1 5711 165 SIRT1 IS A HIGHLY NETWORKED PROTEIN THAT MEDIATES THE ADAPTATION TO CHRONIC PHYSIOLOGICAL STRESS. SIRT1 IS A NAD(+)-DEPENDENT PROTEIN DEACETYLASE THAT HAS A VERY LARGE NUMBER OF ESTABLISHED PROTEIN SUBSTRATES AND AN EQUALLY IMPRESSIVE LIST OF BIOLOGICAL FUNCTIONS THOUGHT TO BE REGULATED BY ITS ACTIVITY. PERHAPS AS NOTABLE IS THE REMARKABLE NUMBER OF POINTS OF CONFLICT CONCERNING THE ROLE OF SIRT1 IN BIOLOGICAL PROCESSES. FOR EXAMPLE, EVIDENCE EXISTS SUGGESTING THAT SIRT1 IS A TUMOR SUPPRESSOR, IS AN ONCOGENE, OR HAS NO EFFECT ON ONCOGENESIS. SIMILARLY, SIRT1 IS VARIABLY REPORTED TO INDUCE, INHIBIT, OR HAVE NO EFFECT ON AUTOPHAGY. WE BELIEVE THAT THE RESOLUTION OF MANY CONFLICTING RESULTS IS POSSIBLE BY CONSIDERING RECENT REPORTS INDICATING THAT SIRT1 IS AN IMPORTANT HUB INTERACTING WITH A COMPLEX NETWORK OF PROTEINS THAT COLLECTIVELY REGULATE A WIDE VARIETY OF BIOLOGICAL PROCESSES INCLUDING CANCER AND AUTOPHAGY. A NUMBER OF THE INTERACTING PROTEINS ARE THEMSELVES HUBS THAT, LIKE SIRT1, UTILIZE INTRINSICALLY DISORDERED REGIONS FOR THEIR PROMISCUOUS INTERACTIONS. MANY STUDIES INVESTIGATING SIRT1 FUNCTION HAVE BEEN CARRIED OUT ON CELL LINES CARRYING UNDETERMINED NUMBERS OF ALTERATIONS TO THE PROTEINS COMPRISING THE SIRT1 NETWORK OR ON INBRED MOUSE STRAINS CARRYING FIXED MUTATIONS AFFECTING SOME OF THESE PROTEINS. THUS, THE EFFECTS OF MODULATING SIRT1 AMOUNT AND/OR ACTIVITY ARE IMPORTANTLY DETERMINED BY THE GENETIC BACKGROUND OF THE CELL (OR THE INBRED STRAIN OF MICE), AND THE EFFECTS ATTRIBUTED TO SIRT1 ARE SYNTHETIC WITH THE BACKGROUND OF MUTATIONS AND EPIGENETIC DIFFERENCES BETWEEN CELLS AND ORGANISMS. WORK ON MICE CARRYING ALTERATIONS TO THE SIRT1 GENE SUGGESTS THAT THE NETWORK IN WHICH SIRT1 FUNCTIONS PLAYS AN IMPORTANT ROLE IN MEDIATING PHYSIOLOGICAL ADAPTATION TO VARIOUS SOURCES OF CHRONIC STRESS SUCH AS CALORIE RESTRICTION AND CALORIE OVERLOAD. WHETHER THE CATALYTIC ACTIVITY OF SIRT1 AND THE NUCLEAR CONCENTRATION OF THE CO-FACTOR, NAD(+), ARE RESPONSIBLE FOR MODULATING THIS ACTIVITY REMAINS TO BE DETERMINED. HOWEVER, THE EFFECT OF MODULATING SIRT1 ACTIVITY MUST BE INTERPRETED IN THE CONTEXT OF THE CELL OR TISSUE UNDER INVESTIGATION. INDEED, FOR SIRT1, WE ARGUE THAT CONTEXT IS EVERYTHING. 2013 2 6342 47 THE ROLE OF EPIGENETIC REGULATOR SIRT1 IN BALANCING THE HOMEOSTASIS AND PREVENTING THE FORMATION OF SPECIFIC "SOIL" OF METABOLIC DISORDERS AND RELATED CANCERS. SIRT1 WAS DISCOVERED IN 1979 BUT GROWING INTEREST IN THIS PROTEIN OCCURRED ONLY 20 YEARS LATER WHEN ITS OVEREXPRESSION WAS REPORTED TO PROLONG THE LIFESPAN OF YEAST. SINCE THEN, SEVERAL STUDIES HAVE SHOWN THE BENEFITS OF ITS INCREASED EXPRESSION IN PREVENTING OR DELAYING OF MANY DISEASES. SIRT1, AS A HISTONE DEACETYLASE, IS AN EPIGENETIC REGULATOR BUT IT HAS WIDE RANGE OF NON-HISTONE TARGETS WHICH ARE INVOLVED IN METABOLISM, ENERGY SENSING PATHWAYS, CIRCADIAN MACHINERY AND IN INFLAMMATORY REGULATION. DISTURBANCES IN THESE INTERCONNECTED PROCESSES CAUSE DIFFERENT DISEASES, HOWEVER IT SEEMS THEY HAVE COMMON ROOTS IN UNBALANCED INFLAMMATORY PROCESSES AND LOWER LEVEL OR INACTIVATION OF SIRT1. SIRT1 INACTIVATION WAS IMPLICATED IN CORONAVIRUS DISEASE (COVID-19) SEVERITY AS WELL AND ITS LOW LEVEL COUNTED AS A PREDICTOR OF UNCONTROLLED COVID-19. SEVERAL OTHER DISEASES SUCH AS METABOLIC DISEASE, OBESITY, DIABETES, ALZHEIMER'S DISEASE, CARDIOVASCULAR DISEASE OR DEPRESSION ARE RELATED TO CHRONIC INFLAMMATION AND SIMILARLY SHOW DECREASED SIRT1 LEVEL. IT HAS RECENTLY BEEN KNOWN THAT SIRT1 IS INDUCIBLE BY CALORIE RESTRICTION/PROPER DIET, PHYSICAL ACTIVITY AND APPROPRIATE EMOTIONAL STATE. INDEED, A HEALTHIER METABOLIC STATE BELONGS TO HIGHER LEVEL OF SIRT1 EXPRESSION. THESE SUGGEST THAT APPROPRIATE LIFESTYLE AS NON-PHARMACOLOGICAL TREATMENT MAY BE A BENEFICIAL TOOL IN THE PREVENTION OF INFLAMMATION OR METABOLIC DISTURBANCE-RELATED DISEASES AS WELL AS COULD BE A PART OF THE COMPLEMENTARY THERAPY IN MEDICAL PRACTICE TO REACH BETTER THERAPEUTIC RESPONSE AND QUALITY OF LIFE. WE AIMED IN THIS REVIEW TO LINK THE BENEFICIAL EFFECT OF SIRT1 WITH THOSE DISEASES, WHERE ITS LEVEL DECREASED. MOREOVER, WE AIMED TO COLLECT EVIDENCES OF INTERVENTIONS OR TREATMENTS, WHICH INCREASE SIRT1 EXPRESSION AND THUS, OPEN THE POSSIBILITY TO USE THEM AS PREVENTIVE OR COMPLEMENTARY THERAPIES IN MEDICAL PRACTICE. 2022 3 2499 28 EPIGENETICS AND EXERCISE. EPIGENETICS CAN BE DEFINED AS 'THE STRUCTURAL ADAPTATION OF CHROMOSOMAL REGIONS SO AS TO REGISTER, SIGNAL, OR PERPETUATE ALTERED ACTIVITY STATES.' INCREASED TRANSCRIPTION OF KEY REGULATORY, METABOLIC, AND MYOGENIC GENES IS AN EARLY RESPONSE TO EXERCISE AND IS IMPORTANT IN MEDIATING SUBSEQUENT ADAPTATIONS IN SKELETAL MUSCLE. DNA HYPOMETHYLATION AND HISTONE HYPERACETYLATION ARE EMERGING AS IMPORTANT CRUCIAL EVENTS FOR INCREASED TRANSCRIPTION. THE COMPLEX INTERACTIONS BETWEEN MULTIPLE EPIGENETIC MODIFICATIONS AND THEIR REGULATION BY METABOLIC CHANGES AND SIGNALING EVENTS DURING EXERCISE, WITH IMPLICATIONS FOR ENHANCED UNDERSTANDING OF THE ACUTE AND CHRONIC ADAPTATIONS TO EXERCISE, ARE QUESTIONS FOR FURTHER INVESTIGATION. 2019 4 6257 32 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 2303 36 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 6 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 7 6533 36 TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES ASSOCIATED WITH SEVERE ASTHMA. THE 10% OF PATIENTS WITH THE MOST SEVERE ASTHMA ARE RESPONSIBLE FOR A LARGE PART OF HEALTHCARE EXPENDITURE AND MORBIDITY. UNDERSTANDING THE PROCESSES INVOLVED IS KEY IF NEW THERAPEUTIC APPROACHES ARE TO BE DEVELOPED. EVIDENCE IS ACCUMULATING THAT CHRONIC DISEASES SUCH AS ASTHMA ARE ASSOCIATED WITH TEMPORAL AND SPATIAL ALTERATIONS IN THE PATTERN OF INFLAMMATORY GENE EXPRESSION WITHIN THE AIRWAYS. EXPRESSION OF THESE GENES CAN BE REGULATED BY TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS. IT IS WELL ESTABLISHED THAT BINDING OF ACTIVATED TRANSCRIPTION FACTORS TO SPECIFIC INDUCIBLE GENE PROMOTER SITES IS TIGHTLY CONTROLLED BY CHROMATIN STATE AS A RESULT OF HISTONE MODIFICATIONS, PARTICULARLY THE BALANCE BETWEEN HISTONE ACETYLATION AND DEACETYLATION [1]. THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND THE PROMOTER IS KEY TO THE DIVERSIFICATION OF GENE EXPRESSION IN A TIME DEPENDENT MANNER LEADING TO ALTERED GENE EXPRESSION PROFILES. ALTERATIONS OF THE ACCESSIBILITY OF TRANSCRIPTION FACTORS TO THE DNA CAN HAVE RESIDING EFFECTS UPON GENE TRANSCRIPTION. THIS REVIEW WILL FOCUS ON THE REGULATION OF SEVERAL GROUPS OF KEY GENES WHICH ARE INVOLVED IN CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA DRAWING MAINLY FROM OUR EXPERIENCE OF STUDYING THESE PROCESSES IN AIRWAY SMOOTH MUSCLE CELLS. AN OVERVIEW IS SHOWN IN FIGURE 1. 2011 8 5581 40 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 9 6527 35 TRANSCRIPTIONAL CONTROL OF MALADAPTIVE AND PROTECTIVE RESPONSES IN ALCOHOLICS: A ROLE OF THE NF-KAPPAB SYSTEM. ALCOHOL DEPENDENCE AND ASSOCIATED COGNITIVE IMPAIRMENT APPEAR TO RESULT FROM MALADAPTIVE NEUROPLASTICITY IN RESPONSE TO CHRONIC ALCOHOL CONSUMPTION, NEUROINFLAMMATION AND NEURODEGENERATION. THE INHERENT STABILITY OF BEHAVIORAL ALTERATIONS ASSOCIATED WITH THE ADDICTED STATE SUGGESTS THAT TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS ARE OPERATIVE. NF-KAPPAB TRANSCRIPTION FACTORS ARE REGULATORS OF SYNAPTIC PLASTICITY AND INFLAMMATION, AND RESPONSIVE TO A VARIETY OF STIMULI INCLUDING ALCOHOL. THESE FACTORS ARE ABUNDANT IN THE BRAIN WHERE THEY HAVE DIVERSE FUNCTIONS THAT DEPEND ON THE COMPOSITION OF THE NF-KAPPAB COMPLEX AND CELLULAR CONTEXT. IN NEURON CELL BODIES, NF-KAPPAB IS CONSTITUTIVELY ACTIVE, AND INVOLVED IN NEURONAL INJURY AND NEUROPROTECTION. HOWEVER, AT THE SYNAPSE, NF-KAPPAB IS PRESENT IN A LATENT FORM AND UPON ACTIVATION IS TRANSPORTED TO THE CELL NUCLEUS. IN GLIA, NF-KAPPAB IS INDUCIBLE AND REGULATES INFLAMMATORY PROCESSES THAT EXACERBATE ALCOHOL-INDUCED NEURODEGENERATION. ANIMAL STUDIES DEMONSTRATE THAT ACUTE ALCOHOL EXPOSURE TRANSIENTLY ACTIVATES NF-KAPPAB, WHICH INDUCES NEUROINFLAMMATORY RESPONSES AND NEURODEGENERATION. POSTMORTEM STUDIES OF BRAINS OF HUMAN ALCOHOLICS SUGGEST THAT REPEATED CYCLES OF ALCOHOL CONSUMPTION AND WITHDRAWAL CAUSE ADAPTIVE CHANGES IN THE NF-KAPPAB SYSTEM THAT MAY PERMIT THE SYSTEM TO BETTER TOLERATE EXCESSIVE STIMULATION. THIS TYPE OF TOLERANCE, ENSURING A LOW DEGREE OF RESPONSIVENESS TO APPLIED STIMULI, APPARENTLY DIFFERS FROM THAT IN THE IMMUNE SYSTEM, AND MAY REPRESENT A COMPENSATORY RESPONSE THAT PROTECTS BRAIN CELLS AGAINST ALCOHOL NEUROTOXICITY. THIS VIEW IS SUPPORTED BY FINDINGS SHOWING PREFERENTIAL DOWNREGULATION OF PRO-APOPTOTIC GENE EXPRESSION IN THE AFFECTED BRAIN AREAS IN HUMAN ALCOHOLICS. ALTHOUGH FURTHER VERIFICATION IS NEEDED, WE SPECULATE THAT NF-KAPPAB-DRIVEN NEUROINFLAMMATION AND DISRUPTION TO NEUROPLASTICITY PLAY A SIGNIFICANT ROLE IN REGULATING ALCOHOL DEPENDENCE AND COGNITIVE IMPAIRMENT. 2011 10 110 23 A ROLE FOR ACTIVITY-DEPENDENT EPIGENETICS IN THE DEVELOPMENT AND TREATMENT OF MAJOR DEPRESSIVE DISORDER. CHRONIC STRESSORS, DURING DEVELOPMENTAL SENSITIVE PERIODS AND BEYOND, CONTRIBUTE TO THE RISK OF DEVELOPING PSYCHIATRIC CONDITIONS, INCLUDING MAJOR DEPRESSIVE DISORDER (MDD). EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS, AT KEY STRESS RESPONSE AND NEUROTROPHIN GENES, ARE INCREASINGLY IMPLICATED IN MEDIATING THIS RISK. ALTHOUGH THE EXACT MECHANISMS THROUGH WHICH STRESSFUL ENVIRONMENTAL STIMULI ALTER THE EPIGENOME ARE STILL UNCLEAR, RESEARCH FROM THE LEARNING AND MEMORY FIELDS INDICATES THAT EPIGENOMIC MARKS CAN BE ALTERED, AT LEAST IN PART, THROUGH CALCIUM-DEPENDENT SIGNALING CASCADES IN DIRECT RESPONSE TO NEURONAL ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT KEY FINDINGS FROM THE STRESS, MDD, AND LEARNING AND MEMORY FIELDS TO PROPOSE A MODEL WHERE STRESS REGULATES DOWNSTREAM CELLULAR FUNCTIONING THROUGH ACTIVITY-DEPENDENT EPIGENETIC CHANGES. FURTHERMORE, WE SUGGEST THAT BOTH TYPICAL AND NOVEL ANTIDEPRESSANT TREATMENTS MAY EXERT POSITIVE INFLUENCE THROUGH SIMILAR, ACTIVITY-DEPENDENT PATHWAYS. 2018 11 6866 43 [PAIN AND EMOTIONAL DYSREGULATION: CELLULAR MEMORY DUE TO PAIN]. GENETIC FACTORS ARE INVOLVED IN DETERMINANTS FOR THE RISK OF PSYCHIATRIC DISORDERS, AND NEUROLOGICAL AND NEURODEGENERATIVE DISEASES. CHRONIC PAIN STIMULI AND INTENSE PAIN HAVE EFFECTS AT A CELLULAR AND/OR GENE EXPRESSION LEVEL, AND WILL EVENTUALLY INDUCE "CELLULAR MEMORY DUE TO PAIN", WHICH MEANS THAT TISSUE DAMAGE, EVEN IF ONLY TRANSIENT, CAN ELICIT EPIGENETICALLY ABNORMAL TRANSCRIPTION/TRANSLATION AND POST-TRANSLATIONAL MODIFICATION IN RELATED CELLS DEPENDING ON THE DEGREE OR KIND OF INJURY OR ASSOCIATED CONDITIONS. SUCH CELL MEMORY/TRANSFORMATION DUE TO PAIN CAN CAUSE AN ABNORMALITY IN A FUNDAMENTAL INTRACELLULAR RESPONSE, SUCH AS A CHANGE IN THE THREE-DIMENSIONAL STRUCTURE OF DNA, TRANSCRIPTION, OR TRANSLATION. ON THE OTHER HAND, PAIN IS A MULTIDIMENSIONAL EXPERIENCE WITH SENSORY-DISCRIMINATIVE AND MOTIVATIONAL-AFFECTIVE COMPONENTS. RECENT HUMAN BRAIN IMAGING STUDIES HAVE EXAMINED DIFFERENCES IN ACTIVITY IN THE NUCLEUS ACCUMBENS BETWEEN CONTROLS AND PATIENTS WITH CHRONIC PAIN, AND HAVE REVEALED THAT THE NUCLEUS ACCUMBENS PLAYS A ROLE IN PREDICTING THE VALUE OF A NOXIOUS STIMULUS AND ITS OFFSET, AND IN THE CONSEQUENT CHANGES IN THE MOTIVATIONAL STATE. IN THIS REVIEW, WE PROVIDE A VERY BRIEF OVERVIEW OF A COMPREHENSIVE UNDERSTANDING OF CHRONIC PAIN ASSOCIATED WITH EMOTIONAL DYSREGULATION DUE TO TRANSCRIPTIONAL REGULATION, EPIGENETIC MODIFICATION AND MIRNA REGULATION. 2015 12 6771 37 [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 13 3837 40 IONIZING RADIATION-INDUCED OXIDATIVE STRESS, EPIGENETIC CHANGES AND GENOMIC INSTABILITY: THE PIVOTAL ROLE OF MITOCHONDRIA. PURPOSE: TO REVIEW THE DATA CONCERNING THE ROLE OF ENDOGENOUSLY GENERATED REACTIVE OXYGEN SPECIES (ROS) IN THE NON-TARGETED IONIZING RADIATION (IR) EFFECTS AND IN DETERMINATION OF THE CELL POPULATION'S FATE, BOTH EARLY AFTER EXPOSURE AND AFTER MANY GENERATIONS. CONCLUSIONS: THE SHORT-TERM AS WELL AS CHRONIC OXIDATIVE STRESS RESPONSES MAINLY ARE PRODUCED DUE TO ROS GENERATION BY THE ELECTRON TRANSPORT CHAIN (ETC) OF THE MITOCHONDRIA AND BY THE CYTOPLASMIC NADPH OXIDASES. WHETHER THE INDUCTION OF THE OXIDATIVE STRESS AND ITS CONSEQUENCES OCCUR OR ARE HAMPERED IN A SINGLE CELL LARGELY DEPENDS ON THE INTERACTION BETWEEN THE NUCLEUS AND THE CELLULAR POPULATION OF SEVERAL HUNDRED OR THOUSANDS OF MITOCHONDRIA THAT ARE GENETICALLY HETEROGENEOUS. HIGH INTRA-MITOCHONDRIAL ROS LEVEL IS DAMAGING THE MITOCHONDRIAL (MT) DNA AND ITS MUTATIONS AFFECT THE EPIGENETIC CONTROL MECHANISMS OF THE NUCLEAR (N) DNA, BY DECREASING THE ACTIVITY OF METHYLTRANSFERASES AND THUS, CAUSING GLOBAL DNA HYPOMETHYLATION. THESE CHANGES ARE TRANSMITTED TO THE PROGENY OF THE IRRADIATED CELLS. THE CHRONIC OXIDATIVE STRESS IS THE MAIN CAUSE OF THE LATE POST-RADIATION EFFECTS, INCLUDING CANCER, AND THIS MAKES IT AN IMPORTANT ADVERSE EFFECT OF EXPOSURE TO IR AND A TARGET FOR RADIOLOGICAL PROTECTION. 2015 14 2523 35 EPIGENETICS AND THE TRANSITION FROM ACUTE TO CHRONIC PAIN. OBJECTIVE: THE OBJECTIVE OF THIS STUDY WAS TO REVIEW THE EPIGENETIC MODIFICATIONS INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN AND TO IDENTIFY POTENTIAL TARGETS FOR THE DEVELOPMENT OF NOVEL, INDIVIDUALIZED PAIN THERAPEUTICS. BACKGROUND: EPIGENETICS IS THE STUDY OF HERITABLE MODIFICATIONS IN GENE EXPRESSION AND PHENOTYPE THAT DO NOT REQUIRE A CHANGE IN GENETIC SEQUENCE TO MANIFEST THEIR EFFECTS. ENVIRONMENTAL TOXINS, MEDICATIONS, DIET, AND PSYCHOLOGICAL STRESSES CAN ALTER EPIGENETIC PROCESSES SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND RNA INTERFERENCE. AS EPIGENETIC MODIFICATIONS POTENTIALLY PLAY AN IMPORTANT ROLE IN INFLAMMATORY CYTOKINE METABOLISM, STEROID RESPONSIVENESS, AND OPIOID SENSITIVITY, THEY ARE LIKELY KEY FACTORS IN THE DEVELOPMENT OF CHRONIC PAIN. ALTHOUGH OUR KNOWLEDGE OF THE HUMAN GENETIC CODE AND DISEASE-ASSOCIATED POLYMORPHISMS HAS GROWN SIGNIFICANTLY IN THE PAST DECADE, WE HAVE NOT YET BEEN ABLE TO ELUCIDATE THE MECHANISMS THAT LEAD TO THE DEVELOPMENT OF PERSISTENT PAIN AFTER NERVE INJURY OR SURGERY. DESIGN: THIS IS A FOCUSED LITERATURE REVIEW OF EPIGENETIC SCIENCE AND ITS RELATIONSHIP TO CHRONIC PAIN. RESULTS: SIGNIFICANT LABORATORY AND CLINICAL DATA SUPPORT THE NOTION THAT EPIGENETIC MODIFICATIONS ARE AFFECTED BY THE ENVIRONMENT AND LEAD TO DIFFERENTIAL GENE EXPRESSION. SIMILAR TO MECHANISMS INVOLVED IN THE DEVELOPMENT OF CANCER, NEURODEGENERATIVE DISEASE, AND INFLAMMATORY DISORDERS, THE LITERATURE ENDORSES AN IMPORTANT POTENTIAL ROLE FOR EPIGENETICS IN CHRONIC PAIN. CONCLUSIONS: EPIGENETIC ANALYSIS MAY IDENTIFY MECHANISMS CRITICAL TO THE DEVELOPMENT OF CHRONIC PAIN AFTER INJURY, AND MAY PROVIDE NEW PATHWAYS AND TARGET MECHANISMS FOR FUTURE DRUG DEVELOPMENT AND INDIVIDUALIZED MEDICINE. 2012 15 2346 36 EPIGENETIC REGULATION OF METABOLISM AND INFLAMMATION BY CALORIE RESTRICTION. CHRONIC CALORIC RESTRICTION (CR) WITHOUT MALNUTRITION IS KNOWN TO AFFECT DIFFERENT CELLULAR PROCESSES SUCH AS STEM CELL FUNCTION, CELL SENESCENCE, INFLAMMATION, AND METABOLISM. DESPITE THE DIFFERENCES IN THE IMPLEMENTATION OF CR, THE REDUCTION OF CALORIES PRODUCES A WIDESPREAD BENEFICIAL EFFECT IN NONCOMMUNICABLE CHRONIC DISEASES, WHICH CAN BE EXPLAINED BY IMPROVEMENTS IN IMMUNO-METABOLIC ADAPTATION. CELLULAR ADAPTATION THAT OCCURS IN RESPONSE TO DIETARY PATTERNS CAN BE EXPLAINED BY ALTERATIONS IN EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNA. IN THIS REVIEW, WE DEFINE THESE MODIFICATIONS AND SYSTEMATICALLY SUMMARIZE THE CURRENT EVIDENCE RELATED TO CR AND THE EPIGENOME. WE THEN EXPLAIN THE SIGNIFICANCE OF GENOME-WIDE EPIGENETIC MODIFICATIONS IN THE CONTEXT OF DISEASE DEVELOPMENT. ALTHOUGH SUBSTANTIAL EVIDENCE EXISTS FOR THE WIDESPREAD EFFECT OF CR ON LONGEVITY, THERE IS NO CONSENSUS REGARDING THE EPIGENETIC REGULATIONS OF THE UNDERLYING CELLULAR MECHANISMS THAT LEAD TO IMPROVED HEALTH. WE PROVIDE COMPELLING EVIDENCE THAT CR PRODUCES LONG-LASTING EPIGENETIC EFFECTS THAT MEDIATE EXPRESSION OF GENES RELATED TO IMMUNO-METABOLIC PROCESSES. EPIGENETIC REPROGRAMMING OF THE UNDERLYING CHRONIC LOW-GRADE INFLAMMATION BY CR CAN LEAD TO IMMUNO-METABOLIC ADAPTATIONS THAT ENHANCE QUALITY OF LIFE, EXTEND LIFESPAN, AND DELAY CHRONIC DISEASE ONSET. 2019 16 5550 42 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 17 5119 32 POSSIBLE CONTRIBUTION OF CHRONIC INFLAMMATION IN THE INDUCTION OF CANCER IN RHEUMATIC DISEASES. SEVERAL CHRONIC INFLAMMATORY CONDITIONS AND AUTOIMMUNE DISEASES INVOLVING DIFFERENT ORGANS AND TISSUES HAVE BEEN FOUND AT RISK OF PROGRESSION TO CANCER. A WIDE ARRAY OF PROINFLAMMATORY CYTOKINES, PROSTAGLANDINS, NITRIC OXIDE PRODUCTS, AND MATRICELLULAR PROTEINS ARE CLOSELY INVOLVED IN PREMALIGNANT AND MALIGNANT TRANSITION OF CELLS ALMOST ALWAYS IN A BACKGROUND OF CHRONIC INFLAMMATION. INTERESTINGLY, EPIGENETIC PERTURBATIONS (I.E. MIRNA ABERRATIONS, ALTERED DNA METHYLATION) TOGETHER WITH IMPORTANT STEROID HORMONE METABOLIC CHANGES (I.E. OESTROGENS), OR THE ALTERED VITAMIN D CONCENTRATIONS THAT MAY UNBALANCE THE IMMUNE / INFLAMMATORY RESPONSE, HAVE BEEN FOUND LINKED TO THE RISK AND SEVERITY IN SEVERAL CHRONIC INFLAMMATORY CONDITIONS, AS WELL AS IN CANCER. IN PARTICULAR, IT IS EVIDENT, THAT NOT ONLY THE PARENT OESTROGEN BUT ALSO OESTROGEN METABOLITES SHOULD BE TAKEN INTO ACCOUNT WHEN THIS PROCESS IS EVALUATED, SPECIALLY THE FORMATION OF CATECHOLOESTROGEN METABOLITES, THAT ARE CAPABLE OF FORMING EITHER STABLE OR DEPURINATING DNA ADDUCTS, WHICH CAN CAUSE EXTENSIVE DNA DAMAGE. IT IS INTERESTING THAT TODAY THE SUCCESSFUL TREATMENT OF SEVERAL CHRONIC IMMUNE/INFLAMMATORY RHEUMATIC DISEASES IS OBTAINED ALSO BY USING MEDICATIONS INITIALLY DEVELOPED FOR THEIR USE IN ONCOLOGY. THE CIRCADIAN INCREASE OF GROWTH FACTORS, SPECIALLY DURING THE LATE NIGHT, IN BOTH CHRONIC INFLAMMATION AND IN CANCER PATIENTS, AS WELL AS THE PRESENCE OF OESTROGEN-REGULATED CIRCADIAN MECHANISMS, SUGGESTS FURTHER IMPORTANT LINKS. 2014 18 5645 34 SEX DEPENDENT ALTERATION OF EPIGENETIC MARKS AFTER CHRONIC MORPHINE TREATMENT IN MICE ORGANS. EPIGENETIC MARKS MAY BE ALSO AFFECTED BY SEVERAL FACTORS, SUCH AS AGE, LIFESTYLE, EARLY LIFE EXPERIENCES AND EXPOSURE TO CHEMICALS OR DRUGS, SUCH AS OPIOIDS. PREVIOUS STUDIES HAVE FOCUSED ON HOW MORPHINE EPIGENETICALLY REGULATES DIFFERENT REGIONS OF THE BRAIN THAT ARE IMPLICATED IN TOLERANCE, DEPENDENCE AND OTHER PSYCHIATRIC DISORDERS MORE RELATED TO THE PHYSIO-PATHOLOGICAL EFFECTS OF OPIOIDS. NEVERTHELESS, A SIGNIFICANT KNOWLEDGE GAP REMAINS REGARDING THE EFFECT OF CHRONIC TREATMENT ON OTHER ORGANS AND BIOLOGICAL SYSTEMS. THEREFORE, THE AIM OF THIS WORK IS TO INCREASE OUR KNOWLEDGE ABOUT THE IMPACT OF CHRONIC MORPHINE EXPOSURE ON DNA METHYLATION AND HISTONE MODIFICATION LEVELS IN EACH OF THE ORGANS OF MALE AND FEMALE MODEL MICE IN VIVO. OUR RESULTS REVEAL, FOR THE FIRST TIME, THAT CHRONIC MORPHINE TREATMENT INDUCED CHANGES IN DNA METHYLATION/HYDROXYMETHYLATION AND HISTONE MODIFICATION IN-VIVO AT THE SYSTEMIC LEVEL, REVEALING A POTENTIAL PHYSIOLOGICAL EFFECT ON THE REGULATION OF GENE EXPRESSION. NOTABLY, MORPHINE-INDUCED EPIGENETIC MODIFICATION OCCURS IN A SEX-DEPENDENT MANNER, REVEALING THE EXISTENCE OF DIFFERENT UNDERLYING MECHANISMS OF EPIGENETIC MODIFICATION IN MALE AND FEMALE MICE. 2021 19 1796 43 EFFECT OF GERM-FREE STATUS ON TRANSCRIPTIONAL PROFILES IN THE NUCLEUS ACCUMBENS AND TRANSCRIPTOMIC RESPONSE TO CHRONIC MORPHINE. OPIOID USE DISORDER IS A PUBLIC HEALTH CRISIS THAT CAUSES TREMENDOUS SUFFERING FOR PATIENTS AS WELL AS SUBSTANTIAL SOCIAL AND ECONOMIC COSTS FOR SOCIETY. THERE ARE CURRENTLY AVAILABLE TREATMENTS FOR PATIENTS WITH OPIOID USE DISORDER, BUT THEY REMAIN INTOLERABLE OR INEFFECTIVE FOR MANY. THUS THE NEED TO DEVELOP NEW AVENUES FOR THERAPEUTICS DEVELOPMENT IN THIS SPACE IS GREAT. SUBSTANTIAL WORK IN MODELS OF SUBSTANCE USE DISORDERS, INCLUDING OPIOID USE DISORDER, DEMONSTRATES THAT PROLONGED EXPOSURE TO DRUGS OF ABUSE LEADS TO MARKED TRANSCRIPTIONAL AND EPIGENETIC DYSREGULATION IN LIMBIC SUBSTRUCTURES. IT IS WIDELY BELIEVED THAT THESE CHANGES IN GENE REGULATION IN RESPONSE TO DRUGS ARE A KEY DRIVING FACTOR IN THE PERPETUATION OF DRUG TAKING AND SEEKING BEHAVIORS. THUS, DEVELOPMENT OF INTERVENTIONS THAT COULD SHAPE TRANSCRIPTIONAL REGULATION IN RESPONSE TO DRUGS OF ABUSE WOULD BE OF HIGH VALUE. OVER THE PAST DECADE THERE HAS BEEN A SURGE IN RESEARCH DEMONSTRATING THAT THE RESIDENT BACTERIA OF THE GASTROINTESTINAL TRACT, COLLECTIVELY THE GUT MICROBIOME, CAN HAVE TREMENDOUS INFLUENCE ON NEUROBIOLOGICAL AND BEHAVIORAL PLASTICITY. PREVIOUS WORK FROM OUR GROUP AND OTHERS HAS DEMONSTRATED THAT ALTERATIONS IN THE GUT MICROBIOME CAN ALTER BEHAVIORAL RESPONSES TO OPIOIDS IN MULTIPLE PARADIGMS. ADDITIONALLY, WE HAVE PREVIOUSLY REPORTED THAT DEPLETION OF THE GUT MICROBIOME WITH ANTIBIOTICS MARKEDLY SHIFTS THE TRANSCRIPTOME OF THE NUCLEUS ACCUMBENS FOLLOWING PROLONGED MORPHINE EXPOSURE. IN THIS MANUSCRIPT WE PRESENT A COMPREHENSIVE ANALYSIS OF THE EFFECTS OF THE GUT MICROBIOME ON TRANSCRIPTIONAL REGULATION OF THE NUCLEUS ACCUMBENS FOLLOWING MORPHINE BY UTILIZING GERM-FREE, ANTIBIOTIC TREATED, AND CONTROL MICE. THIS ALLOWS FOR DETAILED UNDERSTANDING OF THE ROLE OF THE MICROBIOME IN REGULATING BASELINE TRANSCRIPTOMIC CONTROL, AS WELL AS RESPONSE TO MORPHINE. WE FIND THAT GERM-FREE STATUS LEADS TO A MARKED GENE DYSREGULATION IN A MANNER DISTINCT TO ADULT MICE TREATED WITH ANTIBIOTICS, AND THAT ALTERED GENE PATHWAYS ARE HIGHLY RELATED TO CELLULAR METABOLIC PROCESSES. THESE DATA PROVIDE ADDITIONAL INSIGHT INTO THE ROLE OF THE GUT MICROBIOME IN MODULATING BRAIN FUNCTION AND LAY A FOUNDATION FOR FURTHER STUDY IN THIS AREA. 2023 20 3287 47 HIERARCHICAL AND CYBERNETIC NATURE OF BIOLOGIC SYSTEMS AND THEIR RELEVANCE TO HOMEOSTATIC ADAPTATION TO LOW-LEVEL EXPOSURES TO OXIDATIVE STRESS-INDUCING AGENTS. DURING EVOLUTION IN AN AEROBIC ENVIRONMENT, MULTICELLULAR ORGANISMS SURVIVED BY ADAPTIVE RESPONSES TO BOTH THE ENDOGENOUS OXIDATIVE METABOLISM IN THE CELLS OF THE ORGANISM AND THE CHEMICALS AND LOW-LEVEL RADIATION TO WHICH THEY HAD BEEN EXPOSED. THE DEFENSE REPERTOIRE EXISTS AT ALL LEVELS OF THE BIOLOGICAL HIERARCHY--FROM THE MOLECULAR AND BIOCHEMICAL LEVEL TO THE CELLULAR AND TISSUE LEVEL TO THE ORGAN AND ORGAN SYSTEM LEVEL. CELLS CONTAIN PREVENTIVE ANTIOXIDANTS TO SUPPRESS OXIDATIVE DAMAGE TO MEMBRANES. CELLS ALSO CONTAIN PROTEINS AND DNA; BUILT-IN REDUNDANCIES FOR DAMAGED MOLECULES AND ORGANELLES; TIGHTLY COUPLED REDOX SYSTEMS; POOLS OF REDUCTANTS; ANTIOXIDANTS; DNA REPAIR MECHANISMS AND SENSITIVE SENSOR MOLECULES SUCH AS NUCLEAR FACTOR KAPPA BETA; AND SIGNAL TRANSDUCTION MECHANISMS AFFECTING BOTH TRANSCRIPTION AND POST-TRANSLATIONAL MODIFICATION OF PROTEINS NEEDED TO COPE WITH OXIDATIVE STRESS. THE BIOLOGIC CONSEQUENCES OF THE LOW-LEVEL RADIATION THAT EXCEEDS THE BACKGROUND LEVEL OF OXIDATIVE DAMAGE COULD BE NECROSIS OR APOPTOSIS, CELL PROLIFERATION, OR CELL DIFFERENTIATION. THESE EFFECTS ARE TRIGGERED BY OXIDATIVE STRESS-INDUCED SIGNAL TRANSDUCTION MECHANISMS--AN EPIGENETIC, NOT GENOTOXIC, PROCESS. IF THE END POINTS OF CELL PROLIFERATION, DIFFERENTIATION, OR CELL DEATH ARE NOT SEEN AT FREQUENCIES ABOVE BACKGROUND LEVELS IN AN ORGANISM, IT IS UNLIKELY THAT LOW-LEVEL RADIATION WOULD PLAY A ROLE IN THE MULTISTEP PROCESSES OF CHRONIC DISEASES SUCH AS CANCER. THE MECHANISM LINKED TO HOMEOSTATIC REGULATION OF PROLIFERATION AND ADAPTIVE FUNCTIONS IN A MULTICELLULAR ORGANISM COULD PROVIDE PROTECTION OF ANY ONE CELL RECEIVING DEPOSITED ENERGY BY THE RADIATION TRACT THROUGH THE SHARING OF REDUCTANTS AND BY TRIGGERING APOPTOSIS OF TARGET STEM CELLS. EXAMPLES OF THE ROLE OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION IN THE ADAPTIVE RESPONSE OF CELLS AND THE BYSTANDER EFFECT ILLUSTRATE HOW THE INTERACTION OF CELLS CAN MODULATE THE EFFECT OF RADIATION ON THE SINGLE CELL. 1998