1 1884 129 ENDOCANNABINOID-EPIGENETIC CROSS-TALK: A BRIDGE TOWARD STRESS COPING. THERE IS NO ARGUMENT WITH REGARD TO THE PHYSICAL AND PSYCHOLOGICAL STRESS-RELATED NATURE OF NEUROPSYCHIATRIC DISORDERS. YET, THE MECHANISMS THAT FACILITATE DISEASE ONSET STARTING FROM MOLECULAR STRESS RESPONSES ARE ELUSIVE. ENVIRONMENTAL STRESS CHALLENGES INDIVIDUALS' EQUILIBRIUM, ENHANCING HOMEOSTATIC REQUEST IN THE ATTEMPT TO STEER DOWN AROUSAL-INSTRUMENTAL MOLECULAR PATHWAYS THAT UNDERLIE HYPERVIGILANCE AND ANXIETY. A RELEVANT HOMEOSTATIC PATHWAY IS THE ENDOCANNABINOID SYSTEM (ECS). IN THIS REVIEW, WE SUMMARIZE RECENT DISCOVERIES UNAMBIGUOUSLY LISTING ECS AS A STRESS COPING MECHANISM. AS STRESS EVOKES HUGE EXCITATORY RESPONSES IN EMOTIONAL-RELEVANT LIMBIC AREAS, THE ECS LIMITS GLUTAMATE RELEASE VIA 2-ARACHYDONILGLYCEROL (2-AG) STRESS-INDUCED SYNTHESIS AND RETROGRADE CANNABINOID 1 (CB1)-RECEPTOR ACTIVATION AT THE SYNAPSE. HOWEVER, ECS SHOWS INTRINSIC VULNERABILITY AS 2-AG OVERSTIMULATION BY CHRONIC STRESS RAPIDLY LEADS TO CB1-RECEPTOR DESENSITIZATION. IN THIS REVIEW, WE EMPHASIZE THE PROTECTIVE ROLE OF 2-AG IN STRESS-RESPONSE TERMINATION AND STRESS RESILIENCY. INTERESTINGLY, WE DISCUSS ECS REGULATION WITH A FURTHER NUCLEAR HOMEOSTATIC SYSTEM WHOSE NATURE IS EXQUISITELY EPIGENETIC, ORCHESTRATED BY LYSINE SPECIFIC DEMETHYLASE 1. WE HERE EMPHASIZE A REMARKABLE EXAMPLE OF STRESS-COPING NETWORK WHERE TRANSCRIPTIONAL HOMEOSTASIS SUBSERVES SYNAPTIC AND BEHAVIORAL ADAPTATION, AIMING AT REDUCING PSYCHIATRIC EFFECTS OF TRAUMATIC EXPERIENCES. 2020 2 1315 30 DELTA FOSB MEDIATES EPIGENETIC DESENSITIZATION OF THE C-FOS GENE AFTER CHRONIC AMPHETAMINE EXPOSURE. THE MOLECULAR MECHANISMS UNDERLYING THE TRANSITION FROM RECREATIONAL DRUG USE TO CHRONIC ADDICTION REMAIN POORLY UNDERSTOOD. ONE MOLECULE IMPLICATED IN THIS PROCESS IS DELTAFOSB, A TRANSCRIPTION FACTOR THAT ACCUMULATES IN STRIATUM AFTER REPEATED DRUG EXPOSURE AND MEDIATES SENSITIZED BEHAVIORAL RESPONSES TO PSYCHOSTIMULANTS AND OTHER DRUGS OF ABUSE. THE DOWNSTREAM TRANSCRIPTIONAL MECHANISMS BY WHICH DELTAFOSB REGULATES DRUG-INDUCED BEHAVIORS ARE INCOMPLETELY UNDERSTOOD. WE REPORTED PREVIOUSLY THE CHROMATIN REMODELING MECHANISMS BY WHICH DELTAFOSB ACTIVATES THE EXPRESSION OF CERTAIN GENES; HOWEVER, THE MECHANISMS UNDERLYING DELTAFOSB-MEDIATED GENE REPRESSION REMAIN UNKNOWN. HERE, WE IDENTIFY C-FOS, AN IMMEDIATE EARLY GENE RAPIDLY INDUCED IN STRIATUM AFTER ACUTE PSYCHOSTIMULANT EXPOSURE, AS A NOVEL DOWNSTREAM TARGET THAT IS REPRESSED CHRONICALLY BY DELTAFOSB. WE SHOW THAT ACCUMULATION OF DELTAFOSB IN STRIATUM AFTER CHRONIC AMPHETAMINE TREATMENT DESENSITIZES C-FOS MRNA INDUCTION TO A SUBSEQUENT DRUG DOSE. DELTAFOSB DESENSITIZES C-FOS EXPRESSION BY RECRUITING HISTONE DEACETYLASE 1 (HDAC1) TO THE C-FOS GENE PROMOTER, WHICH, IN TURN, DEACETYLATES SURROUNDING HISTONES AND ATTENUATES GENE ACTIVITY. ACCORDINGLY, LOCAL KNOCK-OUT OF HDAC1 IN STRIATUM ABOLISHES AMPHETAMINE-INDUCED DESENSITIZATION OF THE C-FOS GENE. IN CONCERT, CHRONIC AMPHETAMINE INCREASES HISTONE H3 METHYLATION ON THE C-FOS PROMOTER, A CHROMATIN MODIFICATION ALSO KNOWN TO REPRESS GENE ACTIVITY, AS WELL AS EXPRESSION LEVELS OF THE H3 HISTONE METHYLTRANSFERASE, KMT1A (LYSINE METHYLTRANSFERASE 1A, FORMERLY SUV39H1). THIS STUDY REVEALS A NOVEL EPIGENETIC PATHWAY THROUGH WHICH DELTAFOSB MEDIATES DISTINCT TRANSCRIPTIONAL PROGRAMS THAT MAY ULTIMATELY ALTER BEHAVIORAL PLASTICITY TO CHRONIC AMPHETAMINE EXPOSURE. 2008 3 231 25 ADAPTIVE CARDIORESPIRATORY CHANGES TO CHRONIC CONTINUOUS AND INTERMITTENT HYPOXIA. THIS CHAPTER REVIEWS CARDIORESPIRATORY ADAPTATIONS TO CHRONIC HYPOXIA (CH) EXPERIENCED AT HIGH ALTITUDE AND CARDIORESPIRATORY PATHOLOGIES ELICITED BY CHRONIC INTERMITTENT HYPOXIA (CIH) OCCURRING WITH OBSTRUCTIVE SLEEP APNEA (OSA). SHORT-TERM CH INCREASES BREATHING (VENTILATORY ACCLIMATIZATION TO HYPOXIA) AND BLOOD PRESSURE (BP) THROUGH CAROTID BODY (CB) CHEMO REFLEX. HYPERPLASIA OF GLOMUS CELLS, ALTERATIONS IN ION CHANNELS, AND RECRUITMENT OF ADDITIONAL EXCITATORY MOLECULES ARE IMPLICATED IN THE HEIGHTENED CB CHEMO REFLEX BY CH. TRANSCRIPTIONAL ACTIVATION OF HYPOXIA-INDUCIBLE FACTORS (HIF-1 AND 2) IS A MAJOR MOLECULAR MECHANISM UNDERLYING RESPIRATORY ADAPTATIONS TO SHORT-TERM CH. HIGH-ALTITUDE NATIVES EXPERIENCING LONG-TERM CH EXHIBIT BLUNTED HYPOXIC VENTILATORY RESPONSE (HVR) AND REDUCED BP DUE TO DESENSITIZATION OF CB RESPONSE TO HYPOXIA AND IMPAIRED PROCESSING OF CB SENSORY INFORMATION AT THE CENTRAL NERVOUS SYSTEM. VENTILATORY CHANGES EVOKED BY LONG-TERM CH ARE NOT READILY REVERSED AFTER RETURN TO SEA LEVEL. OSA PATIENTS AND RODENTS SUBJECTED TO CIH EXHIBIT HEIGHTENED CB CHEMO REFLEX, INCREASED HYPOXIC VENTILATORY RESPONSE, AND HYPERTENSION. INCREASED GENERATION OF REACTIVE OXYGEN SPECIES (ROS) IS A MAJOR CELLULAR MECHANISM UNDERLYING CIH-INDUCED ENHANCED CB CHEMO REFLEX AND THE ENSUING CARDIORESPIRATORY PATHOLOGIES. ROS GENERATION BY CIH IS MEDIATED BY NONTRANSCRIPTIONAL, DISRUPTED HIF-1 AND HIF-2-DEPENDENT TRANSCRIPTIONS AS WELL AS EPIGENETIC MECHANISMS. 2022 4 4304 23 MICRORNA-223 PROTECTS NEURONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. MULTIPLE SCLEROSIS IS A CHRONIC INFLAMMATORY, DEMYELINATING, AND NEURODEGENERATIVE DISEASE AFFECTING THE BRAIN, SPINAL CORD AND OPTIC NERVES. NEURONAL DAMAGE IS TRIGGERED BY VARIOUS HARMFUL FACTORS THAT ENGAGE DIVERSE SIGNALLING CASCADES IN NEURONS; THUS, THERAPEUTIC APPROACHES TO PROTECT NEURONS WILL NEED TO FOCUS ON AGENTS THAT CAN TARGET MULTIPLE BIOLOGICAL PROCESSES. WE HAVE THEREFORE FOCUSED OUR ATTENTION ON MICRORNAS: SMALL NON-CODING RNAS THAT PRIMARILY FUNCTION AS POST-TRANSCRIPTIONAL REGULATORS THAT TARGET MESSENGER RNAS AND REPRESS THEIR TRANSLATION INTO PROTEINS. A SINGLE MICRORNA CAN TARGET MANY FUNCTIONALLY RELATED MESSENGER RNAS MAKING MICRORNAS POWERFUL EPIGENETIC REGULATORS. DYSREGULATION OF MICRORNAS HAS BEEN DESCRIBED IN MANY NEURODEGENERATIVE DISEASES INCLUDING MULTIPLE SCLEROSIS. HERE, WE REPORT THAT TWO MICRORNAS, MIR-223-3P AND MIR-27A-3P, ARE UPREGULATED IN NEURONS IN THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS MOUSE MODEL OF CNS INFLAMMATION AND IN GREY MATTER-CONTAINING MULTIPLE SCLEROSIS LESIONS. PRIOR WORK HAS SHOWN PERIPHERAL BLOOD MONONUCLEAR CELL CONDITIONED MEDIA CAUSES SUBLETHAL DEGENERATION OF NEURONS IN CULTURE. WE FIND OVEREXPRESSION OF MIR-27A-3P OR MIR-223-3P PROTECTS DISSOCIATED CORTICAL NEURONS FROM CONDITION MEDIA MEDIATED DEGENERATION. INTRODUCTION OF MIR-223-3P IN VIVO IN MOUSE RETINAL GANGLION CELLS PROTECTS THEIR AXONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. IN SILICO ANALYSIS REVEALED THAT MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING ARE ENRICHED AS MIR-27A-3P AND MIR-223-3P TARGETS. WE OBSERVE THAT ANTAGONISM OF NMDA AND AMPA TYPE GLUTAMATE RECEPTORS PROTECTS NEURONS FROM CONDITION MEDIA DEPENDENT DEGENERATION. OUR RESULTS SUGGEST THAT MIR-223-3P AND MIR-27A-3P ARE UPREGULATED IN RESPONSE TO INFLAMMATION TO MEDIATE A COMPENSATORY NEUROPROTECTIVE GENE EXPRESSION PROGRAM THAT DESENSITIZES NEURONS TO GLUTAMATE BY TARGETING MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING. 2019 5 6617 23 UNDERPINNING THE NEUROBIOLOGICAL INTRICACIES ASSOCIATED WITH OPIOID TOLERANCE. THE OPIOID CRISIS IS A MAJOR THREAT OF THE 21ST CENTURY, WITH A REMARKABLE JUXTAPOSITION OF USE AND ABUSE. OPIOIDS ARE THE MOST POTENT AND EFFICACIOUS CLASS OF ANALGESICS, BUT DESPITE THEIR PROVEN THERAPEUTIC EFFICACY, THEY HAVE RECENTLY BEEN DEGRADED TO THIRD-LINE THERAPY FOR THE MANAGEMENT OF CHRONIC PAIN IN CLINICS. THE REASON BEHIND THIS IS THE DEVELOPMENT OF POTENTIAL SIDE EFFECTS AND TOLERANCE AFTER REPEATED DOSING. OPIOID TOLERANCE IS THE MAJOR LIMITING FACTOR LEADING TO THE WITHDRAWAL OF TREATMENT, SEVERE SIDE EFFECTS DUE TO DOSE ESCALATION, AND SOMETIMES EVEN DEATH OF THE PATIENTS. EVERY DAY MORE THAN 90 PEOPLE DIE DUE TO OPIOIDS OVERDOSE IN AMERICA, AND A SIMILAR TREND HAS BEEN SEEN ACROSS THE GLOBE. OVER THE PAST TWO DECADES, RESEARCHERS HAVE BEEN TRYING TO DISSECT THE NEUROBIOLOGICAL MECHANISM OF OPIOID TOLERANCE. RESEARCH ON OPIOID TOLERANCE SHIFTED TOWARD CENTRAL NERVOUS SYSTEM-BASED ADAPTATIONS BECAUSE TOLERANCE IS MUCH MORE THAN JUST A CELLULAR PHENOMENON. THUS, NEUROBIOLOGICAL ADAPTATIONS ASSOCIATED WITH OPIOID TOLERANCE ARE IMPORTANT TO UNDERSTAND IN ORDER TO FIND NEWER PAIN THERAPEUTICS. THESE ADAPTATIONS ARE ASSOCIATED WITH ALTERATIONS IN ASCENDING AND DESCENDING PAIN PATHWAYS, REWARD CIRCUITRY MODULATIONS, RECEPTOR DESENSITIZATION AND DOWN-REGULATION, RECEPTOR INTERNALIZATION, HETERODIMERIZATION, AND ALTERED EPIGENETIC REGULATION. THE PRESENT REVIEW IS FOCUSED ON NOVEL CIRCUITRIES ASSOCIATED WITH OPIOID TOLERANCE IN DIFFERENT AREAS OF THE BRAIN, SUCH AS PERIAQUEDUCTAL GRAY, ROSTRAL VENTROMEDIAL MEDULLA, DORSAL RAPHE NUCLEUS, VENTRAL TEGMENTAL AREA, AND NUCLEUS ACCUMBENS. UNDERSTANDING THE NEUROBIOLOGICAL MODULATIONS ASSOCIATED WITH CHRONIC OPIOID EXPOSURE AND TOLERANCE WILL PAVE THE WAY FOR THE DEVELOPMENT OF NOVEL PHARMACOLOGICAL TOOLS FOR SAFER AND BETTER MANAGEMENT OF CHRONIC PAIN IN PATIENTS. 2020 6 1694 21 DUST MITE ALLERGEN-SPECIFIC IMMUNOTHERAPY INCREASES IL4 DNA METHYLATION AND INDUCES DER P-SPECIFIC T CELL TOLERANCE IN CHILDREN WITH ALLERGIC ASTHMA. ALLERGEN-SPECIFIC IMMUNOTHERAPY (ALLERGEN-SIT) IS A HIGHLY EFFECTIVE TREATMENT FOR CHILDREN WITH ALLERGIC ASTHMA (AA), AN IMMUNE-MEDIATED CHRONIC DISEASE LEADING TO BRONCHIAL MUSCLE HYPERTROPHY AND AIRWAY OBSTRUCTION IN RESPONSE TO SPECIFIC ALLERGENS. T HELPER CELLS AND SECRETED CYTOKINES PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF ASTHMA, AND EPIGENETIC MODULATION CONTROLS GENES IMPORTANT FOR T CELL DEVELOPMENT AND CYTOKINE EXPRESSION. THIS STUDY EVALUATED T HELPER CELL-SECRETED CYTOKINES AND DNA METHYLATION PATTERNS IN CHILDREN TREATED WITH DERMATOPHAGOIDES PTERONYSSINUS (DER P) ALLERGEN-SIT. OUR RESULTS SHOWED THAT AFTER DER P CHALLENGE, PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM THE SIT GROUP, COMPARED WITH THE NON-SIT AA GROUP, PRODUCED LOWER LEVELS OF IL-4, IL-5 AND IL-2. THE SIT GROUP, COMPARED WITH THE AA GROUP, EXHIBITED DECREASED SENSITIVITY TO THE DER P ALLERGEN, CONCURRENT WITH IL-4 DOWN-MODULATION DUE TO INCREASED PROMOTER DNA METHYLATION, AS ESTIMATED IN PBMCS. OUR RESULTS SHOWED THAT SIT DECREASED IL-4 AND IL-5, AND INHIBITED T CELL PROLIFERATION, BY INHIBITING IL-2 PRODUCTION AFTER THE SPECIFIC ALLERGEN CHALLENGE. THESE RESULTS SUGGEST THAT DECREASED IL-2 PRODUCTION AND INCREASED IL-4 CYTOKINE PROMOTER METHYLATION IS A POTENTIAL MECHANISM OF DER P-SPECIFIC ALLERGEN DESENSITIZATION IMMUNOTHERAPY. 2018 7 3406 26 HOW THE IMMUNE SYSTEM RESPONDS TO ALLERGY IMMUNOTHERAPY. IGE-MEDIATED DISEASES REPRESENT A HIGHLY DIVERSIFIED AND MULTIFACTORIAL GROUP OF DISORDERS THAT CAN DEEPLY IMPACT THE PATIENTS' QUALITY OF LIFE. CURRENTLY, ALLERGY IMMUNOTHERAPY (AIT) STILL REMAINS THE GOLD STANDARD FOR THE MANAGEMENT OF SUCH PATHOLOGIES. IN THIS REVIEW, WE COMPREHENSIVELY EXAMINE AND DISCUSS HOW AIT CAN AFFECT BOTH THE INNATE AND THE ADAPTIVE IMMUNE RESPONSES AT DIFFERENT CELL LEVELS AND PROPOSE TIMING-SCHEDULED ALTERATIONS INDUCED BY AIT BY HYPOTHESIZING FIVE SEQUENTIAL PHASES: AFTER THE DESENSITIZATION OF EFFECTOR NON-LYMPHOID CELLS AND A TRANSIENT INCREASE OF IGE (PHASE 1), HIGH DOSES OF ALLERGEN GIVEN BY AIT STIMULATE THE SHIFT FROM TYPE 2/TYPE 3 TOWARDS TYPE 1 RESPONSE (PHASE 2), WHICH IS PROGRESSIVELY POTENTIATED BY THE INCREASE OF IFN-GAMMA THAT PROMOTES THE CHRONIC ACTIVATION OF APCS, PROGRESSIVELY LEADING TO THE HYPEREXPRESSION OF NOTCH1L (DELTA4) AND THE SECRETION OF IL-12 AND IL-27, WHICH ARE ESSENTIAL TO ACTIVATE IL-10 GENE IN TH1 AND ILC1 CELLS. AS CONSEQUENCE, AN EXPANSION OF CIRCULATING MEMORY TH1/TR1 CELLS AND ILC-REG CHARACTERIZES THE THIRD PHASE ADDRESSED TO ANTAGONIZE/BALANCE THE EXCESS OF TYPE 1 RESPONSE (PHASE 3). THE PROGRESSIVE INCREASE OF IL-10 TRIGGERS A NUMBER OF REGULATORY CIRCUITS SUSTAINED BY INNATE AND ADAPTIVE IMMUNE CELLS AND FAVORING T-CELL TOLERANCE (PHASE 4), WHICH MAY ALSO BE MAINTAINED FOR A LONG PERIOD AFTER AIT INTERRUPTION (PHASE 5). DIFFERENT ADMINISTRATION APPROACHES OF AIT HAVE SHOWN A SIMILAR TAILORING OF THE IMMUNE RESPONSES AND CAN BE MONITORED BY TIMELY, OPTIMIZED BIOMARKERS. THE CLINICAL FAILURE OF THIS TREATMENT CAN OCCUR, AND MANY GENETIC/EPIGENETIC POLYMORPHISMS/MUTATIONS INVOLVING SEVERAL IMMUNOLOGICAL MECHANISMS, SUCH AS THE PLASTICITY OF IMMUNE RESPONSES AND THE INDUCTION/MAINTENANCE OF REGULATORY CIRCUITS, HAVE BEEN DESCRIBED. THE KNOWLEDGE OF HOW AIT CAN SHAPE THE IMMUNE SYSTEM AND ITS RESPONSES IS A KEY TOOL TO DEVELOP NOVEL AIT STRATEGIES INCLUDING THE ENGINEERING OF ALLERGEN OR THEIR EPITOPES. WE NOW HAVE THE POTENTIAL TO UNDERSTAND THE PRECISE CAUSES OF AIT FAILURE AND TO ESTABLISH THE BEST BIOMARKERS OF AIT EFFICACY IN EACH PHASE OF THE TREATMENT. 2022 8 598 23 BETA-ADRENERGIC SIGNALING PROMOTES TUMOR ANGIOGENESIS AND PROSTATE CANCER PROGRESSION THROUGH HDAC2-MEDIATED SUPPRESSION OF THROMBOSPONDIN-1. CHRONIC BEHAVIORAL STRESS AND BETA-ADRENERGIC SIGNALING HAVE BEEN SHOWN TO PROMOTE CANCER PROGRESSION, WHOSE UNDERLYING MECHANISMS ARE LARGELY UNCLEAR, ESPECIALLY THE INVOLVEMENT OF EPIGENETIC REGULATION. HISTONE DEACETYLASE-2 (HDAC2), AN EPIGENETIC REGULATOR, IS CRITICAL FOR STRESS-INDUCED CARDIAC HYPERTROPHY. IT IS UNKNOWN WHETHER IT IS NECESSARY FOR BETA-ADRENERGIC SIGNALING-PROMOTED CANCER PROGRESSION. USING XENOGRAFT MODELS, WE SHOWED THAT CHRONIC BEHAVIORAL STRESS AND BETA-ADRENERGIC SIGNALING PROMOTE ANGIOGENESIS AND PROSTATE CANCER PROGRESSION. HDAC2 WAS INDUCED BY BETA-ADRENERGIC SIGNALING IN VITRO AND IN MOUSE XENOGRAFTS. WE NEXT UNCOVERED THAT HDAC2 IS A DIRECT TARGET OF CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB) THAT IS ACTIVATED BY BETA-ADRENERGIC SIGNALING. NOTABLY, HDAC2 IS NECESSARY FOR BETA-ADRENERGIC SIGNALING TO INDUCE ANGIOGENESIS. WE FURTHER DEMONSTRATED THAT, UPON CREB ACTIVATION, HDAC2 REPRESSES THROMBOSPONDIN-1 (TSP1), A POTENT ANGIOGENESIS INHIBITOR, THROUGH EPIGENETIC REGULATION. TOGETHER, THESE DATA ESTABLISH A NOVEL PATHWAY THAT HDAC2 AND TSP1 ACT DOWNSTREAM OF CREB ACTIVATION IN BETA-ADRENERGIC SIGNALING TO PROMOTE CANCER PROGRESSION. 2017 9 1647 28 DOES THE STRESS OF LABORATORY LIFE AND EXPERIMENTATION ON ANIMALS ADVERSELY AFFECT RESEARCH DATA? A CRITICAL REVIEW. RECURRENT ACUTE AND/OR CHRONIC STRESS CAN AFFECT ALL VERTEBRATE SPECIES, AND CAN HAVE SERIOUS CONSEQUENCES. IT IS INCREASINGLY AND WIDELY APPRECIATED THAT LABORATORY ANIMALS EXPERIENCE SIGNIFICANT AND REPEATED STRESS, WHICH IS UNAVOIDABLE AND IS CAUSED BY MANY ASPECTS OF LABORATORY LIFE, SUCH AS CAPTIVITY, TRANSPORT, NOISE, HANDLING, RESTRAINT AND OTHER PROCEDURES, AS WELL AS THE EXPERIMENTAL PROCEDURES APPLIED TO THEM. SUCH STRESS IS DIFFICULT TO MITIGATE, AND LACK OF SIGNIFICANT DESENSITISATION/HABITUATION CAN RESULT IN CONSIDERABLE PSYCHOLOGICAL AND PHYSIOLOGICAL WELFARE PROBLEMS, WHICH ARE MEDIATED BY THE ACTIVATION OF VARIOUS NEUROENDOCRINE NETWORKS THAT HAVE NUMEROUS AND PERVASIVE EFFECTS. PSYCHOLOGICAL DAMAGE CAN BE REFLECTED IN STEREOTYPICAL BEHAVIOURS, INCLUDING REPETITIVE PACING AND CIRCLING, AND EVEN SELF-HARM. PHYSICAL CONSEQUENCES INCLUDE ADVERSE EFFECTS ON IMMUNE FUNCTION, INFLAMMATORY RESPONSES, METABOLISM, AND DISEASE SUSCEPTIBILITY AND PROGRESSION. FURTHER, SOME OF THESE EFFECTS ARE EPIGENETIC, AND ARE THEREFORE POTENTIALLY TRANSGENERATIONAL: THE BIOLOGY OF ANIMALS WHOSE PARENTS/GRANDPARENTS WERE WILD-CAUGHT AND/OR HAVE EXPERIENCED CHRONIC STRESS IN LABORATORIES COULD BE ALTERED, AS COMPARED TO FREE-LIVING INDIVIDUALS. IT IS ARGUED THAT THESE EFFECTS MUST HAVE CONSEQUENCES FOR THE RELIABILITY OF EXPERIMENTAL DATA AND THEIR EXTRAPOLATION TO HUMANS, AND THIS MAY NOT BE RECOGNISED SUFFICIENTLY AMONG THOSE WHO USE ANIMALS IN EXPERIMENTS. 2018 10 2773 33 EXTRACELLULAR SIGNAL-REGULATED PROTEIN KINASES 1 AND 2 ACTIVATION BY ADDICTIVE DRUGS: A SIGNAL TOWARD PATHOLOGICAL ADAPTATION. ADDICTION IS A CHRONIC AND RELAPSING PSYCHIATRIC DISORDER THAT IS THOUGHT TO OCCUR IN VULNERABLE INDIVIDUALS. SYNAPTIC PLASTICITY EVOKED BY DRUGS OF ABUSE IN THE SO-CALLED NEURONAL CIRCUITS OF REWARD HAS BEEN PROPOSED TO UNDERLIE BEHAVIORAL ADAPTATIONS THAT CHARACTERIZE ADDICTION. BY INCREASING DOPAMINE IN THE STRIATUM, ADDICTIVE DRUGS ALTER THE BALANCE OF DOPAMINE AND GLUTAMATE SIGNALS CONVERGING ONTO STRIATAL MEDIUM-SIZED SPINY NEURONS (MSNS) AND ACTIVATE INTRACELLULAR EVENTS INVOLVED IN LONG-TERM BEHAVIORAL ALTERATIONS. OUR LABORATORY CONTRIBUTED TO THE IDENTIFICATION OF SALIENT MOLECULAR CHANGES INDUCED BY ADMINISTRATION OF ADDICTIVE DRUGS TO RODENTS. WE PIONEERED THE OBSERVATION THAT A COMMON FEATURE OF ADDICTIVE DRUGS IS TO ACTIVATE, BY A DOUBLE TYROSINE/THREONINE PHOSPHORYLATION, THE EXTRACELLULAR SIGNAL-REGULATED KINASES 1 AND 2 (ERK1/2) IN THE STRIATUM, WHICH CONTROL A PLETHORA OF SUBSTRATES, SOME OF THEM BEING CRITICALLY INVOLVED IN COCAINE-MEDIATED MOLECULAR AND BEHAVIORAL ADAPTATIONS. HEREIN, WE REVIEW HOW THE INTERPLAY BETWEEN DOPAMINE AND GLUTAMATE SIGNALING CONTROLS COCAINE-INDUCED ERK1/2 ACTIVATION IN MSNS. WE EMPHASIZE THE KEY ROLE OF N-METHYL-D-ASPARTATE RECEPTOR POTENTIATION BY D1 RECEPTOR TO TRIGGER ERK1/2 ACTIVATION AND ITS SUBSEQUENT NUCLEAR TRANSLOCATION WHERE IT MODULATES BOTH EPIGENETIC AND GENETIC PROCESSES ENGAGED BY COCAINE. WE DISCUSS HOW COCAINE-INDUCED LONG-TERM SYNAPTIC AND STRUCTURAL PLASTICITY OF MSNS, AS WELL AS BEHAVIORAL ADAPTATIONS, ARE INFLUENCED BY ERK1/2-CONTROLLED TARGETS. WE CONCLUDE THAT A BETTER KNOWLEDGE OF MOLECULAR MECHANISMS UNDERLYING ERK1/2 ACTIVATION BY DRUGS OF ABUSE AND/OR ITS ROLE IN LONG-TERM NEURONAL PLASTICITY IN THE STRIATUM MAY PROVIDE A NEW ROUTE FOR THERAPEUTIC TREATMENT IN ADDICTION. 2014 11 4138 29 MECHANISMS OF MICROGLIAL ACTIVATION IN MODELS OF INFLAMMATION AND HYPOXIA: IMPLICATIONS FOR CHRONIC INTERMITTENT HYPOXIA. CHRONIC INTERMITTENT HYPOXIA (CIH) IS A HALLMARK OF SLEEP APNOEA, A CONDITION ASSOCIATED WITH DIVERSE CLINICAL DISORDERS. CIH AND SLEEP APNOEA ARE CHARACTERIZED BY INCREASED REACTIVE OXYGEN SPECIES FORMATION, PERIPHERAL AND CNS INFLAMMATION, NEURONAL DEATH AND NEUROCOGNITIVE DEFICITS. FEW STUDIES HAVE EXAMINED THE ROLE OF MICROGLIA, THE RESIDENT CNS IMMUNE CELLS, IN MODELS OF CIH. THUS, LITTLE IS KNOWN CONCERNING THEIR DIRECT CONTRIBUTIONS TO NEUROPATHOLOGY OR THE CELLULAR MECHANISMS REGULATING THEIR ACTIVITIES DURING OR FOLLOWING PATHOLOGICAL CIH. IN THIS REVIEW, WE IDENTIFY GAPS IN KNOWLEDGE REGARDING CIH-INDUCED MICROGLIAL ACTIVATION, AND PROPOSE MECHANISMS BASED ON DATA FROM RELATED MODELS OF HYPOXIA AND/OR HYPOXIA-REOXYGENATION. CIH MAY DIRECTLY AFFECT MICROGLIA, OR MAY HAVE INDIRECT EFFECTS VIA THE PERIPHERY OR OTHER CNS CELLS. PERIPHERAL INFLAMMATION MAY INDIRECTLY ACTIVATE MICROGLIA VIA ENTRY OF PRO-INFLAMMATORY MOLECULES INTO THE CNS, AND/OR ACTIVATION OF VAGAL AFFERENTS THAT TRIGGER CNS INFLAMMATION. CIH-INDUCED RELEASE OF DAMAGE-ASSOCIATED MOLECULAR PATTERNS FROM INJURED CNS CELLS MAY ALSO ACTIVATE MICROGLIA VIA INTERACTIONS WITH PATTERN RECOGNITION RECEPTORS EXPRESSED ON MICROGLIA. FOR EXAMPLE, TOLL-LIKE RECEPTORS ACTIVATE MITOGEN-ACTIVATED PROTEIN KINASE/TRANSCRIPTION FACTOR PATHWAYS REQUIRED FOR MICROGLIAL INFLAMMATORY GENE EXPRESSION. ALTHOUGH EPIGENETIC EFFECTS FROM CIH HAVE NOT YET BEEN STUDIED IN MICROGLIA, POTENTIAL EPIGENETIC MECHANISMS IN MICROGLIAL REGULATION ARE DISCUSSED, INCLUDING MICRORNAS, HISTONE MODIFICATIONS AND DNA METHYLATION. EPIGENETIC EFFECTS CAN OCCUR DURING CIH, OR LONG AFTER IT HAS ENDED. A BETTER UNDERSTANDING OF CIH EFFECTS ON MICROGLIAL ACTIVITIES MAY BE IMPORTANT TO REVERSE CIH-INDUCED NEUROPATHOLOGY IN PATIENTS WITH SLEEP DISORDERED BREATHING. 2016 12 3382 23 HMDB AND 5-AZADC COMBINATION REVERSES TUMOR SUPPRESSOR CCAAT/ENHANCER-BINDING PROTEIN DELTA TO STRENGTHEN THE DEATH OF LIVER CANCER CELLS. HEPATOCELLULAR CARCINOMA (HCC) CAN ARISE FROM CHRONIC INFLAMMATION DUE TO VIRAL INFECTION, ORGAN DAMAGE, DRUG TOXICITY, OR ALCOHOL ABUSE. MOREOVER, GENE DESENSITIZATION VIA ABERRANT CPG ISLAND METHYLATION IS A FREQUENT EPIGENETIC DEFECT IN HCC. HOWEVER, THE DETAILS OF HOW INFLAMMATION IS LINKED WITH EPIGENETIC-MEDIATED DESENSITIZATION OF TUMOR SUPPRESSOR GENES REMAINS LESS INVESTIGATED. IN THIS STUDY, WE FOUND THAT LOSS OF CEBPD ENHANCES THE GROWTH OF LIVER CANCER CELLS AND IS ASSOCIATED WITH THE OCCURRENCE OF LIVER CANCERS, AS DETERMINED BY THE ASSESSMENT OF CLINICAL SPECIMENS AND IN VIVO ANIMAL MODELS. MOREOVER, E2F1-REGULATED EPIGENETIC AXIS ATTENUATED CEBPD EXPRESSION IN LIVER CANCER CELLS. CEBPD IS RESPONSIVE TO THE HYDROXYMETHYLDIBENZOYLMETHANE (HMDB)-INDUCED P38/CREB PATHWAY AND PLAYS AN IMPORTANT ROLE IN THE HMDB-INDUCED APOPTOSIS OF CANCER CELLS. REGARDING DEPRESSION OF EPIGENETIC EFFECTS TO ENHANCE HMDB-INDUCED CEBPD EXPRESSION, THE COMBINATION OF HMDB AND 5-AZA-2'-DEOXYCYTIDINE (5-AZADC) COULD ENHANCE THE DEATH OF LIVER CANCER CELLS AND REDUCE THE TUMOR FORMATION OF HUH7 XENOGRAFT MICE. IN CONCLUSION, THESE RESULTS SUGGEST THAT CEBPD COULD BE A USEFUL DIAGNOSTIC MARKER AND THERAPEUTIC TARGET IN HCC. THE RESULTS ALSO REVEAL THE THERAPEUTIC POTENTIAL FOR LOW-DOSE 5-AZADC TO ENHANCE THE HMDB-INDUCED DEATH OF HCC CELLS. 2015 13 2023 20 EPIGENETIC CHANGES BY DNA METHYLATION IN CHRONIC AND INTERMITTENT HYPOXIA. DNA METHYLATION OF CYTOSINE RESIDUES IS A WELL-STUDIED EPIGENETIC CHANGE, WHICH REGULATES GENE TRANSCRIPTION BY ALTERING ACCESSIBILITY FOR TRANSCRIPTION FACTORS. HYPOXIA IS A PERVASIVE STIMULUS THAT AFFECTS MANY PHYSIOLOGICAL PROCESSES. THE CIRCULATORY AND RESPIRATORY SYSTEMS ADAPT TO CHRONIC SUSTAINED HYPOXIA, SUCH AS THAT ENCOUNTERED DURING A HIGH-ALTITUDE SOJOURN. MANY PEOPLE LIVING AT SEA LEVEL EXPERIENCE CHRONIC INTERMITTENT HYPOXIA (IH) DUE TO SLEEP APNEA, WHICH LEADS TO CARDIOVASCULAR AND RESPIRATORY MALADAPTATION. THIS ARTICLE PRESENTS A BRIEF UPDATE ON EMERGING EVIDENCE SUGGESTING THAT CHANGES IN DNA METHYLATION CONTRIBUTE TO PATHOLOGIES CAUSED BY CHRONIC IH AND POTENTIALLY MEDIATE ADAPTATIONS TO CHRONIC SUSTAINED HYPOXIA BY AFFECTING THE HYPOXIA-INDUCIBLE FACTOR (HIF) SIGNALING PATHWAY. 2017 14 1177 25 CONTROL OF BREATHING AND THE CIRCULATION IN HIGH-ALTITUDE MAMMALS AND BIRDS. HYPOXIA IS AN UNREMITTING STRESSOR AT HIGH ALTITUDES THAT PLACES A PREMIUM ON OXYGEN TRANSPORT BY THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS. PHENOTYPIC PLASTICITY AND GENOTYPIC ADAPTATION AT VARIOUS STEPS IN THE O2 CASCADE COULD HELP OFFSET THE EFFECTS OF HYPOXIA ON CELLULAR O2 SUPPLY IN HIGH-ALTITUDE NATIVES. IN THIS REVIEW, WE WILL DISCUSS THE UNIQUE MECHANISMS BY WHICH VENTILATION, CARDIAC OUTPUT, AND BLOOD FLOW ARE CONTROLLED IN HIGH-ALTITUDE MAMMALS AND BIRDS. ACCLIMATIZATION TO HIGH ALTITUDES LEADS TO SOME CHANGES IN RESPIRATORY AND CARDIOVASCULAR CONTROL THAT INCREASE O2 TRANSPORT IN HYPOXIA (E.G., VENTILATORY ACCLIMATIZATION TO HYPOXIA). HOWEVER, ACCLIMATIZATION OR DEVELOPMENT IN HYPOXIA CAN ALSO MODIFY CARDIORESPIRATORY CONTROL IN WAYS THAT ARE MALADAPTIVE FOR O2 TRANSPORT. HYPOXIA RESPONSES THAT AROSE AS SHORT-TERM SOLUTIONS TO O2 DEPRIVATION (E.G., PERIPHERAL VASOCONSTRICTION) OR REGIONAL VARIATION IN O2 LEVELS IN THE LUNGS (I.E., HYPOXIC PULMONARY VASOCONSTRICTION) ARE DETRIMENTAL AT IN CHRONIC HIGH-ALTITUDE HYPOXIA. EVOLVED CHANGES IN CARDIORESPIRATORY CONTROL HAVE ARISEN IN MANY HIGH-ALTITUDE TAXA, INCLUDING INCREASES IN EFFECTIVE VENTILATION, ATTENUATION OF HYPOXIC PULMONARY VASOCONSTRICTION, AND CHANGES IN CATECHOLAMINE SENSITIVITY OF THE HEART AND SYSTEMIC VASCULATURE. PARALLEL EVOLUTION OF SOME OF THESE CHANGES IN INDEPENDENT HIGHLAND LINEAGES SUPPORTS THEIR ADAPTIVE SIGNIFICANCE. MUCH LESS IS KNOWN ABOUT THE GENOMIC BASES AND POTENTIAL INTERACTIVE EFFECTS OF ADAPTATION, ACCLIMATIZATION, DEVELOPMENTAL PLASTICITY, AND TRANS-GENERATIONAL EPIGENETIC TRANSFER ON CARDIORESPIRATORY CONTROL. FUTURE WORK TO UNDERSTAND THESE VARIOUS INFLUENCES ON BREATHING AND CIRCULATION IN HIGH-ALTITUDE NATIVES WILL HELP ELUCIDATE HOW COMPLEX PHYSIOLOGICAL SYSTEMS CAN BE PUSHED TO THEIR LIMITS TO MAINTAIN CELLULAR FUNCTION IN HYPOXIA. 2015 15 6389 31 THE ROLE OF THE ENDOCANNABINOID SYSTEM IN THE BRAIN-GUT AXIS. THE ACTIONS OF CANNABIS ARE MEDIATED BY RECEPTORS THAT ARE PART OF AN ENDOGENOUS CANNABINOID SYSTEM. THE ENDOCANNABINOID SYSTEM (ECS) CONSISTS OF THE NATURALLY OCCURRING LIGANDS N-ARACHIDONOYLETHANOLAMINE (ANANDAMIDE) AND 2-ARACHIDONOYLGLYCEROL (2-AG), THEIR BIOSYNTHETIC AND DEGRADATIVE ENZYMES, AND THE CANNABINOID (CB) RECEPTORS CB1 AND CB2. THE ECS IS A WIDELY DISTRIBUTED TRANSMITTER SYSTEM THAT CONTROLS GUT FUNCTIONS PERIPHERALLY AND CENTRALLY. IT IS AN IMPORTANT PHYSIOLOGIC REGULATOR OF GASTROINTESTINAL MOTILITY. POLYMORPHISMS IN THE GENE ENCODING CB1 (CNR1) HAVE BEEN ASSOCIATED WITH SOME FORMS OF IRRITABLE BOWEL SYNDROME. THE ECS IS INVOLVED IN THE CONTROL OF NAUSEA AND VOMITING AND VISCERAL SENSATION. THE HOMEOSTATIC ROLE OF THE ECS ALSO EXTENDS TO THE CONTROL OF INTESTINAL INFLAMMATION. WE REVIEW THE MECHANISMS BY WHICH THE ECS LINKS STRESS AND VISCERAL PAIN. CB1 IN SENSORY GANGLIA CONTROLS VISCERAL SENSATION, AND TRANSCRIPTION OF CNR1 IS MODIFIED THROUGH EPIGENETIC PROCESSES UNDER CONDITIONS OF CHRONIC STRESS. THESE PROCESSES MIGHT LINK STRESS WITH ABDOMINAL PAIN. THE ECS IS ALSO INVOLVED CENTRALLY IN THE MANIFESTATION OF STRESS, AND ENDOCANNABINOID SIGNALING REDUCES THE ACTIVITY OF HYPOTHALAMIC-PITUITARY-ADRENAL PATHWAYS VIA ACTIONS IN SPECIFIC BRAIN REGIONS, NOTABLY THE PREFRONTAL CORTEX, AMYGDALA, AND HYPOTHALAMUS. AGENTS THAT MODULATE THE ECS ARE IN EARLY STAGES OF DEVELOPMENT FOR TREATMENT OF GASTROINTESTINAL DISEASES. INCREASING OUR UNDERSTANDING OF THE ECS WILL GREATLY ADVANCE OUR KNOWLEDGE OF INTERACTIONS BETWEEN THE BRAIN AND GUT AND COULD LEAD TO NEW TREATMENTS FOR GASTROINTESTINAL DISORDERS. 2016 16 6104 27 THE EMERGING ROLE OF HISTONE DEACETYLASE 1 IN ALLERGIC DISEASES. HISTONE DEACETYLASE 1 (HDAC1) IS A UNIQUE MEMBER OF THE CLASSES I HDACS AND HELPS TO REGULATE ACUTE AND CHRONIC ADAPTATION TO ENVIRONMENTAL STIMULI SUCH AS ALLERGEN, STRESS. ALLERGIC DISEASES ARE COMPLEX DISEASES RESULTING FROM THE EFFECT OF MULTIPLE GENETIC AND INTERACTING FOREIGN SUBSTANCES. EPIGENETICS PLAY AN IMPORTANT ROLE IN BOTH PATHOLOGICAL AND IMMUNOMODULATORY CONDITIONS OF ALLERGIC DISEASES. TO BE CONSISTENT WITH THIS ROLE, RECENT EVIDENCE STRONGLY SUGGESTS THAT HISTONE DEACETYLASE 1 (HDAC1) PLAYS A CRITICAL ROLE IN ALLERGIC RESPONSE. HDAC1 EXPRESSION IS STIMULATED BY ALLERGEN AND ATTRIBUTES TO INCREASE T HELPER 2 (TH2) CYTOKINE LEVELS, DECREASE TH1/TH17 CELLS AND ANTI-INFLAMMATORY CYTOKINE INTERLEUKIN-10 (IL-10), AND TWIK-RELATED POTASSIUM CHANNEL-1 (TREK-1) EXPRESSION. THIS REVIEW FOCUSES ON THE CONTRIBUTION OF HDAC1 AND THE REGULATORY ROLE IN CHARACTERIZING ALLERGIC ENDOTYPES WITH COMMON MOLECULAR PATHWAYS AND UNDERSTANDING ALLERGIC MULTIMORBIDITY RELATIONSHIPS, AS WELL AS ADDRESSING THEIR POTENTIAL AS THERAPEUTIC TARGETS FOR THESE CONDITIONS. 2022 17 4534 26 MULTIPLE REGULATIONS OF KEAP1/NRF2 SYSTEM BY DIETARY PHYTOCHEMICALS. KEAP1/NRF2 SYSTEM PLAYS A CRITICAL ROLE ON CELLULAR PROTECTION BY REGULATING MANY ANTIOXIDANT AND DETOXIFICATION ENZYME GENES THROUGH THE ANTIOXIDANT RESPONSE ELEMENT (ARE). THUS, IT MUST WORK CONSTANTLY TO PREVENT THE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) BECAUSE EXCESS ROS ARE ASSOCIATED WITH MANY DISEASES SUCH AS CANCER, CARDIOVASCULAR COMPLICATIONS, INFLAMMATION, AND NEURODEGENERATION. DIETARY PHYTOCHEMICALS WIDELY DISTRIBUTING IN FRUITS AND VEGETABLES HAVE BEEN CONSIDERED TO POSSESS CANCER CHEMOPREVENTIVE POTENTIAL THROUGH THE INDUCTION OF KEAP1/NRF2 SYSTEM-MEDIATED ANTIOXIDANT AND DETOXIFICATION ENZYMES IN A VARIETY OF MANNERS. THE DATA ARE EXTENSIVE AND ARE NOT WELL CLASSIFIED ON THE MOLECULAR MECHANISMS. IN THIS REVIEW, WE FIRST BRIEFLY INTRODUCE THE CURRENT KNOWLEDGE ON KEAP1/NRF2 SYSTEM REGULATION INCLUDING KEAP1-DEPENDENT AND KEAP1-INDEPENDENT CASCADES, AND EPIGENETIC PATHWAY. THEN, WE SUMMARIZE THE MOLECULAR TARGETS OF KEAP1/NRF2 SYSTEM BY DIETARY PHYTOCHEMICALS, AND FINALLY REVIEW THE CROSSTALK BETWEEN KEAP1/NRF2 SYSTEM AND OTHER CELLULAR SIGNALING PATHWAYS TO REGULATE DIVERSE CHRONIC DISEASES BY DIETARY PHYTOCHEMICALS. THESE COMPREHENSIVE DATA WILL HELP US TO UNDERSTAND THE POTENTIAL EFFECTS OF DIETARY PHYTOCHEMICALS ON THE PREVENTION OF CHRONIC DISEASES AND MAINTENANCE OF HUMAN HEALTH. 2016 18 602 27 BETTER UNDERSTANDING OF CHILDHOOD ASTHMA, TOWARDS PRIMARY PREVENTION - ARE WE THERE YET? CONSIDERATION OF PERTINENT LITERATURE. ASTHMA IS A CHRONIC DISEASE, CHARACTERIZED BY REVERSIBLE AIRWAY OBSTRUCTION, AIRWAY INFLAMMATION AND HYPER-REACTIVITY. THE PREVALENCE OF ASTHMA HAS RISEN DRAMATICALLY OVER THE PAST DECADE, AFFECTING AROUND 300,000,000 PEOPLE. THE ETIOLOGY IS MULTIFACTORIAL, WITH GENETIC, EPIGENETIC, DEVELOPMENTAL AND ENVIRONMENTAL FACTORS PLAYING A ROLE. A COMPLEX INTERACTION BETWEEN THE INTRAUTERINE ENVIRONMENT, THE DEVELOPING IMMUNE SYSTEM, THE INFANT'S MICROBIOME AND INFECTIOUS ORGANISMS MAY LEAD TO THE DEVELOPMENT OF ALLERGIC SENSITIZATION AND ASTHMA. THUS, A LARGE NUMBER OF STUDIES HAVE INVESTIGATED THE RISK FACTORS FOR CHILDHOOD ASTHMA, WITH A METICULOUS SEARCH OF MODIFIABLE FACTORS THAT COULD AID IN PRIMARY PREVENTION. WE PRESENT A CURRENT LITERATURE REVIEW FROM 2014-2017, AS WELL AS OLDER CLASSIC PUBLICATIONS, ON THE PATHOGENESIS AND THE POTENTIAL MODIFIABLE FACTORS FOR PRIMARY PREVENTION OF ASTHMA. NO IDEAL PREVENTIVE MEASURE HAS YET BEEN FOUND. RATHER, CREATING FAVORABLE PRENATAL AND POSTNATAL ENVIRONMENTS, MINIMAL EXPOSURE TO HOSTILE ENVIRONMENTAL FACTORS, PREVENTION OF INFECTIONS IN EARLY LIFE, ALLERGIC DESENSITIZATION AND NUTRITIONAL MODIFICATIONS COULD POSSIBLY REDUCE ASTHMA INCEPTION. IN THE ERA OF PERSONALIZED MEDICINE, IDENTIFYING INDIVIDUAL RISK FACTORS AND TAILORING SPECIFIC PREVENTIVE MEASURES IS WARRANTED. 2017 19 2339 27 EPIGENETIC REGULATION OF KEAP1-NRF2 SIGNALING. THE KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (KEAP1)-NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) SIGNALING AXIS SERVES AS A "MASTER REGULATOR" IN RESPONSE TO OXIDATIVE/ELECTROPHILIC STRESSES AND CHEMICAL INSULTS THROUGH THE COORDINATED INDUCTION OF A WIDE ARRAY OF CYTOPROTECTIVE GENES. THEREFORE, ACTIVATION OF NRF2 IS CONSIDERED TO BE AN IMPORTANT APPROACH FOR PREVENTING CHRONIC DISEASES TRIGGERED BY STRESSES AND TOXINS, INCLUDING CANCER. DESPITE EXTENSIVE STUDIES SUGGESTED THAT THE KEAP1-NRF2 SIGNALING PATHWAY IS SUBJECT TO MULTIPLE LAYERS OF REGULATION AT THE TRANSCRIPTIONAL, TRANSLATIONAL, AND POST-TRANSLATIONAL LEVELS, THE POTENTIAL EPIGENETIC REGULATION OF NRF2 AND KEAP1 HAS BEGUN TO BE RECOGNIZED ONLY IN RECENT YEARS. EPIGENETIC MODIFICATIONS, HERITABLE ALTERATIONS IN GENE EXPRESSION THAT OCCUR WITHOUT CHANGES IN THE PRIMARY DNA SEQUENCE, HAVE BEEN REPORTED TO BE PROFOUNDLY INVOLVED IN OXIDATIVE STRESS RESPONSES. IN THIS REVIEW, WE DISCUSS THE LATEST FINDINGS REGARDING THE EPIGENETIC REGULATION OF KEAP1-NRF2 SIGNALING BY DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNAS. THE CROSSTALK AMONG THESE EPIGENETIC MODIFICATIONS IN THE REGULATION OF KEAP1-NRF2 SIGNALING PATHWAYS IS ALSO DISCUSSED. STUDIES OF THE EPIGENETIC MODIFICATION OF NRF2 AND KEAP1 HAVE NOT ONLY ENHANCED OUR UNDERSTANDING OF THIS COMPLEX CELLULAR DEFENSE SYSTEM BUT HAVE ALSO PROVIDED POTENTIAL NEW THERAPEUTIC TARGETS FOR THE PREVENTION OF CERTAIN DISEASES. 2015 20 5967 49 TERMINATION OF ACUTE STRESS RESPONSE BY THE ENDOCANNABINOID SYSTEM IS REGULATED THROUGH LYSINE-SPECIFIC DEMETHYLASE 1-MEDIATED TRANSCRIPTIONAL REPRESSION OF 2-AG HYDROLASES ABHD6 AND MAGL. ACUTE ENVIRONMENTAL STRESS RARELY IMPLIES LONG-LASTING NEUROPHYSIOLOGICAL AND BEHAVIORAL ALTERATIONS. ON THE CONTRARY, CHRONIC STRESS EXERTS A POTENT TOXIC EFFECT AT THE GLUTAMATERGIC SYNAPSE WHOSE ALTERED PHYSIOLOGY HAS BEEN RECOGNIZED AS A CORE TRAIT OF NEUROPSYCHIATRIC DISORDERS. THE ENDOCANNABINOID SYSTEM (ECS) PLAYS AN IMPORTANT ROLE IN THE HOMEOSTATIC RESPONSE TO ACUTE STRESS. IN PARTICULAR, STRESS INDUCES SYNTHESIS OF ENDOCANNABINOID (ECB) 2-ARACHIDONYL GLYCEROL (2-AG). 2-AG STIMULATES PRESYNAPTIC CANNABINOID 1 (CB1) RECEPTOR CONTRIBUTING TO STRESS RESPONSE TERMINATION THROUGH INHIBITION OF GLUTAMATE RELEASE, RESTRAINING THEREAFTER ANXIETY AROUSAL. WE EMPLOY MOUSE MODELS OF STRESS RESPONSE COUPLED TO GENE EXPRESSION ANALYSES, UNRAVELLING THAT IN RESPONSE TO ACUTE PSYCHOSOCIAL STRESS IN THE MOUSE HIPPOCAMPUS, ECS-MEDIATED SYNAPTIC MODULATION IS ENHANCED VIA TRANSCRIPTIONAL REPRESSION OF TWO ENZYMES INVOLVED IN 2-AG DEGRADATION: ALPHA/BETA-HYDROLASE DOMAIN CONTAINING 6 (ABHD6) AND MONOACYLGLYCEROL LIPASE (MAGL). SUCH A PROCESS IS ORCHESTRATED BY THE EPIGENETIC COREPRESSOR LSD1 WHO DIRECTLY INTERACTS WITH PROMOTER REGULATORY REGIONS OF ABHD6 AND MAGL. REMARKABLY, NEGATIVE TRANSCRIPTIONAL CONTROL OF ABHD6 AND MAGL IS LOST IN THE HIPPOCAMPUS UPON CHRONIC PSYCHOSOCIAL STRESS, POSSIBLY CONTRIBUTING TO TRAUMA-INDUCED DRIFT OF SYNAPSE PHYSIOLOGY TOWARD UNCONTROLLED GLUTAMATE TRANSMISSION. WE PREVIOUSLY SHOWED THAT IN MICE LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1) INCREASES ITS HIPPOCAMPAL EXPRESSION IN RESPONSE TO PSYCHOSOCIAL STRESS PREVENTING EXCESSIVE CONSOLIDATION OF ANXIETY-RELATED PLASTICITY. IN THIS WORK, WE UNRAVEL A NODAL EPIGENETIC MODULATION OF ECB TURN OVER, SHEDDING NEW LIGHT ON THE MOLECULAR SUBSTRATE OF CONVERGING STRESS-TERMINATING EFFECTS DISPLAYED BY ECS AND LSD1. 2020