1 616 143 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 2 1416 49 DIETARY POLYPHENOLS REMODEL DNA METHYLATION PATTERNS OF NRF2 IN CHRONIC DISEASE. THE NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) IS A TRANSCRIPTION FACTOR CRUCIAL IN REGULATING CELLULAR HOMEOSTASIS AND APOPTOSIS. THE NRF2 GENE HAS BEEN IMPLICATED IN VARIOUS BIOLOGICAL ACTIVITIES, INCLUDING ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTICANCER PROPERTIES. NRF2 CAN BE REGULATED GENETICALLY AND EPIGENETICALLY AT THE TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND TRANSLATIONAL LEVELS. ALTHOUGH DNA METHYLATION IS ONE OF THE CRITICAL BIOLOGICAL PROCESSES VITAL FOR GENE EXPRESSION, SOMETIMES, ANOMALOUS METHYLATION PATTERNS RESULT IN THE DYSREGULATION OF GENES AND CONSEQUENT DISEASES AND DISORDERS. SEVERAL STUDIES HAVE REPORTED PROMOTER HYPERMETHYLATION DOWNREGULATED NRF2 EXPRESSION AND ITS DOWNSTREAM TARGETS. IN CONTRAST TO THE UNALTERABLE NATURE OF GENETIC PATTERNS, EPIGENETIC CHANGES CAN BE REVERSED, OPENING UP NEW POSSIBILITIES IN DEVELOPING THERAPIES FOR VARIOUS METABOLIC DISORDERS AND DISEASES. THIS REVIEW DISCUSSES THE CURRENT STATE OF THE NRF2-MEDIATED ANTIOXIDATIVE AND CHEMOPREVENTIVE ACTIVITIES OF SEVERAL NATURAL PHYTOCHEMICALS, INCLUDING SULFORAPHANE, RESVERATROL, CURCUMIN, LUTEOLIN, COROSOLIC ACID, APIGENIN, AND MOST OTHER COMPOUNDS THAT HAVE BEEN FOUND TO ACTIVATE NRF2. THIS EPIGENETIC REVERSAL OF HYPERMETHYLATED NRF2 STATES PROVIDES NEW OPPORTUNITIES FOR RESEARCH INTO DIETARY PHYTOCHEMISTRY THAT AFFECTS THE HUMAN EPIGENOME AND THE POSSIBILITY FOR CUTTING-EDGE APPROACHES TO TARGET NRF2-MEDIATED SIGNALING TO PREVENT CHRONIC DISORDERS. 2023 3 4149 32 MECHANISTIC INSIGHT INTO THE EFFECTS OF CURCUMIN ON NEUROINFLAMMATION-DRIVEN CHRONIC PAIN. CHRONIC PAIN IS A PERSISTENT AND UNREMITTING CONDITION THAT HAS IMMENSE EFFECTS ON PATIENTS' QUALITY OF LIFE. STUDIES HAVE SHOWN THAT NEUROINFLAMMATION IS ASSOCIATED WITH THE INDUCTION AND PROGRESSION OF CHRONIC PAIN. THE ACTIVATION OF MICROGLIA AND ASTROCYTES IS THE MAJOR HALLMARK OF SPINAL NEUROINFLAMMATION LEADING TO NEURONAL EXCITABILITY IN THE PROJECTION NEURONS. EXCESSIVE ACTIVATION OF MICROGLIA AND ASTROCYTES IS ONE OF THE MAJOR CONTRIBUTING FACTORS TO THE EXACERBATION OF PAIN. HOWEVER, THE CURRENT CHRONIC PAIN TREATMENTS, MAINLY BY TARGETING THE NEURONAL CELLS, REMAIN INEFFECTIVE AND UNABLE TO MEET THE PATIENTS' NEEDS. CURCUMIN, A NATURAL PLANT PRODUCT FOUND IN THE CURCUMA GENUS, IMPROVES CHRONIC PAIN BY DIMINISHING THE RELEASE OF INFLAMMATORY MEDIATORS FROM THE SPINAL GLIA. THIS REVIEW DETAILS THE ROLE OF CURCUMIN IN MICROGLIA AND ASTROCYTES BOTH IN VITRO AND IN VIVO AND HOW IT IMPROVES PAIN. WE ALSO DESCRIBE THE MECHANISM OF CURCUMIN BY HIGHLIGHTING THE MAJOR GLIA-MEDIATED CASCADES IN PAIN. MOREOVER, THE ROLE OF CURCUMIN ON INFLAMMASOME AND EPIGENETIC REGULATION IS DISCUSSED. FURTHERMORE, WE DISCUSS THE STRATEGIES USED TO IMPROVE THE EFFICACY OF CURCUMIN. THIS REVIEW ILLUSTRATES THAT CURCUMIN MODULATING MICROGLIA AND ASTROCYTES COULD ASSURE THE TREATMENT OF CHRONIC PAIN BY SUPPRESSING SPINAL NEUROINFLAMMATION. 2021 4 4792 43 NUTRITIONAL EPIGENETICS AND PHYTOCHEMICALS IN CANCER FORMATION. NUTRIGENETICS AND NUTRIGENOMICS ARE TWO CONCEPTS IN THE AREA OF NUTRITIONAL GENOMICS. EPIGENETICS IS A NEW DISCIPLINE WITH SIGNIFICANT POTENTIAL IN THE PREVENTION AND MANAGEMENT OF CERTAIN CARCINOMAS AND DISEASES. EPIGENETICS CONSISTS OF DNA METHYLATION, HISTONE MODIFICATION, NON-CODING RNAS, AND TELOMERASE ACTIVITY. EPIGENETIC-BASED MECHANISMS ACT ON THE INHIBITION OF CANCER CELLS BY MODULATING ENZYMES SUCH AS DNA METHYLTRANSFERASE AND HISTONE DEACETYLASE, AS WELL AS NON-CODING RNAS. PHYTOCHEMICALS ARE NATURAL BIOACTIVE COMPONENTS OF PLANT ORIGIN THAT HAVE ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTI-ANGIOGENIC EFFECTS ON VARIOUS DISEASES, ESPECIALLY CANCER. THE EPIGENETIC DIET IS A NUTRITIONAL MODEL BASED ON THE CONSUMPTION OF VARIOUS PHYTOCHEMICALS SUCH AS EPIGALLOCATECHIN-3-GALLATE, MORIN, CAFFEIC ACID PHENYL ESTER, APIGENIN, GENISTEIN, CURCUMIN, RESVERATROL, AND SULFORAPHANE. PHYTOCHEMICALS EXERT THEIR EFFECTS ON CANCER-BASED BY REDUCING CELL PROLIFERATION, INVASION, AND METASTASIS AND INCREASING CELL APOPTOSIS. SIMULTANEOUSLY, IT HAS FUNCTIONS SUCH AS REDUCING ONCOGENES THAT HAVE EFFECTS ON CANCER ETIOLOGY AND INCREASING TUMOR SUPPRESSOR GENES.KEY TEACHING POINTSCANCER IS A CHRONIC DISEASE WITH A HIGH MORTALITY RATE, IN WHICH VARIOUS GENETIC AND ENVIRONMENTAL FACTORS ARE INVOLVED IN ITS ETIOLOGY.PROTOONCOGENES, TUMOR SUPPRESSOR GENES, AND DNA REPAIR GENES ARE AMONG THE GENE GROUPS THAT FORM THE BASIS OF CANCER AND GENETIC STRUCTURE.THE BIDIRECTIONAL INTERACTION BETWEEN NUTRITION AND THE HUMAN GENOME HAS BEEN EFFECTIVE IN THE EMERGENCE OF THE CONCEPTS OF NUTRIGENETICS AND NUTRIGENOMICS.EPIGENETIC DIET IS A DIET BASED ON THE CONSUMPTION OF FOODS SUCH AS SOY, GRAPES, BLUEBERRIES, TURMERIC, CRUCIFEROUS VEGETABLES, AND GREEN TEA, WHICH INDUCE EPIGENETIC MECHANISMS THAT PROTECT AGAINST CANCER AND AGING. 2023 5 2607 36 EPIGENETICS/EPIGENOMICS AND PREVENTION BY CURCUMIN OF EARLY STAGES OF INFLAMMATORY-DRIVEN COLON CANCER. COLORECTAL CANCER (CRC) IS ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY IN THE US AND WORLDWIDE. CRC IS THE SECOND MOST COMMON CANCER-RELATED DEATH IN BOTH MEN AND WOMEN GLOBALLY. CHRONIC INFLAMMATION HAS BEEN IDENTIFIED AS ONE OF THE MAJOR RISK FACTORS OF CRC. IT MAY DRIVE GENETIC AND EPIGENETIC/EPIGENOMIC ALTERATIONS, SUCH AS DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA REGULATION. CURRENT PREVENTION MODALITIES FOR CRC ARE LIMITED AND SOME TREATMENT REGIMENS SUCH AS USE THE NONSTEROIDAL ANTI-INFLAMMATORY DRUG ASPIRIN MAY HAVE SEVERE SIDE EFFECTS, NAMELY GASTROINTESTINAL ULCERATION AND BLEEDING. THEREFORE, THERE IS AN URGENT NEED OF DEVELOPING ALTERNATIVE STRATEGIES. RECENTLY, INCREASING EVIDENCE SUGGESTS THAT SEVERAL DIETARY CANCER CHEMOPREVENTIVE PHYTOCHEMICALS POSSESS ANTI-INFLAMMATION AND ANTIOXIDATIVE STRESS ACTIVITIES, AND MAY PREVENT CANCERS INCLUDING CRC. CURCUMIN (CUR) IS THE YELLOW PIGMENT THAT IS FOUND IN THE RHIZOMES OF TURMERIC (CURCUMA LONGA). MANY STUDIES HAVE DEMONSTRATED THAT CUR EXHIBIT STRONG ANTICANCER, ANTIOXIDATIVE STRESS, AND ANTI-INFLAMMATORY ACTIVITIES BY REGULATING SIGNALING PATHWAYS, SUCH AS NUCLEAR FACTOR ERYTHROID-2-RELATED FACTOR 2, NUCLEAR FACTOR-KAPPAB, AND EPIGENETICS/EPIGENOMICS PATHWAYS OF HISTONES MODIFICATIONS, AND DNA METHYLATION. IN THIS REVIEW, WE WILL DISCUSS THE LATEST EVIDENCE IN EPIGENETICS/EPIGENOMICS ALTERATIONS BY CUR IN CRC AND THEIR POTENTIAL CONTRIBUTION IN THE PREVENTION OF CRC. 2020 6 2352 43 EPIGENETIC REGULATION OF NRF2/KEAP1 BY PHYTOCHEMICALS. EPIGENETICS HAS PROVIDED A NEW DIMENSION TO OUR UNDERSTANDING OF NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2/KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (HUMAN NRF2/KEAP1 AND MURINE NRF2/KEAP1) SIGNALING. UNLIKE THE GENETIC CHANGES AFFECTING DNA SEQUENCE, THE REVERSIBLE NATURE OF EPIGENETIC ALTERATIONS PROVIDES AN ATTRACTIVE AVENUE FOR CANCER INTERCEPTION. THUS, TARGETING EPIGENETIC MECHANISMS IN THE CORRESPONDING SIGNALING NETWORKS REPRESENTS AN ENTICING STRATEGY FOR THERAPEUTIC INTERVENTION WITH DIETARY PHYTOCHEMICALS ACTING AT TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND POST-TRANSLATIONAL LEVELS. THIS REGULATION INVOLVES THE INTERPLAY OF HISTONE MODIFICATIONS AND DNA METHYLATION STATES IN THE HUMAN NFE2L2/KEAP1 AND MURINE NFE2L2/KEAP1 GENES, ACETYLATION OF LYSINE RESIDUES IN NRF2 AND NRF2, INTERACTION WITH BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) ACETYL "READER" PROTEINS, AND NON-CODING RNAS SUCH AS MICRORNA (MIRNA) AND LONG NON-CODING RNA (LNCRNA). PHYTOCHEMICALS DOCUMENTED TO MODULATE NRF2 SIGNALING ACT BY REVERSING HYPERMETHYLATED STATES IN THE CPG ISLANDS OF NFE2L2 OR NFE2L2, VIA THE INHIBITION OF DNA METHYLTRANSFERASES (DNMTS) AND HISTONE DEACETYLASES (HDACS), THROUGH THE INDUCTION OF TEN-ELEVEN TRANSLOCATION (TET) ENZYMES, OR BY INDUCING MIRNA TO TARGET THE 3'-UTR OF THE CORRESPONDING MRNA TRANSCRIPTS. TO DATE, FEWER THAN TWENTY PHYTOCHEMICALS HAVE BEEN REPORTED AS NRF2 EPIGENETIC MODIFIERS, INCLUDING CURCUMIN, SULFORAPHANE, RESVERATROL, RESERPINE, AND URSOLIC ACID. THIS OPENS AVENUES FOR EXPLORING ADDITIONAL DIETARY PHYTOCHEMICALS THAT REGULATE THE HUMAN EPIGENOME, AND THE POTENTIAL FOR NOVEL STRATEGIES TO TARGET NRF2 SIGNALING WITH A VIEW TO BENEFICIAL INTERCEPTION OF CANCER AND OTHER CHRONIC DISEASES. 2020 7 3191 32 HDAC AND HAT INHIBITORS DIFFERENTLY AFFECT ANALGESIA MEDIATED BY GROUP II METABOTROPIC GLUTAMATE RECEPTORS. BACKGROUND: HISTONE DEACETYLASES (HDACS) AND HISTONE ACETYLTRANSFERASES (HATS) ARE KEY PLAYERS IN EPIGENETIC REGULATION OF GENE EXPRESSION. ANALGESIC ACTIVITY BY HDAC INHIBITORS HAS BEEN REPORTED IN DIFFERENT PAIN MODELS INCLUDING INFLAMMATORY AND NEUROPATHIC PAIN. THESE DRUGS INTERFERE WITH GENE EXPRESSION THROUGH DIFFERENT MECHANISMS INCLUDING CHROMATIN REMODELING AND/OR ACTIVATION OF TRANSCRIPTION FACTORS. AMONG OTHER TARGETS, HDAC INHIBITORS REGULATE METABOTROPIC GLUTAMATE RECEPTORS TYPE 2 (MGLU2) EXPRESSION IN CENTRAL AND PERIPHERAL CENTRAL NERVOUS SYSTEM. HOWEVER WHETHER INHIBITION OF HAT ACTIVITY ALSO REGULATES MGLU2 EXPRESSION HAS NOT BEEN REPORTED. FINDINGS: HERE WE REPORT THAT CURCUMIN (CUR), A NATURALLY OCCURRING COMPOUND ENDOWED WITH P300/CREB-BINDING PROTEIN HAT INHIBITORY ACTIVITY, IS ABLE TO INDUCE A DRASTIC DOWN-REGULATION OF THE MGLU2 RECEPTOR IN THE MOUSE SPINAL CORD AFTER SYSTEMIC ADMINISTRATION TOGETHER WITH A MARKED HYPOACETYLATION OF HISTONES H3 AND H4 IN DORSAL ROOT GANGLIA (DRG). FURTHERMORE, THE ANALGESIC ACTIVITY OF THE MGLU2/3 AGONIST, LY379268 IS LOST AFTER A 3-DAY TREATMENT WITH CUR. CONVERSELY THE ANALGESIC ACTIVITY OF LY379268 IS POTENTIATED IN MICE PRETREATED FOR 5 CONSECUTIVE DAYS WITH THE HDAC INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), KNOWN TO INDUCE MGLU2-UPREGULATION. CONCLUSIONS: OUR RESULTS DEMONSTRATE THAT SYSTEMICALLY INJECTED CUR IS ABLE TO INHIBIT H3 AND H4 ACETYLATION IN THE DRG AND TO DOWN-REGULATE MGLU2 RECEPTORS IN THE SPINAL CORD. WE ALSO DEMONSTRATE THAT LONG TERM MODIFICATION OF THE MGLU2 EXPRESSION AFFECTS THE ANALGESIC PROPERTIES OF THE ORTHOSTERIC MGLU2/3 AGONIST, LY379268. THESE DATA OPEN UP THE POSSIBILITY THAT EPIGENETIC MODULATORS MIGHT BE GIVEN IN COMBINATION WITH "TRADITIONAL" DRUGS IN A CONTEXT OF A MULTI TARGET APPROACH FOR A BETTER ANALGESIC EFFICACY. 2014 8 5858 38 SULFORAPHANE AND EPIGALLOCATECHIN GALLATE RESTORE ESTROGEN RECEPTOR EXPRESSION BY MODULATING EPIGENETIC EVENTS IN THE BREAST CANCER CELL LINE MDA-MB-231: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND/AIMS: EPIGENETICS REFERS TO MODIFICATIONS IN GENE ACTIVITY AND EXPRESSION WITHOUT ALTERATION AT THE DNA SEQUENCE. ENVIRONMENT AND DIET COULD INFLUENCE GENE EXPRESSION. DIET MODIFICATIONS MAY BE MEANINGFUL IN PREVENTING AND TREATING CHRONIC DISEASES, CANCER INCLUDED. DIETARY BIOACTIVE COMPOUNDS, SUCH AS POLYPHENOLS (E.G., CURCUMIN, RESVERATROL, OR EPIGALLOCATECHIN GALLATE [EGCG]) OR ISOTHIOCYANATE (E.G., SULFORAPHANE [SFN]), CAN REGULATE HISTONE ACETYLATION. THE AIM OF THIS SYSTEMATIC REVIEW AND META-ANALYSIS WAS TO EVALUATE THE EFFECT OF SFN AND EGCG ON BREAST CANCER (BC) CELLS CULTURED IN VITRO. METHODS: DUE TO THE ENORMOUS VARIABILITY OBSERVED IN STUDY PROTOCOLS AND THE INNUMERABLE GENES INVOLVED, ONLY STUDIES ANALYZING THE NUMBER OF APOPTOTIC CELLS IN THE MDA-MB-231 CELL LINE WERE EVALUATED. THE EFFECT SIZE (ES) WAS COMPUTED AS THE RATIO OF MEANS. RESULTS: WE IDENTIFIED 7 STUDIES, 4 REGARDING THE EFFECT OF 10 MICROM SFN ON MDA-MB-231 CELLS (ES = 4.59, 95% CONFIDENCE INTERVAL 4.05-5.20) AND 3 FOCUSING ON THE IMPACT OF 20 MICROM EGCG (ES = 2.84, 95% CONFIDENCE INTERVAL 2.60-3.10). CONCLUSION: THE FINDINGS SUGGEST BENEFICIAL EFFECTS OF DIETARY BIOACTIVE COMPOUNDS SUCH AS SFN AND EGCG AND THEIR EFFECT ON BC CELLS BY RESTORING ESTROGEN RECEPTOR GENE EXPRESSION, MODULATING EPIGENETIC CHANGES AND EVENTS, AND INTERFERING WITH TUMOR GROWTH RATE. PUBLICATION BIAS LIMITS THE GENERALIZABILITY OF THE CONCLUSIONS. HIGH-QUALITY STUDIES ARE NEEDED. 2017 9 6166 40 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 10 5043 31 PHARMACOKINETICS AND PHARMACODYNAMICS OF CURCUMIN IN REGULATING ANTI-INFLAMMATORY AND EPIGENETIC GENE EXPRESSION. CHRONIC INFLAMMATION IS A KEY DRIVER OF CANCER DEVELOPMENT. NITRITE LEVELS, WHICH ARE REGULATED BY INDUCIBLE NITRIC OXIDE SYNTHASE (INOS), PLAY A CRITICAL ROLE IN INFLAMMATION. WHILE THE ANTI-OXIDANT AND ANTI-INFLAMMATORY EFFECTS OF CURCUMIN, A NATURAL PRODUCT PRESENT IN THE ROOTS OF CURCUMA LONGA HAVE BEEN STUDIED WIDELY, THE ACUTE PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD) OF CURCUMIN IN SUPPRESSING PRO-INFLAMMATORY MARKERS AND EPIGENETIC MODULATORS REMAIN UNCLEAR. THIS STUDY EVALUATED THE PK AND PD OF CURCUMIN-INDUCED SUPPRESSION OF LIPOPOLYSACCHARIDE (LPS)-MEDIATED INFLAMMATION IN RAT LYMPHOCYTES. LPS WAS ADMINISTERED INTRAVENOUSLY EITHER ALONE OR WITH CURCUMIN TO FEMALE SPRAGUE-DAWLEY RATS. PLASMA SAMPLES WERE ANALYSED FOR CURCUMIN CONCENTRATION AND MRNA EXPRESSION WAS QUANTIFIED IN LYMPHOCYTES. THE RELATIVE GENE EXPRESSION OF SEVERAL INFLAMMATORY AND EPIGENETIC MODULATORS WAS ANALYSED. TO INVESTIGATE THE RELATIONSHIP BETWEEN CURCUMIN CONCENTRATION AND INOS, TNF-ALPHA, AND IL-6 GENE EXPRESSION, PK/PD MODELING USING JUSKO'S INDIRECT RESPONSE MODEL (IDR) INTEGRATING TRANSIT COMPARTMENTS (TC) DESCRIBING THE DELAYED RESPONSE WAS CONDUCTED. THE CONCENTRATION-TIME PROFILE OF CURCUMIN EXHIBITED A BI-EXPONENTIAL DECLINE, WHICH WAS WELL DESCRIBED BY A TWO-COMPARTMENTAL PHARMACOKINETIC MODEL. IMPORTANTLY THE RESULTS DEMONSTRATE THAT LPS INDUCED GENE EXPRESSION OF PRO-INFLAMMATORY MARKERS IN LYMPHOCYTES, WITH PEAK EXPRESSION AT APPROXIMATELY 3 H AND CURCUMIN SUPPRESSED THE GENE EXPRESSION IN ANIMALS ADMINISTERED WITH LPS. THESE EFFECTS WERE WELL CAPTURED USING THE IDR MODEL AND AN IDR MODEL WITH THE TRANSIT COMPARTMENTS. IN SUMMARY, THE PK/PD MODELING APPROACH COULD POTENTIALLY PROVIDE A ROBUST QUANTITATIVE FRAMEWORK FOR EVALUATING THE ACUTE ANTI-INFLAMMATORY AND EPIGENETIC EFFECTS OF CURCUMIN IN FUTURE CLINICAL TRIALS. 2018 11 1406 39 DIETARY HISTONE DEACETYLASE INHIBITORS: FROM CELLS TO MICE TO MAN. SULFORAPHANE (SFN) IS AN ISOTHIOCYANATE FOUND IN CRUCIFEROUS VEGETABLES, SUCH AS BROCCOLI AND BROCCOLI SPROUTS. THIS ANTICARCINOGEN WAS FIRST IDENTIFIED AS A POTENT INDUCER OF PHASE 2 DETOXIFICATION ENZYMES, BUT EVIDENCE IS MOUNTING THAT SFN ALSO ACTS THROUGH EPIGENETIC MECHANISMS. SFN HAS BEEN SHOWN TO INHIBIT HISTONE DEACETYLASE (HDAC) ACTIVITY IN HUMAN COLON AND PROSTATE CANCER LINES, WITH AN INCREASE IN GLOBAL AND LOCAL HISTONE ACETYLATION STATUS, SUCH AS ON THE PROMOTER REGIONS OF P21 AND BAX GENES. SFN ALSO INHIBITED THE GROWTH OF PROSTATE CANCER XENOGRAFTS AND SPONTANEOUS INTESTINAL POLYPS IN MOUSE MODELS, WITH EVIDENCE FOR ALTERED HISTONE ACETYLATION AND HDAC ACTIVITIES IN VIVO. IN HUMAN SUBJECTS, A SINGLE INGESTION OF 68 G BROCCOLI SPROUTS INHIBITED HDAC ACTIVITY IN CIRCULATING PERIPHERAL BLOOD MONONUCLEAR CELLS 3-6 H AFTER CONSUMPTION, WITH CONCOMITANT INDUCTION OF HISTONE H3 AND H4 ACETYLATION. THESE FINDINGS PROVIDE EVIDENCE THAT ONE MECHANISM OF CANCER CHEMOPREVENTION BY SFN IS VIA EPIGENETIC CHANGES ASSOCIATED WITH INHIBITION OF HDAC ACTIVITY. OTHER DIETARY AGENTS SUCH AS BUTYRATE, BIOTIN, LIPOIC ACID, GARLIC ORGANOSULFUR COMPOUNDS, AND METABOLITES OF VITAMIN E HAVE STRUCTURAL FEATURES COMPATIBLE WITH HDAC INHIBITION. THE ABILITY OF DIETARY COMPOUNDS TO DE-REPRESS EPIGENETICALLY SILENCED GENES IN CANCER CELLS, AND TO ACTIVATE THESE GENES IN NORMAL CELLS, HAS IMPORTANT IMPLICATIONS FOR CANCER PREVENTION AND THERAPY. IN A BROADER CONTEXT, THERE IS GROWING INTEREST IN DIETARY HDAC INHIBITORS AND THEIR IMPACT ON EPIGENETIC MECHANISMS AFFECTING OTHER CHRONIC CONDITIONS, SUCH AS CARDIOVASCULAR DISEASE, NEURODEGENERATION AND AGING. 2007 12 2353 22 EPIGENETIC REGULATION OF OPIOID-INDUCED HYPERALGESIA, DEPENDENCE, AND TOLERANCE IN MICE. REPEATED ADMINISTRATION OF OPIOIDS SUCH AS MORPHINE INDUCES PERSISTENT BEHAVIORAL CHANGES INCLUDING OPIOID-INDUCED HYPERALGESIA (OIH), TOLERANCE, AND PHYSICAL DEPENDENCE. IN THE CURRENT WORK WE EXPLORED HOW THE BALANCE OF HISTONE ACETYLTRANSFERASE (HAT) VERSUS HISTONE DEACETYLASE (HDAC) MIGHT REGULATE THESE MORPHINE-INDUCED CHANGES. NOCICEPTIVE THRESHOLDS, ANALGESIA, AND PHYSICAL DEPENDENCE WERE ASSESSED DURING AND FOR A PERIOD OF SEVERAL WEEKS AFTER MORPHINE EXPOSURE. TO PROBE THE ROLES OF HISTONE ACETYLATION, THE HAT INHIBITOR CURCUMIN OR A SELECTIVE HDAC INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) WAS ADMINISTERED DAILY TO GROUPS OF ANIMALS. HISTONE ACETYLATION IN SPINAL CORD WAS ASSESSED BY WESTERN BLOT AND IMMUNOHISTOCHEMISTRY. CONCURRENT ADMINISTRATION OF CURCUMIN WITH MORPHINE FOR 4 DAYS SIGNIFICANTLY REDUCED DEVELOPMENT OF OPIOID-INDUCED MECHANICAL ALLODYNIA, THERMAL HYPERALGESIA, TOLERANCE, AND PHYSICAL DEPENDENCE. CONVERSELY, THE HDAC INHIBITOR SAHA ENHANCED THESE RESPONSES. INTERESTINGLY, SAHA TREATMENT AFTER THE TERMINATION OF OPIOID ADMINISTRATION SUSTAINED THESE BEHAVIORAL CHANGES FOR AT LEAST 4 WEEKS. HISTONE H3 ACETYLATION IN THE DORSAL HORN OF THE SPINAL CORD WAS INCREASED AFTER CHRONIC MORPHINE TREATMENT, BUT H4 ACETYLATION WAS UNCHANGED. MOREOVER, WE OBSERVED A DECREASE IN HDAC ACTIVITY IN THE SPINAL CORDS OF MORPHINE-TREATED MICE WHILE OVERALL HAT ACTIVITY WAS UNCHANGED, SUGGESTING A SHIFT TOWARD A STATE OF ENHANCED HISTONE ACETYLATION. PERSPECTIVE: THE CURRENT STUDY INDICATES THAT EPIGENETIC MECHANISMS PLAY A CRUCIAL ROLE IN OPIOID-INDUCED LONG-LASTING NEUROPLASTICITY. THESE RESULTS PROVIDE NEW SIGHT INTO UNDERSTANDING THE MECHANISMS OF OPIOID-INDUCED NEUROPLASTICITY AND SUGGEST NEW STRATEGIES TO LIMIT OPIOID ABUSE POTENTIAL AND INCREASE THE VALUE OF THESE DRUGS AS ANALGESICS. 2013 13 1945 38 EPIGALLOCATECHIN-3-GALLATE, A HISTONE ACETYLTRANSFERASE INHIBITOR, INHIBITS EBV-INDUCED B LYMPHOCYTE TRANSFORMATION VIA SUPPRESSION OF RELA ACETYLATION. BECAUSE THE P300/CBP-MEDIATED HYPERACETYLATION OF RELA (P65) IS CRITICAL FOR NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) ACTIVATION, THE ATTENUATION OF P65 ACETYLATION IS A POTENTIAL MOLECULAR TARGET FOR THE PREVENTION OF CHRONIC INFLAMMATION. DURING OUR ONGOING SCREENING STUDY TO IDENTIFY NATURAL COMPOUNDS WITH HISTONE ACETYLTRANSFERASE INHIBITOR (HATI) ACTIVITY, WE IDENTIFIED EPIGALLOCATECHIN-3-GALLATE (EGCG) AS A NOVEL HATI WITH GLOBAL SPECIFICITY FOR THE MAJORITY OF HAT ENZYMES BUT WITH NO ACTIVITY TOWARD EPIGENETIC ENZYMES INCLUDING HDAC, SIRT1, AND HMTASE. AT A DOSE OF 100 MICROMOL/L, EGCG ABROGATES P300-INDUCED P65 ACETYLATION IN VITRO AND IN VIVO, INCREASES THE LEVEL OF CYTOSOLIC IKAPPABALPHA, AND SUPPRESSES TUMOR NECROSIS FACTOR ALPHA (TNFALPHA)-INDUCED NF-KAPPAB ACTIVATION. WE ALSO SHOWED THAT EGCG PREVENTS TNFALPHA-INDUCED P65 TRANSLOCATION TO THE NUCLEUS, CONFIRMING THAT HYPERACETYLATION IS CRITICAL FOR NF-KAPPAB TRANSLOCATION AS WELL AS ACTIVITY. FURTHERMORE, EGCG TREATMENT INHIBITED THE ACETYLATION OF P65 AND THE EXPRESSION OF NF-KAPPAB TARGET GENES IN RESPONSE TO DIVERSE STIMULI. FINALLY, EGCG REDUCED THE BINDING OF P300 TO THE PROMOTER REGION OF INTERLEUKIN-6 GENE WITH AN INCREASED RECRUITMENT OF HDAC3, WHICH HIGHLIGHTS THE IMPORTANCE OF THE BALANCE BETWEEN HATS AND HISTONE DEACETYLASES IN THE NF-KAPPAB-MEDIATED INFLAMMATORY SIGNALING PATHWAY. IMPORTANTLY, EGCG AT 50 MICROMOL/L DOSE COMPLETELY BLOCKS EBV INFECTION-INDUCED CYTOKINE EXPRESSION AND SUBSEQUENTLY THE EBV-INDUCED B LYMPHOCYTE TRANSFORMATION. THESE RESULTS SHOW THE CRUCIAL ROLE OF ACETYLATION IN THE DEVELOPMENT OF INFLAMMATORY-RELATED DISEASES. 2009 14 1238 20 CURCUMIN BLOCKS CHRONIC MORPHINE ANALGESIC TOLERANCE AND BRAIN-DERIVED NEUROTROPHIC FACTOR UPREGULATION. THIS STUDY WAS CARRIED OUT BASED ON THE ASSUMPTION THAT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MAY COUNTERBALANCE THE ACTION OF MORPHINE IN THE BRAIN. MORPHINE ANALGESIC TOLERANCE AFTER DAILY ADMINISTRATIONS FOR SIX DAYS WAS BLOCKED BY INTRACEREBROVENTRICULAR INJECTION OF ANTI-BDNF IGG ON DAY 5, BUT NOT BY ADMINISTRATIONS ON DAYS 1-4. CHRONIC MORPHINE TREATMENT SIGNIFICANTLY INCREASED THE EXPRESSION OF EXON I AND IV BDNF TRANSCRIPTS, INDICATING DIFFERENTIAL REGULATION OF BDNF GENE EXPRESSION. DAILY ADMINISTRATION OF THE CREB-BINDING PROTEIN INHIBITOR CURCUMIN ABOLISHED THE UPREGULATION OF BDNF TRANSCRIPTION AND MORPHINE ANALGESIC TOLERANCE. THESE RESULTS SUGGEST THAT CURCUMIN MIGHT BE A PROMISING ADJUVANT TO REDUCE MORPHINE ANALGESIC TOLERANCE, AND THAT EPIGENETIC CONTROL COULD BE A NEW STRATEGY USEFUL FOR THE CONTROL OF THIS PROBLEM. 2009 15 1413 39 DIETARY PHYTOCHEMICALS AND CANCER CHEMOPREVENTION: A PERSPECTIVE ON OXIDATIVE STRESS, INFLAMMATION, AND EPIGENETICS. OXIDATIVE STRESS OCCURS WHEN CELLULAR REACTIVE OXYGEN SPECIES LEVELS EXCEED THE SELF-ANTIOXIDANT CAPACITY OF THE BODY. OXIDATIVE STRESS INDUCES MANY PATHOLOGICAL CHANGES, INCLUDING INFLAMMATION AND CANCER. CHRONIC INFLAMMATION IS BELIEVED TO BE STRONGLY ASSOCIATED WITH THE MAJOR STAGES OF CARCINOGENESIS. THE NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2) PATHWAY PLAYS A CRUCIAL ROLE IN REGULATING OXIDATIVE STRESS AND INFLAMMATION BY MANIPULATING KEY ANTIOXIDANT AND DETOXIFICATION ENZYME GENES VIA THE ANTIOXIDANT RESPONSE ELEMENT. MANY DIETARY PHYTOCHEMICALS WITH CANCER CHEMOPREVENTIVE PROPERTIES, SUCH AS POLYPHENOLS, ISOTHIOCYANATES, AND TRITERPENOIDS, EXERT ANTIOXIDANT AND ANTI-INFLAMMATORY FUNCTIONS BY ACTIVATING THE NRF2 PATHWAY. FURTHERMORE, EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS, AND MIRNA-MEDIATED POST-TRANSCRIPTIONAL ALTERATIONS, ALSO LEAD TO VARIOUS CARCINOGENESIS PROCESSES BY SUPPRESSING CANCER REPRESSOR GENE TRANSCRIPTION. USING EPIGENETIC RESEARCH TOOLS, INCLUDING NEXT-GENERATION SEQUENCING TECHNOLOGIES, MANY DIETARY PHYTOCHEMICALS ARE SHOWN TO MODIFY AND REVERSE ABERRANT EPIGENETIC/EPIGENOME CHANGES, POTENTIALLY LEADING TO CANCER PREVENTION/TREATMENT. THUS, THE BENEFICIAL EFFECTS OF DIETARY PHYTOCHEMICALS ON CANCER DEVELOPMENT WARRANT FURTHER INVESTIGATION TO PROVIDE ADDITIONAL IMPETUS FOR CLINICAL TRANSLATIONAL STUDIES. 2016 16 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 17 4044 29 MACROPHAGES IN OXIDATIVE STRESS AND MODELS TO EVALUATE THE ANTIOXIDANT FUNCTION OF DIETARY NATURAL COMPOUNDS. ANTIOXIDANT TESTING OF NATURAL PRODUCTS HAS ATTRACTED INCREASING INTEREST IN RECENT YEARS, MAINLY DUE TO THE FACT THAT AN ANTIOXIDANT-RICH DIET MIGHT PROVIDE HEALTH BENEFITS. ACTIVATED MACROPHAGES ARE A MAJOR SOURCE OF REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES, AND PEROXYNITRITE GENERATED THROUGH THE SO-CALLED RESPIRATORY BURST. CONSTITUTIVELY RELEASED PROINFLAMMATORY CYTOKINE, ESPECIALLY TUMOR NECROSIS FACTOR-ALPHA, TRIGGERS NUCLEAR FACTOR-KAPPAB, AND ACTIVATOR PROTEIN-1 TRANSLOCATION LEADING TO THE OVER PRODUCTION OF REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN SPECIES IN MACROPHAGES. ACTIVATION OF TRANSCRIPTION FACTORS IN THE LONG-LIVED TISSUE-RESIDENT MACROPHAGES AND/OR MONOCYTE-DERIVED MACROPHAGES, TRIGGER EPIGENETIC MODIFICATIONS LEADING TO THE PATHOGENESIS OF CHRONIC DISEASES. NUTRACEUTICALS INCLUDING LIPID RAFT STRUCTURE DISRUPTION AGENT, CHOLESTEROL DEPLETION AGENT, FARNESYLTRANSFERASE INHIBITOR, NUCLEAR FACTOR-KAPPAB BLOCKER (ALPHA,BETA-UNSATURATED CARBONYL COMPOUNDS), GLUCOCORTICOID RECEPTOR AGONIST, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST HAVE LONG BEEN USED TO INACTIVE MACROPHAGE. THE INHIBITION EFFECTS ON THE FORMATION OF NITRIC OXIDE, SUPEROXIDE, AND NITRITE PEROXIDE MAY BE RESPONSIBLE FOR THE ANTI-INFLAMMATORY FUNCTIONALITIES. ACTIVATED MACROPHAGE MODELS COULD BE USED TO IDENTIFY THE ACTIVE COMPONENTS FOR FUNCTIONAL DIETS DEVELOPMENT THROUGH A MULTIPLE TARGETS STRATEGY. 2017 18 4396 33 MODULATION OF CHRONIC INFLAMMATION BY QUERCETIN: THE BENEFICIAL EFFECTS ON OBESITY. OBESITY HAS BECOME A MAJOR RISK FACTOR FOR THE DEVELOPMENT OF CHRONIC DISEASES SUCH AS INSULIN RESISTANCE, TYPE 2 DIABETES MELLITUS, AND CARDIOVASCULAR DISEASE. MOREOVER, OBESITY INDUCES CHRONIC INFLAMMATION IN ADIPOSE TISSUE, LIVER, SKELETAL MUSCLE, AND THE VASCULAR SYSTEM. QUERCETIN IS THE MAJOR REPRESENTATIVE OF THE FLAVONOID SUBCLASS OF FLAVONOLS, WHICH IS UBIQUITOUSLY CONTAINED WITHIN NATURAL PLANTS SUCH AS GREEN TEA, AND VEGETABLES, INCLUDING ONIONS AND APPLES. RESEARCHERS HAVE FOCUSED GREATER ATTENTION TO THE BENEFICIAL PHYSIOLOGICAL ROLES OF QUERCETIN, WHICH HAS ANTI-OXIDATIVE, ANTI-INFLAMMATORY, AND ANTI-FIBROTIC EFFECTS ON INSULIN RESISTANCE AND ATHEROSCLEROSIS IN OBESITY-RELATED DISEASES. ALSO, THE ANTI-INFLAMMATORY EFFECTS OF QUERCETIN ON INTESTINAL MICROBIOTA HAVE BEEN DEMONSTRATED IN OBESITY. IN ADDITION, THERE IS INCREASING EVIDENCE THAT QUERCETIN IS ASSOCIATED WITH EPIGENETIC ACTIVITIES IN CANCER, AND IN MATERNAL UNDERNUTRITION DURING GESTATION AND LACTATION. IN THIS REVIEW, WE FOCUS ON THE CHEMICAL PROPERTIES OF QUERCETIN, ITS DIETARY SOURCES IN OBESITY, AND ITS ANTI-INFLAMMATORY EFFECTS ON INSULIN RESISTANCE, ATHEROSCLEROSIS, INTESTINAL MICROBIOTA, AND MATERNAL UNDER-NUTRITION WITH EPIGENETIC ACTIVITY. 2020 19 3212 30 HEALTH PROMOTING EFFECTS OF BRASSICA-DERIVED PHYTOCHEMICALS: FROM CHEMOPREVENTIVE AND ANTI-INFLAMMATORY ACTIVITIES TO EPIGENETIC REGULATION. A HIGH INTAKE OF BRASSICA VEGETABLES MAY BE ASSOCIATED WITH A DECREASED CHRONIC DISEASE RISK. HEALTH PROMOTING EFFECTS OF BRASSICACEAE HAVE BEEN PARTLY ATTRIBUTED TO GLUCOSINOLATES AND IN PARTICULAR TO THEIR HYDROLYZATION PRODUCTS INCLUDING ISOTHIOCYANATES. IN VITRO AND IN VIVO STUDIES SUGGEST A CHEMOPREVENTIVE ACTIVITY OF ISOTHIOCYANATES THROUGH THE REDOX-SENSITIVE TRANSCRIPTION FACTOR NRF2. FURTHERMORE, STUDIES IN CULTURED CELLS, IN LABORATORY RODENTS, AND ALSO IN HUMANS SUPPORT AN ANTI-INFLAMMATORY EFFECT OF BRASSICA-DERIVED PHYTOCHEMICALS. HOWEVER, THE UNDERLYING MECHANISMS OF HOW THESE COMPOUNDS MEDIATE THEIR HEALTH PROMOTING EFFECTS ARE YET NOT FULLY UNDERSTOOD. RECENT FINDINGS SUGGEST THAT BRASSICA-DERIVED COMPOUNDS ARE REGULATORS OF EPIGENETIC MECHANISMS. IT HAS BEEN SHOWN THAT ISOTHIOCYANATES MAY INHIBIT HISTONE DEACETYLASE TRANSFERASES AND DNA-METHYLTRANSFERASES IN CULTURED CELLS. ONLY A FEW PAPERS HAVE DEALT WITH THE EFFECT OF BRASSICA-DERIVED COMPOUNDS ON EPIGENETIC MECHANISMS IN LABORATORY ANIMALS, WHEREAS DATA IN HUMANS ARE CURRENTLY LACKING. THE PRESENT REVIEW AIMS TO SUMMARIZE THE CURRENT KNOWLEDGE REGARDING THE BIOLOGICAL ACTIVITIES OF BRASSICA-DERIVED PHYTOCHEMICALS REGARDING CHEMOPREVENTIVE, ANTI-INFLAMMATORY, AND EPIGENETIC PATHWAYS. 2013 20 5046 47 PHARMACOLOGICAL AND DIETARY ANTIOXIDANT THERAPIES FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE PROGRESSION AND EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE INTIMATELY ASSOCIATED WITH TOBACCO SMOKE/BIOMASS FUEL-INDUCED OXIDATIVE AND ALDEHYDE/CARBONYL STRESS. ALTERATIONS IN REDOX SIGNALING PROINFLAMMATORY KINASES AND TRANSCRIPTION FACTORS, STEROID RESISTANCE, UNFOLDED PROTEIN RESPONSE, MUCUS HYPERSECRETION, EXTRACELLULAR MATRIX REMODELING, AUTOPHAGY/APOPTOSIS, EPIGENETIC CHANGES, CELLULAR SENESCENCE/AGING, ENDOTHELIAL DYSFUNCTION, AUTOIMMUNITY, AND SKELETAL MUSCLE DYSFUNCTION ARE SOME OF THE PATHOLOGICAL HALLMARKS OF COPD. IN LIGHT OF THE ABOVE IT WOULD BE PRUDENT TO TARGET SYSTEMIC AND LOCAL OXIDATIVE STRESS WITH AGENTS THAT CAN MODULATE THE ANTIOXIDANTS/ REDOX SYSTEM OR BY BOOSTING THE ENDOGENOUS LEVELS OF ANTIOXIDANTS FOR THE TREATMENT AND MANAGEMENT OF COPD. IDENTIFICATION OF VARIOUS ANTIOXIDANT AGENTS, SUCH AS THIOL MOLECULES (GLUTATHIONE AND MUCOLYTIC DRUGS, SUCH AS N-ACETYL-L-CYSTEINE, N-ACYSTELYN, ERDOSTEINE, FUDOSTEINE, ERGOTHIONEINE, AND CARBOCYSTEINE LYSINE SALT), DIETARY NATURAL PRODUCT-DERIVED POLYPHENOLS AND OTHER COMPOUNDS (CURCUMIN, RESVERATROL, GREEN TEA CATECHINS, QUERCETIN SULFORAPHANE, LYCOPENE, ACAI, ALPHA-LIPOIC ACID, TOCOTRIENOLS, AND APOCYNIN) HAVE MADE IT POSSIBLE TO MODULATE VARIOUS BIOCHEMICAL ASPECTS OF COPD. VARIOUS RESEARCHES AND CLINICAL TRIALS HAVE REVEALED THAT THESE ANTIOXIDANTS CAN DETOXIFY FREE RADICALS AND OXIDANTS, CONTROL EXPRESSION OF REDOX AND GLUTATHIONE BIOSYNTHESIS GENES, CHROMATIN REMODELING, AND ULTIMATELY INFLAMMATORY GENE EXPRESSION. IN ADDITION, MODULATION OF CIGARETTE SMOKE-INDUCED OXIDATIVE STRESS AND RELATED CELLULAR CHANGES HAVE ALSO BEEN REPORTED TO BE EFFECTED BY SYNTHETIC MOLECULES. THIS INCLUDES SPECIFIC SPIN TRAPS LIKE ALPHA-PHENYL-N-TERT-BUTYL NITRONE, A CATALYTIC ANTIOXIDANT (ECSOD MIMETIC), PORPHYRINS (AEOL 10150 AND AEOL 10113), AND A SUPEROXIDE DISMUTASE MIMETIC M40419, LIPID PEROXIDATION AND PROTEIN CARBONYLATION BLOCKERS/INHIBITORS, SUCH AS EDARAVONE AND LAZAROIDS/TIRILAZAD, MYELOPEROXIDASE INHIBITORS, AS WELL AS SPECIALIZED PRO-RESOLVING MEDIATORS/INFLAMMATORY RESOLVING LIPID MEDIATORS, OMEGA-3 FATTY ACIDS, VITAMIN D, AND HYDROGEN SULFIDE. ACCORDING TO VARIOUS STUDIES IT APPEARS THAT THE ADMINISTRATION OF MULTIPLE ANTIOXIDANTS COULD BE A MORE EFFECTIVE MODE USED IN THE TREATMENT OF COPD. IN THIS REVIEW, VARIOUS PHARMACOLOGICAL AND DIETARY APPROACHES TO ENHANCE LUNG ANTIOXIDANT LEVELS AND BENEFICIAL EFFECTS OF ANTIOXIDANT THERAPEUTICS IN TREATING OR INTERVENING THE PROGRESSION OF COPD HAVE BEEN DISCUSSED. 2013