPMENT OF MORE SPECIFIC INHIBITORS, METHODS TO INCREASE THE EFFICACY OF VACCINATION METHODS, AND PERSONALIZED APPROACHES. TELOMERASE ACTIVATION AND CELL REJUVENATION IS SUCCESSFULLY USED IN REGENERATIVE MEDICINE FOR TISSUE ENGINEERING AND RECONSTRUCTIVE SURGERY. HOWEVER, THERE ARE ALSO A NUMBER OF PITFALLS IN THE TREATMENT WITH TELOMERASE ACTIVATING PROCEDURES FOR THE WHOLE ORGANISM AND FOR LONGER PERIODS OF TIME. EXTENDED CELL LIFESPAN MAY ACCUMULATE RARE GENETIC AND EPIGENETIC ABERRATIONS THAT CAN CONTRIBUTE TO MALIGNANT TRANSFORMATION. THEREFORE, NOVEL VECTOR SYSTEMS HAVE BEEN DEVELOPED FOR A 'MILD' INTEGRATION OF TELOMERASE INTO THE HOST GENOME AND LOSS OF THE VECTOR IN RAPIDLY-PROLIFERATING CELLS. IT IS CURRENTLY UNCLEAR IF THIS TECHNIQUE CAN ALSO BE USED IN HUMAN BEINGS TO TREAT CHRONIC DISEASES, SUCH AS ATHEROSCLEROSIS. 2016 15 2306 26 EPIGENETIC REGULATION OF CELL-FATE CHANGES THAT DETERMINE ADULT LIVER REGENERATION AFTER INJURY. THE ADULT LIVER HAS EXCELLENT REGENERATIVE POTENTIAL FOLLOWING INJURY. IN CONTRAST TO OTHER ORGANS OF THE BODY THAT HAVE HIGH CELLULAR TURNOVER DURING HOMEOSTASIS (E.G., INTESTINE, STOMACH, AND SKIN), THE ADULT LIVER IS A SLOWLY SELF-RENEWING ORGAN AND DOES NOT CONTAIN A DEFINED STEM-CELL COMPARTMENT THAT MAINTAINS HOMEOSTASIS. HOWEVER, TISSUE DAMAGE INDUCES SIGNIFICANT PROLIFERATION ACROSS THE LIVER AND CAN TRIGGER CELL-FATE CHANGES, SUCH AS TRANS-DIFFERENTIATION AND DE-DIFFERENTIATION INTO LIVER PROGENITORS, WHICH CONTRIBUTE TO EFFICIENT TISSUE REGENERATION AND RESTORATION OF LIVER FUNCTIONS. EPIGENETIC MECHANISMS HAVE BEEN SHOWN TO REGULATE CELL-FATE DECISIONS IN BOTH EMBRYONIC AND ADULT TISSUES IN RESPONSE TO ENVIRONMENTAL CUES. UNDERLYING THEIR RELEVANCE IN LIVER BIOLOGY, EXPRESSION LEVELS AND EPIGENETIC ACTIVITY OF CHROMATIN MODIFIERS ARE OFTEN ALTERED IN CHRONIC LIVER DISEASE AND LIVER CANCER. IN THIS REVIEW, I EXAMINE THE ROLE OF SEVERAL CHROMATIN MODIFIERS IN THE REGULATION OF CELL-FATE CHANGES THAT DETERMINE EFFICIENT ADULT LIVER EPITHELIAL REGENERATION IN RESPONSE TO TISSUE INJURY IN MOUSE MODELS. SPECIFICALLY, I FOCUS ON EPIGENETIC MECHANISMS SUCH AS CHROMATIN REMODELLING, DNA METHYLATION AND HYDROXYMETHYLATION, AND HISTONE METHYLATION AND DEACETYLATION. FINALLY, I ADDRESS HOW ALTERED EPIGENETIC MECHANISMS AND THE INTERPLAY BETWEEN EPIGENETICS AND METABOLISM MAY CONTRIBUTE TO THE INITIATION AND PROGRESSION OF LIVER DISEASE AND CANCER. 2021 16 1150 39 CONNECTION BETWEEN INFLAMMATION AND CARCINOGENESIS IN GASTROINTESTINAL TRACT: FOCUS ON TGF-BETA SIGNALING. INFLAMMATION IS A PRIMARY DEFENSE PROCESS AGAINST VARIOUS EXTRACELLULAR STIMULI, SUCH AS VIRUSES, PATHOGENS, FOODS, AND ENVIRONMENTAL POLLUTANTS. WHEN CELLS RESPOND TO STIMULI FOR SHORT PERIODS OF TIME, IT RESULTS IN ACUTE OR PHYSIOLOGICAL INFLAMMATION. HOWEVER, IF THE STIMULATION IS SUSTAINED FOR LONGER TIME OR A PATHOLOGICAL STATE OCCURS, IT IS KNOWN AS CHRONIC OR PATHOLOGICAL INFLAMMATION. SEVERAL STUDIES HAVE SHOWN THAT TUMORIGENESIS IN THE GASTROINTESTINAL (GI) TRACT IS CLOSELY ASSOCIATED WITH CHRONIC INFLAMMATION, FOR WHICH ABNORMAL CELLULAR ALTERATIONS THAT ACCOMPANY CHRONIC INFLAMMATION SUCH AS OXIDATIVE STRESSES, GENE MUTATIONS, EPIGENETIC CHANGES, AND INFLAMMATORY CYTOKINES, ARE SHARED WITH CARCINOGENIC PROCESSES, WHICH FORMS A CRITICAL CROSS-LINK BETWEEN CHRONIC INFLAMMATION AND CARCINOGENESIS. TRANSFORMING GROWTH FACTOR (TGF)-BETA IS A MULTI-POTENT CYTOKINE THAT PLAYS AN IMPORTANT ROLE IN REGULATION OF CELL GROWTH, APOPTOSIS AND DIFFERENTIATION. MOST IMPORTANTLY, TGF-BETA IS A STRONG ANTI-INFLAMMATORY CYTOKINE THAT REGULATES THE DEVELOPMENT OF EFFECTOR CELLS. TGF-BETA HAS A SUPPRESSIVE EFFECT ON CARCINOGENESIS UNDER NORMAL CONDITIONS BY INHIBITING ABNORMAL CELL GROWTH, BUT ON THE OTHER HAND, MANY GI CANCERS ORIGINATE FROM UNCONTROLLED CELL GROWTH AND DIFFERENTIATION BY GENETIC LOSS OF TGF-BETA SIGNALING MOLECULES OR PERTURBATION OF TGF-BETA ADAPTORS. ONCE A TUMOR HAS DEVELOPED, TGF-BETA EXERTS A PROMOTING EFFECT ON THE TUMOR ITSELF AND STROMAL CELLS TO ENHANCE CELL GROWTH, ALTER THE RESPONSIVENESS OF TUMOR CELLS TO STIMULATE INVASION AND METASTASIS, AND INHIBITED IMMUNE SURVEILLANCE. THEREFORE, NOVEL DEVELOPMENT OF THERAPEUTIC AGENTS TO INHIBIT TGF-BETA-INDUCED PROGRESSION OF TUMOR AND TO RETAIN ITS GROWTH INHIBITORY ACTIVITIES, IN ADDITION TO ANTI-INFLAMMATORY ACTIONS, COULD BE USEFUL IN ONCOLOGY. IN THIS REVIEW, WE DISCUSS THE ROLE OF TGF-BETA IN INFLAMMATION AND CARCINOGENESIS OF THE GI TRACT RELATED TO ABNORMAL TGF-BETA SIGNALING. 2010 17 4200 47 METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS: REGULATION AND DEFECTS IN HEALTH AND IN INFLAMMATORY DISEASES. THE IMMUNE SYSTEM PROTECTS FROM INFECTIONS AND CANCER THROUGH COMPLEX CELLULAR NETWORKS. FOR THIS PURPOSE, IMMUNE CELLS REQUIRE WELL-DEVELOPED MECHANISMS OF ENERGY GENERATION. HOWEVER, THE IMMUNE SYSTEM ITSELF CAN ALSO CAUSE DISEASES WHEN DEFECTIVE REGULATION RESULTS IN THE EMERGENCE OF AUTOREACTIVE LYMPHOCYTES. RECENT STUDIES PROVIDE INSIGHTS INTO HOW DIFFERENTIAL PATTERNS OF IMMUNE CELL RESPONSES ARE ASSOCIATED WITH SELECTIVE METABOLIC PATHWAYS. THIS REVIEW WILL EXAMINE THE CHANGING METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS AT DIFFERENT STAGES OF THEIR DEVELOPMENT AND ACTIVATION. BOTH CELLS PROVIDE PROTECTION BUT CAN ALSO MEDIATE DISEASES THROUGH THE PRODUCTION OF AUTOANTIBODIES AND THE PRODUCTION OF PROINFLAMMATORY MEDIATORS. IN HEALTH, B CELLS PRODUCE ANTIBODIES AND CYTOKINES AND PRESENT ANTIGENS TO T CELLS TO MOUNT SPECIFIC IMMUNITY. TH17 CELLS, ON THE OTHER HAND, PROVIDE PROTECTION AGAINST EXTRA CELLULAR PATHOGENS AT MUCOSAL SURFACES BUT CAN ALSO DRIVE CHRONIC INFLAMMATION. THE LATTER CELLS CAN ALSO PROMOTE THE DIFFERENTIATION OF B CELLS TO PLASMA CELLS TO PRODUCE MORE AUTOANTIBODIES. METABOLISM-REGULATED CHECKPOINTS AT DIFFERENT STAGES OF THEIR DEVELOPMENT ENSURE THE THAT SELF-REACTIVE B CELLS CLONES AND NEEDLESS PRODUCTION OF INTERLEUKIN (IL-)17 ARE LIMITED. THE METABOLIC REGULATION OF THE TWO CELL TYPES HAS SOME SIMILARITIES, E.G. THE UTILITY OF HYPOXIA INDUCED FACTOR (HIF)1ALPHA DURING LOW OXYGEN TENSION, TO PREVENT AUTOIMMUNITY AND REGULATE INFLAMMATION. THERE ARE ALSO CLEAR DIFFERENCES, AS TH17 CELLS ONLY ARE VULNERABLE TO THE LACK OF CERTAIN AMINO ACIDS. B CELLS, UNLIKE TH17 CELLS, ARE ALSO DEPENDENT OF MECHANISTIC TARGET OF RAPAMYCIN 2 (MTORC2) TO FUNCTION. SIGNIFICANT KNOWLEDGE HAS RECENTLY BEEN GAINED, PARTICULARLY ON TH17 CELLS, ON HOW METABOLISM REGULATES THESE CELLS THROUGH INFLUENCING THEIR EPIGENOME. METABOLIC DYSREGULATION OF TH17 CELLS AND B CELLS CAN LEAD TO CHRONIC INFLAMMATION. DISEASE ASSOCIATED ALTERATIONS IN THE GENOME CAN, IN ADDITION, CAUSE DYSREGULATION TO METABOLISM AND, THEREBY, RESULT IN EPIGENETIC ALTERATIONS IN THESE CELLS. RECENT STUDIES HIGHLIGHT HOW PATHOLOGY CAN RESULT FROM THE COOPERATION BETWEEN THE TWO CELL TYPES BUT ONLY FEW HAVE SO FAR ADDRESSED THE KEY METABOLIC ALTERATIONS IN SUCH SETTINGS. KNOWLEDGE OF THE IMPACT OF METABOLIC DYSFUNCTION ON CHRONIC INFLAMMATION AND PATHOLOGY CAN REVEAL NOVEL THERAPEUTIC TARGETS TO TREAT SUCH DISEASES. 2022 18 6771 32 [ACQUIRED DISORDERS AND EPIGENETICS]. EPIGENETIC MODIFICATIONS, INVOLVING DNA METHYLATION AND HISTONE MODIFICATIONS, ARE MAINTAINED UPON SOMATIC CELL REPLICATION, AND ARE FUNDAMENTAL MECHANISMS FOR CELLULAR MEMORY. DNA METHYLATION OF PROMOTER CPG ISLANDS OF TUMOR-SUPPRESSOR GENES CAN SILENCE THEIR DOWNSTREAM GENES, AND CAN BE CAUSALLY INVOLVED IN CANCER DEVELOPMENT AND PROGRESSION. SINCE THIS EFFECT IS THE SAME WITH THAT OF INACTIVATING MUTATIONS, THE NATURES OF DNA METHYLATION WERE ONCE CONSIDERED TO BE SIMILAR TO MUTATIONS. HOWEVER, RECENTLY, IT WAS REVEALED THAT A LARGE NUMBER OF EPIGENETIC ALTERATIONS ARE PRESENT IN A SINGLE CANCER CELL, THAT A LARGE NUMBER OF CELLS HAVE AN EPIGENETIC ALTERATION OF A SPECIFIC GENE IN NON-CANCEROUS, THUS POLYCLONAL, TISSUES, THAT GENE SPECIFICITY IN METHYLATION INDUCTION IS PRESENT ACCORDING TO TISSUE TYPES AND INDUCERS, AND THAT CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN METHYLATION INDUCTION. THESE FACTS SUGGEST THAT EPIGENETIC ALTERATIONS OF KEY GENES INVOLVED IN ACQUIRED CHRONIC DISORDERS CAN BE PRESENT IN A SIGNIFICANT FRACTION OF CELLS IN A TISSUE, AND THUS CAN IMPAIR THE FUNCTION OF THE TISSUE. ASSOCIATIONS BETWEEN EPIGENETIC ALTERATIONS AND BEHAVIOR, MEMORY, MENTAL DISORDERS, NEUROLOGICAL DISORDERS, METABOLIC DISORDERS, ALLERGY, AUTOIMMUNE DISORDERS, AND OTHER DISORDERS HAVE BEEN REPORTED. FURTHER RESEARCH IN THE FIELD IS NECESSARY TO CLARIFY THE CAUSAL ROLES OF THESE EPIGENETIC ALTERATIONS IN DISEASE DEVELOPMENT, AND TO APPLY THE FINDINGS TO NEW STRATEGIES OF DISEASE PREVENTION, DIAGNOSIS, AND TREATMENT. 2010 19 1641 34 DOES GUT-BREAST MICROBIOTA AXIS ORCHESTRATES CANCER PROGRESSION? BREAST CANCER, EVEN TODAY, CAN CAUSE DEATH. THEREFORE, PREVENTION AND EARLY DETECTION ARE FUNDAMENTAL FACTORS. THE MECHANISMS THAT FAVOUR IT ARE GENETIC AND EPIGENETIC, AND SEEM TO PLAY A SIGNIFICANT ROLE; ALSO, THE MICROBIOTA CAN CHANGE ESTROGEN LEVELS AND CAN INDUCE CHRONIC INFLAMMATION IN THE NEOPLASTIC SITE, ALTERNATING THE BALANCE BETWEEN PROLIFERATION AND CELL DEATH. ACTIVATED STEROID HORMONE RECEPTORS INDUCE TRANSCRIPTION OF GENES THAT ENCODE FOR PROTEINS INVOLVED IN CELL PROLIFERATION AND ACTIVATE ANOTHER TRANSDUCTION PATHWAY, INDUCING CELL CYCLE PROGRESSION AND CELL MIGRATION. THESE IMPORTANT STUDIES HAVE ALLOWED TO DEVELOP THERAPIES WITH SELECTIVE MODULATORS OF ESTROGEN RECEPTORS (SERMS), ABLE TO BLOCK THEIR PROLIFERATIVE AND PRO-TUMORIGENIC ACTION. OF FUNDAMENTAL IMPORTANCE IS ALSO THE ROLE PLAYED BY THE MICROBIOTA IN REGULATING THE METABOLISM OF ESTROGENS AND THEIR LEVELS IN THE BLOOD. THERE ARE MICROBIAL POPULATIONS THAT ARE ABLE TO PROMOTE THE DEVELOPMENT OF BREAST CANCER, THROUGH THE PRODUCTION OF ENZYMES RESPONSIBLE FOR THE DECONJUGATION OF ESTROGENS, THE INCREASE OF THESE IN THE INTESTINE, SUBSEQUENT CIRCULATION AND MIGRATION TO OTHER LOCATIONS, SUCH AS THE UDDER. OTHER MICROBIAL POPULATIONS ARE, INSTEAD, ABLE TO SYNTHESIZE ESTROGEN COMPOUNDS OR MIMIC ESTROGENIC ACTION, AND INTERFERE WITH THE METABOLISM OF DRUGS, AFFECTING THE OUTCOME OF THERAPIES. THE MICROBIAL COMPOSITION OF THE INTESTINE AND HORMONAL METABOLISM DEPEND LARGELY ON EATING HABITS; THE CONSUMPTION OF FATS AND PROTEINS FAVOURS THE INCREASE OF ESTROGEN IN THE BLOOD, UNLIKE A DIET RICH IN FIBER. THEREFORE, IN-DEPTH KNOWLEDGE OF THE MICROBIOTA PRESENT IN THE INTESTINE-BREAST AXIS COULD, IN THE FUTURE, ENCOURAGE THE DEVELOPMENT OF NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES TO BREAST CANCERS. 2022 20 4453 32 MOLECULAR MECHANISMS AND PATHWAYS AS TARGETS FOR CANCER PREVENTION AND PROGRESSION WITH DIETARY COMPOUNDS. A UNIQUE FEATURE OF BIOACTIVE FOOD INGREDIENTS IS THEIR BROAD ANTIOXIDANT FUNCTION. ANTIOXIDANTS HAVING A WIDE SPECTRUM OF CHEMICAL STRUCTURE AND ACTIVITY BEYOND BASIC NUTRITION; DISPLAY DIFFERENT HEALTH BENEFITS BY THE PREVENTION AND PROGRESSION OF CHRONIC DISEASES. FUNCTIONAL FOOD COMPONENTS ARE CAPABLE OF ENHANCING THE NATURAL ANTIOXIDANT DEFENSE SYSTEM BY SCAVENGING REACTIVE OXYGEN AND NITROGEN SPECIES, PROTECTING AND REPAIRING DNA DAMAGE, AS WELL AS MODULATING THE SIGNAL TRANSDUCTION PATHWAYS AND GENE EXPRESSION. MAJOR PATHWAYS AFFECTED BY BIOACTIVE FOOD INGREDIENTS INCLUDE THE PRO-INFLAMMATORY PATHWAYS REGULATED BY NUCLEAR FACTOR KAPPA B (NF-KAPPAB), AS WELL AS THOSE ASSOCIATED WITH CYTOKINES AND CHEMOKINES. THE PRESENT REVIEW SUMMARIZES THE IMPORTANCE OF PLANT BIOACTIVES AND THEIR ROLES IN THE REGULATION OF INFLAMMATORY PATHWAYS. BIOACTIVES INFLUENCE SEVERAL PHYSIOLOGICAL PROCESSES SUCH AS GENE EXPRESSION, CELL CYCLE REGULATION, CELL PROLIFERATION, CELL MIGRATION, ETC., RESULTING IN CANCER PREVENTION. CANCER INITIATION IS ASSOCIATED WITH CHANGES IN METABOLIC PATHWAYS SUCH AS GLUCOSE METABOLISM, AND THE EFFECT OF BIOACTIVES IN NORMALIZING THIS PROCESS HAS BEEN PROVIDED. INITIATION AND PROGRESSION OF INFLAMMATORY BOWEL DISEASES (IBD) WHICH INCREASE THE CHANCES OF DEVELOPING OF COLORECTAL CANCERS CAN BE DOWNREGULATED BY PLANT BIOACTIVES. SEVERAL ASPECTS OF THE POTENTIAL ROLES OF MICRORNAS AND EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF CANCERS HAVE ALSO BEEN PRESENTED. 2017