1 6425 138 THE TRANSCRIPTION FACTOR REST UP-REGULATES TYROSINE HYDROXYLASE AND ANTIAPOPTOTIC GENES AND PROTECTS DOPAMINERGIC NEURONS AGAINST MANGANESE TOXICITY. DOPAMINERGIC FUNCTIONS ARE IMPORTANT FOR VARIOUS BIOLOGICAL ACTIVITIES, AND THEIR IMPAIRMENT LEADS TO NEURODEGENERATION, A HALLMARK OF PARKINSON'S DISEASE (PD). CHRONIC MANGANESE (MN) EXPOSURE CAUSES THE NEUROLOGICAL DISORDER MANGANISM, PRESENTING SYMPTOMS SIMILAR TO THOSE OF PD. EMERGING EVIDENCE HAS LINKED THE TRANSCRIPTION FACTOR RE1-SILENCING TRANSCRIPTION FACTOR (REST) TO PD AND ALSO ALZHEIMER'S DISEASE. BUT REST'S ROLE IN DOPAMINERGIC NEURONS IS UNCLEAR. HERE, WE INVESTIGATED WHETHER REST PROTECTS DOPAMINERGIC NEURONS AGAINST MN-INDUCED TOXICITY AND ENHANCES EXPRESSION OF THE DOPAMINE-SYNTHESIZING ENZYME TYROSINE HYDROXYLASE (TH). WE REPORT THAT REST BINDS TO RE1 CONSENSUS SITES IN THE TH GENE PROMOTER, STIMULATES TH TRANSCRIPTION, AND INCREASES TH MRNA AND PROTEIN LEVELS IN DOPAMINERGIC CELLS. REST BINDING TO THE TH PROMOTER RECRUITED THE EPIGENETIC MODIFIER CAMP-RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN/P300 AND THEREBY UP-REGULATED TH EXPRESSION. REST RELIEVED MN-INDUCED REPRESSION OF TH PROMOTER ACTIVITY, MRNA, AND PROTEIN LEVELS AND ALSO REDUCED MN-INDUCED OXIDATIVE STRESS, INFLAMMATION, AND APOPTOSIS IN DOPAMINERGIC NEURONS. REST REDUCED MN-INDUCED PROINFLAMMATORY CYTOKINES, INCLUDING TUMOR NECROSIS FACTOR ALPHA, INTERLEUKIN 1BETA (IL-1BETA), IL-6, AND INTERFERON GAMMA. MOREOVER, REST INHIBITED THE MN-INDUCED PROAPOPTOTIC PROTEINS BCL-2-ASSOCIATED X PROTEIN (BAX) AND DEATH-ASSOCIATED PROTEIN 6 (DAXX) AND ATTENUATED AN MN-INDUCED DECREASE IN THE ANTIAPOPTOTIC PROTEINS BCL-2 AND BCL-XL. REST ALSO ENHANCED THE EXPRESSION OF ANTIOXIDANT PROTEINS, INCLUDING CATALASE, NF-E2-RELATED FACTOR 2 (NRF2), AND HEME OXYGENASE 1 (HO-1). OUR FINDINGS INDICATE THAT REST ACTIVATES TH EXPRESSION AND THEREBY PROTECTS NEURONS AGAINST MN-INDUCED TOXICITY AND NEUROLOGICAL DISORDERS ASSOCIATED WITH DOPAMINERGIC NEURODEGENERATION. 2020 2 533 59 ASTROCYTIC TRANSCRIPTION FACTOR REST UPREGULATES GLUTAMATE TRANSPORTER EAAT2, PROTECTING DOPAMINERGIC NEURONS FROM MANGANESE-INDUCED EXCITOTOXICITY. CHRONIC EXPOSURE TO HIGH LEVELS OF MANGANESE (MN) LEADS TO MANGANISM, A NEUROLOGICAL DISORDER WITH SIMILAR SYMPTOMS TO THOSE INHERENT TO PARKINSON'S DISEASE. HOWEVER, THE UNDERLYING MECHANISMS OF THIS PATHOLOGICAL CONDITION HAVE YET TO BE ESTABLISHED. SINCE THE HUMAN EXCITATORY AMINO ACID TRANSPORTER 2 (EAAT2) (GLUTAMATE TRANSPORTER 1 IN RODENTS) IS PREDOMINANTLY EXPRESSED IN ASTROCYTES AND ITS DYSREGULATION IS INVOLVED IN MN-INDUCED EXCITOTOXIC NEURONAL INJURY, CHARACTERIZATION OF THE MECHANISMS THAT MEDIATE THE MN-INDUCED IMPAIRMENT IN EAAT2 FUNCTION IS CRUCIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS AGAINST MN NEUROTOXICITY. REPRESSOR ELEMENT 1-SILENCING TRANSCRIPTION FACTOR (REST) EXERTS PROTECTIVE EFFECTS IN MANY NEURODEGENERATIVE DISEASES. BUT THE EFFECTS OF REST ON EAAT2 EXPRESSION AND ENSUING NEUROPROTECTION ARE UNKNOWN. GIVEN THAT THE EAAT2 PROMOTER CONTAINS REST BINDING SITES, THE PRESENT STUDY INVESTIGATED THE ROLE OF REST IN EAAT2 EXPRESSION AT THE TRANSCRIPTIONAL LEVEL IN ASTROCYTES AND MN-INDUCED NEUROTOXICITY IN AN ASTROCYTE-NEURON COCULTURE SYSTEM. THE RESULTS REVEAL THAT ASTROCYTIC REST POSITIVELY REGULATES EAAT2 EXPRESSION WITH THE RECRUITMENT OF AN EPIGENETIC MODIFIER, CAMP RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN/P300, TO ITS CONSENSUS BINDING SITES IN THE EAAT2 PROMOTER. MOREOVER, ASTROCYTIC OVEREXPRESSION OF REST ATTENUATES MN-INDUCED REDUCTION IN EAAT2 EXPRESSION, LEADING TO ATTENUATION OF GLUTAMATE-INDUCED NEUROTOXICITY IN THE ASTROCYTE-NEURON COCULTURE SYSTEM. OUR FINDINGS DEMONSTRATE THAT ASTROCYTIC REST PLAYS A CRITICAL ROLE IN PROTECTION AGAINST MN-INDUCED NEUROTOXICITY BY ATTENUATING MN-INDUCED EAAT2 REPRESSION AND THE ENSUING EXCITOTOXIC DOPAMINERGIC NEURONAL INJURY. THIS INDICATES THAT ASTROCYTIC REST COULD BE A POTENTIAL MOLECULAR TARGET FOR THE TREATMENT OF MN TOXICITY AND OTHER NEUROLOGICAL DISORDERS ASSOCIATED WITH EAAT2 DYSREGULATION. 2021 3 4136 38 MECHANISMS OF MANGANESE-INDUCED NEUROTOXICITY AND THE PURSUIT OF NEUROTHERAPEUTIC STRATEGIES. CHRONIC EXPOSURE TO ELEVATED LEVELS OF MANGANESE VIA OCCUPATIONAL OR ENVIRONMENTAL SETTINGS CAUSES A NEUROLOGICAL DISORDER KNOWN AS MANGANISM, RESEMBLING THE SYMPTOMS OF PARKINSON'S DISEASE, SUCH AS MOTOR DEFICITS AND COGNITIVE IMPAIRMENT. NUMEROUS STUDIES HAVE BEEN CONDUCTED TO CHARACTERIZE MANGANESE'S NEUROTOXICITY MECHANISMS IN SEARCH OF EFFECTIVE THERAPEUTICS, INCLUDING NATURAL AND SYNTHETIC COMPOUNDS TO TREAT MANGANESE TOXICITY. SEVERAL POTENTIAL MOLECULAR TARGETS OF MANGANESE TOXICITY AT THE EPIGENETIC AND TRANSCRIPTIONAL LEVELS HAVE BEEN IDENTIFIED RECENTLY, WHICH MAY CONTRIBUTE TO DEVELOP MORE PRECISE AND EFFECTIVE GENE THERAPIES. THIS REVIEW UPDATES FINDINGS ON MANGANESE-INDUCED NEUROTOXICITY MECHANISMS ON INTRACELLULAR INSULTS SUCH AS OXIDATIVE STRESS, INFLAMMATION, EXCITOTOXICITY, AND MITOPHAGY, AS WELL AS TRANSCRIPTIONAL DYSREGULATIONS INVOLVING YIN YANG 1, RE1-SILENCING TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR EB, AND NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 THAT COULD BE TARGETS OF MANGANESE NEUROTOXICITY THERAPIES. THIS REVIEW ALSO FEATURES INTRACELLULAR PROTEINS SUCH AS PTEN-INDUCIBLE KINASE 1, PARKIN, SIRTUINS, LEUCINE-RICH REPEAT KINASE 2, AND ALPHA-SYNUCLEIN, WHICH ARE ASSOCIATED WITH MANGANESE-INDUCED DYSREGULATION OF AUTOPHAGY/MITOPHAGY. IN ADDITION, NEWER THERAPEUTIC APPROACHES TO TREAT MANGANESE'S NEUROTOXICITY INCLUDING NATURAL AND SYNTHETIC COMPOUNDS MODULATING EXCITOTOXICITY, AUTOPHAGY, AND MITOPHAGY, WERE REVIEWED. TAKEN TOGETHER, IN-DEPTH MECHANISTIC KNOWLEDGE ACCOMPANIED BY ADVANCES IN GENE AND DRUG DELIVERY STRATEGIES WILL MAKE SIGNIFICANT PROGRESS IN THE DEVELOPMENT OF RELIABLE THERAPEUTIC INTERVENTIONS AGAINST MANGANESE-INDUCED NEUROTOXICITY. 2022 4 5143 35 POTENTIAL ROLE OF EPIGENETIC MECHANISM IN MANGANESE INDUCED NEUROTOXICITY. MANGANESE IS A VITAL NUTRIENT AND IS MAINTAINED AT AN OPTIMAL LEVEL (2.5-5 MG/DAY) IN HUMAN BODY. CHRONIC EXPOSURE TO MANGANESE IS ASSOCIATED WITH NEUROTOXICITY AND CORRELATED WITH THE DEVELOPMENT OF VARIOUS NEUROLOGICAL DISORDERS SUCH AS PARKINSON'S DISEASE. OXIDATIVE STRESS MEDIATED APOPTOTIC CELL DEATH HAS BEEN WELL ESTABLISHED MECHANISM IN MANGANESE INDUCED TOXICITY. OXIDATIVE STRESS HAS A POTENTIAL TO ALTER THE EPIGENETIC MECHANISM OF GENE REGULATION. EPIGENETIC INSIGHT OF MANGANESE NEUROTOXICITY IN CONTEXT OF ITS CORRELATION WITH THE DEVELOPMENT OF PARKINSONISM IS POORLY UNDERSTOOD. PARKINSON'S DISEASE IS CHARACTERIZED BY THE ALPHA-SYNUCLEIN AGGREGATION IN THE FORM OF LEWY BODIES IN NEURONAL CELLS. RECENT FINDINGS ILLUSTRATE THAT MANGANESE CAN CAUSE OVEREXPRESSION OF ALPHA-SYNUCLEIN. ALPHA-SYNUCLEIN ACTS EPIGENETICALLY VIA INTERACTION WITH HISTONE PROTEINS IN REGULATING APOPTOSIS. ALPHA-SYNUCLEIN ALSO CAUSES GLOBAL DNA HYPOMETHYLATION THROUGH SEQUESTRATION OF DNA METHYLTRANSFERASE IN CYTOPLASM. AN INDIVIDUAL GENETIC DIFFERENCE MAY ALSO HAVE AN INFLUENCE ON EPIGENETIC SUSCEPTIBILITY TO MANGANESE NEUROTOXICITY AND THE DEVELOPMENT OF PARKINSON'S DISEASE. THIS REVIEW PRESENTS THE CURRENT STATE OF FINDINGS IN RELATION TO ROLE OF EPIGENETIC MECHANISM IN MANGANESE INDUCED NEUROTOXICITY, WITH A SPECIAL EMPHASIS ON THE DEVELOPMENT OF PARKINSON'S DISEASE. 2016 5 3137 38 GLOBAL DNA METHYLATION PROFILING OF MANGANESE-EXPOSED HUMAN NEUROBLASTOMA SH-SY5Y CELLS REVEALS EPIGENETIC ALTERATIONS IN PARKINSON'S DISEASE-ASSOCIATED GENES. MANGANESE (MN) IS AN ESSENTIAL TRACE ELEMENT REQUIRED FOR OPTIMAL FUNCTIONING OF CELLULAR BIOCHEMICAL PATHWAYS IN THE CENTRAL NERVOUS SYSTEM. ELEVATED EXPOSURE TO MN THROUGH ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE CAN CAUSE NEUROTOXIC EFFECTS RESULTING IN MANGANISM, A CONDITION WITH CLINICAL SYMPTOMS IDENTICAL TO IDIOPATHIC PARKINSON'S DISEASE. EPIGENETICS IS NOW RECOGNIZED AS A BIOLOGICAL MECHANISM INVOLVED IN THE ETIOLOGY OF VARIOUS DISEASES. HERE, WE INVESTIGATED THE ROLE OF DNA METHYLATION ALTERATIONS INDUCED BY CHRONIC MN (100 MICROM) EXPOSURE IN HUMAN NEUROBLASTOMA (SH-SY5Y) CELLS IN RELEVANCE TO PARKINSON'S DISEASE. A COMBINED ANALYSIS OF DNA METHYLATION AND GENE EXPRESSION DATA FOR PARKINSON'S DISEASE-ASSOCIATED GENES WAS CARRIED OUT. WHOLE-GENOME BISULFITE CONVERSION AND SEQUENCING INDICATE EPIGENETIC PERTURBATION OF KEY GENES INVOLVED IN BIOLOGICAL PROCESSES ASSOCIATED WITH NEURONAL CELL HEALTH. INTEGRATION OF DNA METHYLATION DATA WITH GENE EXPRESSION REVEALS EPIGENETIC ALTERATIONS TO PINK1, PARK2 AND TH GENES THAT PLAY CRITICAL ROLES IN THE ONSET OF PARKINSONISM. THE PRESENT STUDY SUGGESTS THAT MN-INDUCED ALTERATION OF DNA METHYLATION OF PINK1-PARK2 MAY INFLUENCE MITOCHONDRIAL FUNCTION AND PROMOTE PARKINSONISM. OUR FINDINGS PROVIDE A BASIS TO FURTHER EXPLORE AND VALIDATE THE EPIGENETIC BASIS OF MN-INDUCED NEUROTOXICITY . 2017 6 1734 26 EAAT2 AS A RESEARCH TARGET IN BIPOLAR DISORDER AND UNIPOLAR DEPRESSION: A SYSTEMATIC REVIEW. GLUTAMATE IS IMPLICATED IN THE NEUROPATHOLOGY OF BOTH MAJOR DEPRESSIVE DISORDER AND BIPOLAR DISORDER. EXCITATORY AMINO ACID TRANSPORTER 2 (EAAT2) IS THE MAJOR GLUTAMATE TRANSPORTER IN THE MAMMALIAN BRAIN, REMOVING GLUTAMATE FROM THE SYNAPTIC CLEFT AND TRANSPORTING IT INTO GLIA FOR RECYCLING. IT IS THEREBY THE PRINCIPAL REGULATOR OF EXTRACELLULAR GLUTAMATE LEVELS AND PREVENTS NEURONAL EXCITOTOXICITY. EAAT2 IS A PROMISING TARGET FOR ELUCIDATING THE MECHANISMS BY WHICH THE GLUTAMATE-GLUTAMINE CYCLE INTERACTS WITH NEURONAL SYSTEMS IN MOOD DISORDERS. FORTY EAAT2 STUDIES (PUBLISHED JANUARY 1992-JANUARY 2018) WERE IDENTIFIED VIA A SYSTEMATIC LITERATURE SEARCH. THE STUDIES DEMONSTRATED THAT CHRONIC STRESS/STEROIDS WERE MOST COMMONLY ASSOCIATED WITH DECREASED EAAT2. IN RODENTS, EAAT2 INHIBITION WORSENED DEPRESSIVE BEHAVIORS. HUMAN EAAT2 EXPRESSION USUALLY DECREASED IN DEPRESSION, WITH SOME REGIONAL BRAIN DIFFERENCES. FEWER DATA HAVE BEEN COLLECTED REGARDING THE ROLES AND REGULATION OF EAAT2 IN BIPOLAR DISORDER. FUTURE DIRECTIONS FOR RESEARCH INCLUDE CORRELATING EAAT2 AND GLUTAMATE LEVELS IN VIVO, ELUCIDATING GENETIC VARIABILITY AND EPIGENETIC REGULATION, CLARIFYING INTRACELLULAR PROTEIN AND PHARMACOLOGIC INTERACTIONS, AND EXAMINING EAAT2 IN DIFFERENT BIPOLAR MOOD STATES. AS PART OF A MACROMOLECULAR COMPLEX WITHIN GLIA, EAAT2 MAY CONTRIBUTE SIGNIFICANTLY TO INTRACELLULAR SIGNALING, ENERGY REGULATION, AND CELLULAR HOMEOSTASIS. AN ENHANCED UNDERSTANDING OF THIS SYSTEM IS NEEDED. 2020 7 5052 36 PHARMACOLOGICAL TARGETING OF HEME OXYGENASE-1 IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGING-ASSOCIATED DISEASE THAT CLINICALLY MANIFESTS AS JOINT PAIN, MOBILITY LIMITATIONS, AND COMPROMISED QUALITY OF LIFE. TODAY, OA TREATMENT IS LIMITED TO PAIN MANAGEMENT AND JOINT ARTHROPLASTY AT THE LATER STAGES OF DISEASE PROGRESSION. OA PATHOGENESIS IS PREDOMINANTLY MEDIATED BY OXIDATIVE DAMAGE TO JOINT CARTILAGE EXTRACELLULAR MATRIX AND LOCAL CELLS SUCH AS CHONDROCYTES, OSTEOCLASTS, OSTEOBLASTS, AND SYNOVIAL FIBROBLASTS. UNDER NORMAL CONDITIONS, CELLS PREVENT THE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) UNDER OXIDATIVELY STRESSFUL CONDITIONS THROUGH THEIR ADAPTIVE CYTOPROTECTIVE MECHANISMS. HEME OXYGENASE-1 (HO-1) IS AN IRON-DEPENDENT CYTOPROTECTIVE ENZYME THAT FUNCTIONS AS THE INDUCIBLE FORM OF HO. HO-1 AND ITS METABOLITES CARBON MONOXIDE AND BILIVERDIN CONTRIBUTE TOWARDS THE MAINTENANCE OF REDOX HOMEOSTASIS. HO-1 EXPRESSION IS PRIMARILY REGULATED AT THE TRANSCRIPTIONAL LEVEL THROUGH TRANSCRIPTIONAL FACTOR NUCLEAR FACTOR ERYTHROID 2 (NF-E2)-RELATED FACTOR 2 (NRF2), SPECIFICITY PROTEIN 1 (SP1), TRANSCRIPTIONAL REPRESSOR BTB-AND-CNC HOMOLOGY 1 (BACH1), AND EPIGENETIC REGULATION. SEVERAL STUDIES REPORT THAT HO-1 EXPRESSION CAN BE REGULATED USING VARIOUS ANTIOXIDATIVE FACTORS AND CHEMICAL COMPOUNDS, SUGGESTING THERAPEUTIC IMPLICATIONS IN OA PATHOGENESIS AS WELL AS IN THE WIDER CONTEXT OF JOINT DISEASE. HERE, WE REVIEW THE PROTECTIVE ROLE OF HO-1 IN OA WITH A FOCUS ON THE REGULATORY MECHANISMS THAT MEDIATE HO-1 ACTIVITY. 2021 8 5165 35 PRECLINICAL RESERPINE MODELS RECAPITULATING MOTOR AND NON-MOTOR FEATURES OF PARKINSON'S DISEASE: ROLES OF EPIGENETIC UPREGULATION OF ALPHA-SYNUCLEIN AND AUTOPHAGY IMPAIRMENT. RESERPINE IS AN EFFECTIVE DRUG FOR THE CLINICAL TREATMENT OF HYPERTENSION. IT ALSO INDUCES PARKINSON'S DISEASE (PD)-LIKE SYMPTOMS IN HUMANS AND ANIMALS POSSIBLE THROUGH THE INHIBITION OF MONOAMINE VESICULAR TRANSPORTERS, THUS DECREASING THE LEVELS OF MONOAMINE NEUROTRANSMITTERS IN THE BRAIN. HOWEVER, THE PRECISE MECHANISMS REMAIN UNCLEAR. HEREIN, WE AIMED TO DEVELOP A PRECLINICAL RESERPINE MODEL RECAPITULATING THE NON-MOTOR AND MOTOR SYMPTOMS OF PD AND INVESTIGATE THE UNDERLYING POTENTIAL CELLULAR MECHANISMS. INCUBATION OF RESERPINE INDUCED APOPTOSIS, LED TO THE ACCUMULATION OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS), LOWERED DNA METHYLATION OF ALPHA-SYNUCLEIN GENE, RESULTED IN ALPHA-SYNUCLEIN PROTEIN DEPOSITION, AND ELEVATED THE RATIO OF LC3-II/LC3-I AND P62 IN CULTURED SH-SY5Y CELLS. FEEDING RESERPINE DOSE-DEPENDENTLY SHORTENED THE LIFESPAN AND CAUSED IMPAIRMENT OF MOTOR FUNCTIONS IN MALE AND FEMALE DROSOPHILA. MOREOVER, LONG-TERM ORAL ADMINISTRATION OF RESERPINE LED TO MULTIPLE MOTOR AND NON-MOTOR SYMPTOMS, INCLUDING CONSTIPATION, PAIN HYPERSENSITIVITY, OLFACTORY IMPAIRMENT, AND DEPRESSION-LIKE BEHAVIORS IN MICE. THE MECHANISTIC STUDIES SHOWED THAT CHRONIC RESERPINE EXPOSURE CAUSED HYPOMETHYLATION OF THE ALPHA-SYNUCLEIN GENE AND UP-REGULATED ITS EXPRESSION AND ELEVATED THE RATIO OF LC3-II/LC3-I AND EXPRESSION OF P62 IN THE SUBSTANTIA NIGRA OF MICE. THUS, WE ESTABLISHED PRECLINICAL ANIMAL MODELS USING RESERPINE TO RECAPITULATE THE MOTOR AND NON-MOTOR SYMPTOMS OF PD. CHRONIC RESERPINE EXPOSURE EPIGENETICALLY ELEVATED THE LEVELS OF ALPHA-SYNUCLEIN EXPRESSION POSSIBLE BY LOWERING THE DNA METHYLATION STATUS AND INDUCING AUTOPHAGIC IMPAIRMENT IN VITRO AND IN VIVO. 2022 9 616 37 BIOACTIVE COMPOUNDS IN OXIDATIVE STRESS-MEDIATED DISEASES: TARGETING THE NRF2/ARE SIGNALING PATHWAY AND EPIGENETIC REGULATION. OXIDATIVE STRESS IS A PATHOLOGICAL CONDITION OCCURRING DUE TO AN IMBALANCE BETWEEN THE OXIDANTS AND ANTIOXIDANT DEFENSE SYSTEMS IN THE BODY. NUCLEAR FACTOR E2-RELATED FACTOR 2 (NRF2), ENCODED BY THE GENE NFE2L2, IS THE MASTER REGULATOR OF PHASE II ANTIOXIDANT ENZYMES THAT PROTECT AGAINST OXIDATIVE STRESS AND INFLAMMATION. NRF2/ARE SIGNALING HAS BEEN CONSIDERED AS A PROMISING TARGET AGAINST OXIDATIVE STRESS-MEDIATED DISEASES LIKE DIABETES, FIBROSIS, NEUROTOXICITY, AND CANCER. THE CONSUMPTION OF DIETARY PHYTOCHEMICALS ACTS AS AN EFFECTIVE MODULATOR OF NRF2/ARE IN VARIOUS ACUTE AND CHRONIC DISEASES. IN THE PRESENT REVIEW, WE DISCUSSED THE ROLE OF NRF2 IN DIABETES, ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), CANCER, AND ATHEROSCLEROSIS. ADDITIONALLY, WE DISCUSSED THE PHYTOCHEMICALS LIKE CURCUMIN, QUERCETIN, RESVERATROL, EPIGALLOCATECHIN GALLATE, APIGENIN, SULFORAPHANE, AND URSOLIC ACID THAT HAVE EFFECTIVELY MODIFIED NRF2 SIGNALING AND PREVENTED VARIOUS DISEASES IN BOTH IN VITRO AND IN VIVO MODELS. BASED ON THE LITERATURE, IT IS CLEAR THAT DIETARY PHYTOCHEMICALS CAN PREVENT DISEASES BY (1) BLOCKING OXIDATIVE STRESS-INHIBITING INFLAMMATORY MEDIATORS THROUGH INHIBITING KEAP1 OR ACTIVATING NRF2 EXPRESSION AND ITS DOWNSTREAM TARGETS IN THE NUCLEUS, INCLUDING HO-1, SOD, AND CAT; (2) REGULATING NRF2 SIGNALING BY VARIOUS KINASES LIKE GSK3BETA, PI3/AKT, AND MAPK; AND (3) MODIFYING EPIGENETIC MODULATION, SUCH AS METHYLATION, AT THE NRF2 PROMOTER REGION; HOWEVER, FURTHER INVESTIGATION INTO OTHER UPSTREAM SIGNALING MOLECULES LIKE NRF2 AND THE EFFECT OF PHYTOCHEMICALS ON THEM STILL NEED TO BE INVESTIGATED IN THE NEAR FUTURE. 2021 10 6045 34 THE COMPLEXITY OF THE NRF2 PATHWAY: BEYOND THE ANTIOXIDANT RESPONSE. THE NF-E2-RELATED FACTOR 2 (NRF2)-MEDIATED SIGNALLING PATHWAY PROVIDES LIVING ORGANISMS AN EFFICIENT AND PIVOTAL LINE OF DEFENSIVE TO COUNTERACT ENVIRONMENTAL INSULTS AND ENDOGENOUS STRESSORS. NRF2 COORDINATES THE BASAL AND INDUCIBLE EXPRESSION OF ANTIOXIDANT AND PHASE II DETOXIFICATION ENZYMES TO ADAPT TO DIFFERENT STRESS CONDITIONS. THE STABILITY AND CELLULAR DISTRIBUTION OF NRF2 IS TIGHTLY CONTROLLED BY ITS INHIBITORY BINDING PROTEIN KELCH-LIKE ECH-ASSOCIATED PROTEIN 1. NRF2 SIGNALLING IS ALSO REGULATED BY POSTTRANSLATIONAL, TRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS, AS WELL AS BY OTHER PROTEIN PARTNERS, INCLUDING P62, P21 AND IQ MOTIF-CONTAINING GTPASE ACTIVATING PROTEIN 1. MANY STUDIES HAVE DEMONSTRATED THAT NRF2 IS A PROMISING TARGET FOR PREVENTING CARCINOGENESIS AND OTHER CHRONIC DISEASES, INCLUDING CARDIOVASCULAR DISEASES, NEURODEGENERATIVE DISEASES AND PULMONARY INJURY. HOWEVER, CONSTITUTIVE ACTIVATION OF NRF2 IN ADVANCED CANCER CELLS MAY CONFER DRUG RESISTANCE. HERE, WE REVIEW THE MOLECULAR MECHANISMS OF NRF2 SIGNALLING, THE DIVERSE CLASSES OF NRF2 ACTIVATORS, INCLUDING BIOACTIVE NUTRIENTS AND OTHER CHEMICALS, AND THE CELLULAR FUNCTIONS AND DISEASE RELEVANCE OF NRF2 AND DISCUSS THE DUAL ROLE OF NRF2 IN DIFFERENT CONTEXTS. 2015 11 5354 43 RE1-SILENCING TRANSCRIPTION FACTOR CONTROLS THE ACUTE-TO-CHRONIC NEUROPATHIC PAIN TRANSITION AND CHRM2 RECEPTOR GENE EXPRESSION IN PRIMARY SENSORY NEURONS. NEUROPATHIC PAIN IS ASSOCIATED WITH PERSISTENT CHANGES IN GENE EXPRESSION IN PRIMARY SENSORY NEURONS, BUT THE UNDERLYING EPIGENETIC MECHANISMS THAT CAUSE THESE CHANGES REMAIN UNCLEAR. THE MUSCARINIC CHOLINERGIC RECEPTORS (MACHRS), PARTICULARLY THE M2 SUBTYPE (ENCODED BY THE CHOLINERGIC RECEPTOR MUSCARINIC 2 (CHRM2) GENE), ARE CRITICALLY INVOLVED IN THE REGULATION OF SPINAL NOCICEPTIVE TRANSMISSION. HOWEVER, LITTLE IS KNOWN ABOUT HOW CHRM2 EXPRESSION IS TRANSCRIPTIONALLY REGULATED. HERE WE SHOW THAT NERVE INJURY PERSISTENTLY INCREASED THE EXPRESSION OF RE1-SILENCING TRANSCRIPTION FACTOR (REST, ALSO KNOWN AS NEURON-RESTRICTIVE SILENCING FACTOR [NRSF]), A GENE-SILENCING TRANSCRIPTION FACTOR, IN THE DORSAL ROOT GANGLION (DRG). REMARKABLY, NERVE INJURY-INDUCED CHRONIC BUT NOT ACUTE PAIN HYPERSENSITIVITY WAS ATTENUATED IN MICE WITH REST KNOCKOUT IN DRG NEURONS. ALSO, SIRNA-MEDIATED REST KNOCKDOWN REVERSED NERVE INJURY-INDUCED CHRONIC PAIN HYPERSENSITIVITY IN RATS. NERVE INJURY PERSISTENTLY REDUCED CHRM2 EXPRESSION IN THE DRG AND DIMINISHED THE ANALGESIC EFFECT OF MUSCARINE. THE RE1 BINDING SITE ON THE CHRM2 PROMOTER IS REQUIRED FOR REST-MEDIATED CHRM2 REPRESSION, AND NERVE INJURY INCREASED THE ENRICHMENT OF REST IN THE CHRM2 PROMOTER IN THE DRG. FURTHERMORE, REST KNOCKDOWN OR GENETIC ABLATION IN DRG NEURONS NORMALIZED CHRM2 EXPRESSION AND AUGMENTED MUSCARINE'S ANALGESIC EFFECT ON NEUROPATHIC PAIN AND FULLY REVERSED THE NERVE INJURY-INDUCED REDUCTION IN THE INHIBITORY EFFECT OF MUSCARINE ON GLUTAMATERGIC INPUT TO SPINAL DORSAL HORN NEURONS. OUR FINDINGS INDICATE THAT NERVE INJURY-INDUCED REST UP-REGULATION IN DRG NEURONS PLAYS AN IMPORTANT ROLE IN THE ACUTE-TO-CHRONIC PAIN TRANSITION AND IS ESSENTIAL FOR THE TRANSCRIPTIONAL REPRESSION OF CHRM2 IN NEUROPATHIC PAIN. 2018 12 6166 34 THE GLUTATHIONE SYSTEM: A NEW DRUG TARGET IN NEUROIMMUNE DISORDERS. GLUTATHIONE (GSH) HAS A CRUCIAL ROLE IN CELLULAR SIGNALING AND ANTIOXIDANT DEFENSES EITHER BY REACTING DIRECTLY WITH REACTIVE OXYGEN OR NITROGEN SPECIES OR BY ACTING AS AN ESSENTIAL COFACTOR FOR GSH S-TRANSFERASES AND GLUTATHIONE PEROXIDASES. GSH ACTING IN CONCERT WITH ITS DEPENDENT ENZYMES, KNOWN AS THE GLUTATHIONE SYSTEM, IS RESPONSIBLE FOR THE DETOXIFICATION OF REACTIVE OXYGEN AND NITROGEN SPECIES (ROS/RNS) AND ELECTROPHILES PRODUCED BY XENOBIOTICS. ADEQUATE LEVELS OF GSH ARE ESSENTIAL FOR THE OPTIMAL FUNCTIONING OF THE IMMUNE SYSTEM IN GENERAL AND T CELL ACTIVATION AND DIFFERENTIATION IN PARTICULAR. GSH IS A UBIQUITOUS REGULATOR OF THE CELL CYCLE PER SE. GSH ALSO HAS CRUCIAL FUNCTIONS IN THE BRAIN AS AN ANTIOXIDANT, NEUROMODULATOR, NEUROTRANSMITTER, AND ENABLER OF NEURON SURVIVAL. DEPLETION OF GSH LEADS TO EXACERBATION OF DAMAGE BY OXIDATIVE AND NITROSATIVE STRESS; HYPERNITROSYLATION; INCREASED LEVELS OF PROINFLAMMATORY MEDIATORS AND INFLAMMATORY POTENTIAL; DYSFUNCTIONS OF INTRACELLULAR SIGNALING NETWORKS, E.G., P53, NUCLEAR FACTOR-KAPPAB, AND JANUS KINASES; DECREASED CELL PROLIFERATION AND DNA SYNTHESIS; INACTIVATION OF COMPLEX I OF THE ELECTRON TRANSPORT CHAIN; ACTIVATION OF CYTOCHROME C AND THE APOPTOTIC MACHINERY; BLOCKADE OF THE METHIONINE CYCLE; AND COMPROMISED EPIGENETIC REGULATION OF GENE EXPRESSION. AS SUCH, GSH DEPLETION HAS MARKED CONSEQUENCES FOR THE HOMEOSTATIC CONTROL OF THE IMMUNE SYSTEM, OXIDATIVE AND NITROSATIVE STRESS (O&NS) PATHWAYS, REGULATION OF ENERGY PRODUCTION, AND MITOCHONDRIAL SURVIVAL AS WELL. GSH DEPLETION AND CONCOMITANT INCREASE IN O&NS AND MITOCHONDRIAL DYSFUNCTIONS PLAY A ROLE IN THE PATHOPHYSIOLOGY OF DIVERSE NEUROIMMUNE DISORDERS, INCLUDING DEPRESSION, MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME AND PARKINSON'S DISEASE, SUGGESTING THAT DEPLETED GSH IS AN INTEGRAL PART OF THESE DISEASES. THERAPEUTICAL INTERVENTIONS THAT AIM TO INCREASE GSH CONCENTRATIONS IN VIVO INCLUDE N-ACETYL CYSTEINE; NRF-2 ACTIVATION VIA HYPERBARIC OXYGEN THERAPY; DIMETHYL FUMARATE; PHYTOCHEMICALS, INCLUDING CURCUMIN, RESVERATROL, AND CINNAMON; AND FOLATE SUPPLEMENTATION. 2014 13 1654 31 DORSAL ROOT GANGLIA COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1 CONTRIBUTES TO PERIPHERAL NERVE INJURY-INDUCED PAIN HYPERSENSITIVITIES. NEUROPATHIC PAIN IS ASSOCIATED WITH GENE EXPRESSION CHANGES WITHIN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY, WHICH INVOLVES EPIGENETIC MECHANISMS. COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1 (CARM1), AN EPIGENETIC ACTIVATOR, REGULATES GENE TRANSCRIPTIONAL ACTIVITY BY PROTEIN POSTTRANSLATIONAL MODIFICATIONS. HOWEVER, WHETHER CARM1 PLAYS AN ESSENTIAL ROLE IN THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN IS UNKNOWN. WE REPORT HERE THAT PERIPHERAL NERVE INJURY INDUCED THE UPREGULATION OF THE MRNA AND PROTEIN EXPRESSION OF CARM1 IN THE INJURED DRG, AND BLOCKING ITS EXPRESSION THROUGH SMALL INTERFERING RNA (SIRNA) IN THE INJURED DRG ATTENUATED THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN. FURTHERMORE, PHARMACOLOGICAL INHIBITION OF CARM1 MITIGATED PERIPHERAL NERVE INJURY-INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA. GIVEN THAT CARM1 INHIBITION OR KNOCKDOWN ATTENUATED THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY, OUR FINDINGS SUGGEST THAT CARM1 MAY SERVE AS A PROMISING THERAPEUTIC TARGET FOR NEUROPATHIC PAIN TREATMENT IN CLINICAL APPLICATIONS. 2018 14 2885 30 G9A PARTICIPATES IN NERVE INJURY-INDUCED KCNA2 DOWNREGULATION IN PRIMARY SENSORY NEURONS. NERVE INJURY-INDUCED DOWNREGULATION OF VOLTAGE-GATED POTASSIUM CHANNEL SUBUNIT KCNA2 IN THE DORSAL ROOT GANGLION (DRG) IS CRITICAL FOR DRG NEURONAL EXCITABILITY AND NEUROPATHIC PAIN GENESIS. HOWEVER, HOW NERVE INJURY CAUSES THIS DOWNREGULATION IS STILL ELUSIVE. EUCHROMATIC HISTONE-LYSINE N-METHYLTRANSFERASE 2, ALSO KNOWN AS G9A, METHYLATES HISTONE H3 ON LYSINE RESIDUE 9 TO PREDOMINANTLY PRODUCE A DYNAMIC HISTONE DIMETHYLATION, RESULTING IN CONDENSED CHROMATIN AND GENE TRANSCRIPTIONAL REPRESSION. WE SHOWED HERE THAT BLOCKING NERVE INJURY-INDUCED INCREASE IN G9A RESCUED KCNA2 MRNA AND PROTEIN EXPRESSION IN THE AXOTOMIZED DRG AND ATTENUATED THE DEVELOPMENT OF NERVE INJURY-INDUCED PAIN HYPERSENSITIVITY. MIMICKING THIS INCREASE DECREASED KCNA2 MRNA AND PROTEIN EXPRESSION, REDUCED KV CURRENT, AND INCREASED EXCITABILITY IN THE DRG NEURONS AND LED TO SPINAL CORD CENTRAL SENSITIZATION AND NEUROPATHIC PAIN-LIKE SYMPTOMS. G9A MRNA IS CO-LOCALIZED WITH KCNA2 MRNA IN THE DRG NEURONS. THESE FINDINGS INDICATE THAT G9A CONTRIBUTES TO NEUROPATHIC PAIN DEVELOPMENT THROUGH EPIGENETIC SILENCING OF KCNA2 IN THE AXOTOMIZED DRG. 2016 15 1166 29 CONTRIBUTION OF DNMT1 TO NEUROPATHIC PAIN GENESIS PARTIALLY THROUGH EPIGENETICALLY REPRESSING KCNA2 IN PRIMARY AFFERENT NEURONS. EXPRESSIONAL CHANGES OF PAIN-ASSOCIATED GENES IN PRIMARY SENSORY NEURONS OF DRG ARE CRITICAL FOR NEUROPATHIC PAIN GENESIS. DNA METHYLTRANSFERASE (DNMT)-TRIGGERED DNA METHYLATION SILENCES GENE EXPRESSION. WE SHOW HERE THAT DNMT1, A CANONICAL MAINTENANCE METHYLTRANSFERASE, ACTS AS THE DE NOVO DNMT AND IS REQUIRED FOR NEUROPATHIC PAIN GENESIS LIKELY THROUGH REPRESSING AT LEAST DRG KCNA2 GENE EXPRESSION IN MALE MICE. PERIPHERAL NERVE INJURY UPREGULATED DNMT1 EXPRESSION IN THE INJURED DRG THROUGH THE TRANSCRIPTION FACTOR CAMP RESPONSE ELEMENT BINDING PROTEIN-TRIGGERED TRANSCRIPTIONAL ACTIVATION OF DNMT1 GENE. BLOCKING THIS UPREGULATION PREVENTED NERVE INJURY-INDUCED DNA METHYLATION WITHIN THE PROMOTER AND 5'-UNTRANSLATED REGION OF KCNA2 GENE, RESCUED KCNA2 EXPRESSION AND TOTAL KV CURRENT, ATTENUATED HYPEREXCITABILITY IN THE INJURED DRG NEURONS, AND ALLEVIATED NERVE INJURY-INDUCED PAIN HYPERSENSITIVITIES. GIVEN THAT KCNA2 IS A KEY PLAYER IN NEUROPATHIC PAIN, OUR FINDINGS SUGGEST THAT DRG DNMT1 MAY BE A POTENTIAL TARGET FOR NEUROPATHIC PAIN MANAGEMENT.SIGNIFICANCE STATEMENT IN THE PRESENT STUDY, WE REPORTED THAT DNMT1, A CANONICAL DNA MAINTENANCE METHYLTRANSFERASE, IS UPREGULATED VIA THE ACTIVATION OF THE TRANSCRIPTION FACTOR CREB IN THE INJURED DRG AFTER PERIPHERAL NERVE INJURY. THIS UPREGULATION WAS RESPONSIBLE FOR NERVE INJURY-INDUCED DE NOVO DNA METHYLATION WITHIN THE PROMOTER AND 5'-UNTRANSLATED REGION OF THE KCNA2 GENE, REDUCTIONS IN KCNA2 EXPRESSION AND KV CURRENT AND INCREASES IN NEURONAL EXCITABILITY IN THE INJURED DRG. SINCE PHARMACOLOGICAL INHIBITION OR GENETIC KNOCKDOWN OF DRG DNMT1 ALLEVIATED NERVE INJURY-INDUCED PAIN HYPERSENSITIVITIES, DRG DNMT1 CONTRIBUTES TO NEUROPATHIC PAIN GENESIS PARTIALLY THROUGH REPRESSION OF DRG KCNA2 GENE EXPRESSION. 2019 16 2350 34 EPIGENETIC REGULATION OF NEUROINFLAMMATION IN PARKINSON'S DISEASE. NEUROINFLAMMATION IS ONE OF THE MOST SIGNIFICANT FACTORS INVOLVED IN THE INITIATION AND PROGRESSION OF PARKINSON'S DISEASE. PD IS A NEURODEGENERATIVE DISORDER WITH A MOTOR DISABILITY LINKED WITH VARIOUS COMPLEX AND DIVERSIFIED RISK FACTORS. THESE FACTORS TRIGGER MYRIADS OF CELLULAR AND MOLECULAR PROCESSES, SUCH AS MISFOLDING DEFECTIVE PROTEINS, OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND NEUROTOXIC SUBSTANCES THAT INDUCE SELECTIVE NEURODEGENERATION OF DOPAMINE NEURONS. THIS NEURONAL DAMAGE ACTIVATES THE NEURONAL IMMUNE SYSTEM, INCLUDING GLIAL CELLS AND INFLAMMATORY CYTOKINES, TO TRIGGER NEUROINFLAMMATION. THE TRANSITION OF ACUTE TO CHRONIC NEUROINFLAMMATION ENHANCES THE SUSCEPTIBILITY OF INFLAMMATION-INDUCED DOPAMINERGIC NEURON DAMAGE, FORMING A VICIOUS CYCLE AND PROMPTING AN INDIVIDUAL TO PD DEVELOPMENT. EPIGENETIC MECHANISMS RECENTLY HAVE BEEN AT THE FOREFRONT OF THE REGULATION OF NEUROINFLAMMATORY FACTORS IN PD, PROPOSING A NEW DAWN FOR BREAKING THIS VICIOUS CYCLE. THIS REVIEW EXAMINED THE CORE EPIGENETIC MECHANISMS INVOLVED IN THE ACTIVATION AND PHENOTYPIC TRANSFORMATION OF GLIAL CELLS MEDIATED NEUROINFLAMMATION IN PD. WE FOUND THAT EPIGENETIC MECHANISMS DO NOT WORK INDEPENDENTLY, DESPITE BEING COORDINATED WITH EACH OTHER TO ACTIVATE NEUROINFLAMMATORY PATHWAYS. IN THIS REGARD, WE ATTEMPTED TO FIND THE SYNERGIC CORRELATION AND CONTRIBUTION OF THESE EPIGENETIC MODIFICATIONS WITH VARIOUS NEUROINFLAMMATORY PATHWAYS TO BROADEN THE CANVAS OF UNDERLYING PATHOLOGICAL MECHANISMS INVOLVED IN PD DEVELOPMENT. MOREOVER, THIS STUDY HIGHLIGHTED THE DUAL CHARACTERISTICS (NEUROPROTECTIVE/NEUROTOXIC) OF THESE EPIGENETIC MARKS, WHICH MAY COUNTERACT PD PATHOGENESIS AND MAKE THEM POTENTIAL CANDIDATES FOR DEVISING FUTURE PD DIAGNOSIS AND TREATMENT. 2021 17 1869 30 EMERGING ROLE OF DREAM IN HEALTHY BRAIN AND NEUROLOGICAL DISEASES. THE DOWNSTREAM REGULATORY ELEMENT ANTAGONIST MODULATOR (DREAM) IS A MULTIFUNCTIONAL CA(2+)-SENSITIVE PROTEIN EXERTING A DUAL MECHANISM OF ACTION TO REGULATE SEVERAL CA(2+)-DEPENDENT PROCESSES. UPON SUMOYLATION, DREAM ENTERS IN NUCLEUS WHERE IT DOWNREGULATES THE EXPRESSION OF SEVERAL GENES PROVIDED WITH A CONSENSUS SEQUENCE NAMED DREAM REGULATORY ELEMENT (DRE). ON THE OTHER HAND, DREAM COULD ALSO DIRECTLY MODULATE THE ACTIVITY OR THE LOCALIZATION OF SEVERAL CYTOSOLIC AND PLASMA MEMBRANE PROTEINS. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES IN THE KNOWLEDGE OF DREAM DYSREGULATION AND DREAM-DEPENDENT EPIGENETIC REMODELING AS A CENTRAL MECHANISM IN THE PROGRESSION OF SEVERAL DISEASES AFFECTING CENTRAL NERVOUS SYSTEM, INCLUDING STROKE, ALZHEIMER'S AND HUNTINGTON'S DISEASES, AMYOTROPHIC LATERAL SCLEROSIS, AND NEUROPATHIC PAIN. INTERESTINGLY, DREAM SEEMS TO EXERT A COMMON DETRIMENTAL ROLE IN THESE DISEASES BY INHIBITING THE TRANSCRIPTION OF SEVERAL NEUROPROTECTIVE GENES, INCLUDING THE SODIUM/CALCIUM EXCHANGER ISOFORM 3 (NCX3), BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), PRO-DYNORPHIN, AND C-FOS. THESE FINDINGS LEAD TO THE CONCEPT THAT DREAM MIGHT REPRESENT A PHARMACOLOGICAL TARGET TO AMELIORATE SYMPTOMS AND REDUCE NEURODEGENERATIVE PROCESSES IN SEVERAL PATHOLOGICAL CONDITIONS AFFECTING CENTRAL NERVOUS SYSTEM. 2023 18 6904 25 [THE ROLE OF ALUMINUM AND LEAD IN THE DEVELOPMENT OF ALZHEIMER'S AND PARKINSON'S DISEASES]. THE ARTICLE SUMMARIZES THE DATA AVAILABLE IN THE LITERATURE ON THE TOXIC EFFECTS OF ALUMINUM AND LEAD ON THE HUMAN BRAIN AND ASSESSES THE RELATIONSHIP OF THESE EFFECTS TO THE ETIOPATHOGENESIS OF THE MOST COMMON NEURODEGENERATIVE DISEASES, SUCH AS ALZHEIMER'S AND PARKINSON'S DISEASES. THE ACCUMULATION OF IONS OF THESE METALS IN THE BRAIN STRUCTURES LEADS TO CHRONIC INTOXICATION THAT IS MANIFESTED BY THE MORPHOLOGICAL SIGNS THAT ARE TYPICAL FOR ALZHEIMER'S DISEASE, SUCH AS DEPOSITS OF BETA-AMYLOID AND TAU-PROTEIN MAINLY IN THE FRONTAL AND TEMPORAL REGIONS OF THE CORTEX, AND FOR PARKINSON'S DISEASE, SUCH AS DEGENERATION OF DOPAMINE NEURONS IN THE SUBSTANTIA NIGRA AND THEIR ACCUMULATION OF ALPHA-SYNUCLEIN. THE MOST LIKELY FORMS OF PARTICIPATION OF ALUMINUM AND LEAD IONS IN THE MECHANISMS OF NEURODEGENERATION ARE THE REPLACEMENT OF BIVALENT METAL IONS NECESSARY FOR BRAIN FUNCTIONING, OXIDATIVE STRESS INITIATION, EPIGENETIC MODIFICATIONS OF HISTONES, AND INCREASED EXPRESSION OF NONCODING RIBONUCLEIC ACIDS. 2021 19 4427 36 MOLECULAR BASIS OF ELECTROPHILIC AND OXIDATIVE DEFENSE: PROMISES AND PERILS OF NRF2. INDUCTION OF DRUG-METABOLIZING ENZYMES THROUGH THE ANTIOXIDANT RESPONSE ELEMENT (ARE)-DEPENDENT TRANSCRIPTION WAS INITIALLY IMPLICATED IN CHEMOPREVENTION AGAINST CANCER BY ANTIOXIDANTS. RECENT PROGRESS IN UNDERSTANDING THE BIOLOGY AND MECHANISM OF INDUCTION REVEALED A CRITICAL ROLE OF INDUCTION IN CELLULAR DEFENSE AGAINST ELECTROPHILIC AND OXIDATIVE STRESS. INDUCTION IS MEDIATED THROUGH A NOVEL SIGNALING PATHWAY VIA TWO REGULATORY PROTEINS, THE NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) AND THE KELCH-LIKE ERYTHROID CELL-DERIVED PROTEIN WITH CNC HOMOLOGY-ASSOCIATED PROTEIN 1 (KEAP1). NRF2 BINDS TO KEAP1 AT A TWO SITE-BINDING INTERFACE AND IS UBIQUITINATED BY THE KEAP1/CULLIN 3/RING BOX PROTEIN-1-UBIQUITIN LIGASE, RESULTING IN A RAPID TURNOVER OF NRF2 PROTEIN. ELECTROPHILES AND OXIDANTS MODIFY CRITICAL CYSTEINE THIOLS OF KEAP1 AND NRF2 TO INHIBIT NRF2 UBIQUITINATION, LEADING TO NRF2 ACTIVATION AND INDUCTION. INDUCTION INCREASES STRESS RESISTANCE CRITICAL FOR CELL SURVIVAL, BECAUSE KNOCKOUT OF NRF2 IN MICE INCREASED SUSCEPTIBILITY TO A VARIETY OF TOXICITY AND DISEASE PROCESSES. COLLATERAL TO DIVERSE FUNCTIONS OF NRF2, GENOME-WIDE SEARCH HAS LED TO THE IDENTIFICATION OF A PLETHORA OF ARE-DEPENDENT GENES REGULATED BY NRF2 IN AN INDUCER-, TISSUE-, AND DISEASE-DEPENDENT MANNER TO CONTROL DRUG METABOLISM, ANTIOXIDANT DEFENSE, STRESS RESPONSE, PROTEASOMAL DEGRADATION, AND CELL PROLIFERATION. THE PROTECTIVE NATURE OF NRF2 COULD ALSO BE HIJACKED IN A NUMBER OF PATHOLOGICAL CONDITIONS BY MEANS OF SOMATIC MUTATION, EPIGENETIC ALTERATION, AND ACCUMULATION OF DISRUPTOR PROTEINS, PROMOTING DRUG RESISTANCE IN CANCER AND PATHOLOGIC LIVER FEATURES IN AUTOPHAGY DEFICIENCY. THE REPERTOIRE OF ARE INDUCERS HAS EXPANDED ENORMOUSLY; THE THERAPEUTIC POTENTIAL OF THE INDUCERS HAS BEEN EXAMINED BEYOND CANCER PREVENTION. DEVELOPING POTENT AND SPECIFIC ARE INDUCERS AND NRF2 INHIBITORS HOLDS CERTAIN NEW PROMISE FOR THE PREVENTION AND THERAPY AGAINST CANCER, CHRONIC DISEASE, AND TOXICITY. 2012 20 5427 32 REGULATION OF SOCIAL STRESS AND NEURAL DEGENERATION BY ACTIVITY-REGULATED GENES AND EPIGENETIC MECHANISMS IN DOPAMINERGIC NEURONS. TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF BOTH DOPAMINERGIC NEURONS AND THEIR ACCOMPANYING GLIAL CELLS IS OF GREAT INTEREST IN THE SEARCH FOR THERAPIES FOR NEURODEGENERATIVE DISORDERS SUCH AS PARKINSON'S DISEASE (PD). IN THIS REVIEW, WE COLLATE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IDENTIFIED IN ADULT DROSOPHILA MELANOGASTER DOPAMINERGIC NEURONS IN RESPONSE TO EITHER PROLONGED SOCIAL DEPRIVATION OR SOCIAL ENRICHMENT, AND COMPARE THEM WITH CHANGES IDENTIFIED IN MAMMALIAN DOPAMINERGIC NEURONS DURING NORMAL DEVELOPMENT, STRESS, INJURY, AND NEURODEGENERATION. SURPRISINGLY, A SMALL SET OF ACTIVITY-REGULATED GENES (ARG) ENCODING TRANSCRIPTION FACTORS, AND A SPECIFIC PATTERN OF EPIGENETIC MARKS ON GENE PROMOTERS, ARE CONSERVED IN DOPAMINERGIC NEURONS OVER THE LONG EVOLUTIONARY PERIOD BETWEEN MAMMALS AND INSECTS. IN ADDITION TO THEIR CLASSICAL FUNCTION AS IMMEDIATE EARLY GENES TO MARK ACUTE NEURONAL ACTIVITY, THESE ARG TRANSCRIPTION FACTORS ARE REPURPOSED IN BOTH INSECTS AND MAMMALS TO RESPOND TO CHRONIC PERTURBATIONS SUCH AS SOCIAL ENRICHMENT, SOCIAL STRESS, NERVE INJURY, AND NEURODEGENERATION. WE SUGGEST THAT THESE ARG TRANSCRIPTION FACTORS AND EPIGENETIC MARKS MAY REPRESENT IMPORTANT TARGETS FOR FUTURE THERAPEUTIC INTERVENTION STRATEGIES IN VARIOUS NEURODEGENERATIVE DISORDERS INCLUDING PD. 2020