1   294 82 AGING INCREASES VULNERABILITY TO STRESS-INDUCED DEPRESSION VIA UPREGULATION OF NADPH OXIDASE IN MICE. BRAIN AGING PROCEEDS WITH CELLULAR AND MOLECULAR CHANGES IN THE LIMBIC SYSTEM. AGING-DEPENDENT CHANGES MIGHT AFFECT EMOTION AND STRESS COPING, YET THE UNDERLYING MECHANISMS REMAIN UNCLEAR. HERE, WE SHOW AGED (18-MONTH-OLD) MICE EXHIBIT UPREGULATION OF NADPH OXIDASE AND OXIDATIVE STRESS IN THE HIPPOCAMPUS, WHICH MIRRORS THE CHANGES IN YOUNG (2-MONTH-OLD) MICE SUBJECTED TO CHRONIC STRESS. AGED MICE THAT LACK P47PHOX, A KEY SUBUNIT OF NADPH OXIDASE, DO NOT SHOW INCREASED OXIDATIVE STRESS. AGED MICE EXHIBIT DEPRESSION-LIKE BEHAVIOR FOLLOWING WEAK STRESS THAT DOES NOT PRODUCE DEPRESSIVE BEHAVIOR IN YOUNG MICE. AGED MICE HAVE REDUCED EXPRESSION OF THE EPIGENETIC FACTOR SUV39H1 AND ITS UPSTREAM REGULATOR P-AMPK, AND INCREASED EXPRESSION OF PPP2CA IN THE HIPPOCAMPUS-CHANGES THAT OCCUR IN YOUNG MICE EXPOSED TO CHRONIC STRESS. SUV39H1 MEDIATES STRESS- AND AGING-INDUCED SUSTAINED UPREGULATION OF P47PHOX AND OXIDATIVE STRESS. THESE RESULTS SUGGEST THAT AGING INCREASES SUSCEPTIBILITY TO STRESS BY UPREGULATING NADPH OXIDASE IN THE HIPPOCAMPUS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2  2181 21 EPIGENETIC MECHANISMS REGULATE NADPH OXIDASE-4 EXPRESSION IN CELLULAR SENESCENCE. AGING IS A WELL-KNOWN RISK FACTOR FOR A LARGE NUMBER OF CHRONIC DISEASES, INCLUDING THOSE OF THE LUNG. CELLULAR SENESCENCE IS ONE OF THE HALLMARKS OF AGING, AND CONTRIBUTES TO THE PATHOGENESIS OF AGE-RELATED DISEASES. RECENT STUDIES IMPLICATE THE REACTIVE OXYGEN SPECIES (ROS)-GENERATING ENZYME, NADPH OXIDASE 4 (NOX4) IN CELLULAR SENESCENCE. IN THIS STUDY, WE INVESTIGATED POTENTIAL MECHANISMS FOR EPIGENETIC REGULATION OF NOX4. WE OBSERVED CONSTITUTIVELY HIGH LEVELS OF NOX4 GENE/PROTEIN AND ACTIVITY IN A MODEL OF REPLICATION-INDUCED CELLULAR SENESCENCE OF LUNG FIBROBLASTS. IN REPLICATIVE SENESCENT FIBROBLASTS, THE NOX4 GENE IS ENRICHED WITH THE ACTIVATION HISTONE MARK, H4K16AC, AND INVERSELY ASSOCIATED WITH THE REPRESSIVE HISTONE MARK, H4K20ME3, SUPPORTING AN ACTIVE TRANSCRIPTIONAL CHROMATIN CONFORMATION. SILENCING OF THE HISTONE ACETYLTRANSFERASE MOF, WHICH SPECIFICALLY ACETYLATES H4K16, DOWN-REGULATES NOX4 GENE/PROTEIN EXPRESSION. THE NOX4 GENE PROMOTER IS RICH IN CPG SITES; MIXED COPIES OF METHYLATED AND UNMETHYLATED NOX4 DNA WERE DETECTED IN BOTH NONSENESCENT AND SENESCENT CELLS. INTERESTINGLY, THE NOX4 GENE IS VARIABLY ASSOCIATED WITH SPECIFIC DNA METHYLTRANSFERASES AND METHYL BINDING PROTEINS IN THESE TWO CELL POPULATIONS. THESE RESULTS INDICATE A CRITICAL ROLE FOR HISTONE MODIFICATIONS INVOLVING H4K16AC IN EPIGENETIC ACTIVATION OF THE NOX4 GENE, WHILE THE ROLE OF DNA METHYLATION MAY BE CONTEXTUAL. DEFINING MECHANISMS FOR THE EPIGENETIC REGULATION OF NOX4 WILL AID IN THE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES FOR AGE-RELATED DISEASES IN WHICH THIS GENE IS OVEREXPRESSED, IN PARTICULAR IDIOPATHIC PULMONARY FIBROSIS AND CANCER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3   199 20 ACTIVATED HISTONE ACETYLTRANSFERASE P300/CBP-RELATED SIGNALLING PATHWAYS MEDIATE UP-REGULATION OF NADPH OXIDASE, INFLAMMATION, AND FIBROSIS IN DIABETIC KIDNEY. ACCUMULATING EVIDENCE IMPLICATES THE HISTONE ACETYLATION-BASED EPIGENETIC MECHANISMS IN THE PATHOETIOLOGY OF DIABETES-ASSOCIATED MICRO-/MACROVASCULAR COMPLICATIONS. DIABETIC KIDNEY DISEASE (DKD) IS A PROGRESSIVE CHRONIC INFLAMMATORY MICROVASCULAR DISORDER ULTIMATELY LEADING TO GLOMERULOSCLEROSIS AND KIDNEY FAILURE. WE HYPOTHESIZED THAT HISTONE ACETYLTRANSFERASE P300/CBP MAY BE INVOLVED IN MEDIATING DIABETES-ACCELERATED RENAL DAMAGE. IN THIS STUDY, WE AIMED AT INVESTIGATING THE POTENTIAL ROLE OF P300/CBP IN THE UP-REGULATION OF RENAL NADPH OXIDASE (NOX), REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, INFLAMMATION, AND FIBROSIS IN DIABETIC MICE. DIABETIC C57BL/6J MICE WERE RANDOMIZED TO RECEIVE 10 MG/KG C646, A SELECTIVE P300/CBP INHIBITOR, OR ITS VEHICLE FOR 4 WEEKS. WE FOUND THAT IN THE KIDNEY OF C646-TREATED DIABETIC MICE, THE LEVEL OF H3K27AC, AN EPIGENETIC MARK OF ACTIVE GENE EXPRESSION, WAS SIGNIFICANTLY REDUCED. PHARMACOLOGICAL INHIBITION OF P300/CBP SIGNIFICANTLY DOWN-REGULATED THE DIABETES-INDUCED ENHANCED EXPRESSION OF NOX SUBTYPES, PRO-INFLAMMATORY, AND PRO-FIBROTIC MOLECULES IN THE KIDNEY OF MICE, AND THE GLOMERULAR ROS OVERPRODUCTION. OUR STUDY PROVIDES EVIDENCE THAT THE ACTIVATION OF P300/CBP ENHANCES ROS PRODUCTION, POTENTIALLY GENERATED BY UP-REGULATED NOX, INFLAMMATION, AND THE PRODUCTION OF EXTRACELLULAR MATRIX PROTEINS IN THE DIABETIC KIDNEY. THE DATA SUGGEST THAT P300/CBP-PHARMACOLOGICAL INHIBITORS MAY BE ATTRACTIVE TOOLS TO MODULATE DIABETES-ASSOCIATED PATHOLOGICAL PROCESSES TO EFFICIENTLY REDUCE THE BURDEN OF DKD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4  4890 25 OXIDATIVE STRESS AND HEPATIC NOX PROTEINS IN CHRONIC HEPATITIS C AND HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON LIVER CANCER AND A LEADING CAUSE OF CANCER-RELATED MORTALITY IN THE WORLD. HEPATITIS C VIRUS (HCV) IS A MAJOR ETIOLOGIC AGENT OF HCC. A MAJORITY OF HCV INFECTIONS LEAD TO CHRONIC INFECTION THAT CAN PROGRESS TO CIRRHOSIS AND, EVENTUALLY, HCC AND LIVER FAILURE. A COMMON PATHOGENIC FEATURE PRESENT IN HCV INFECTION, AND OTHER CONDITIONS LEADING TO HCC, IS OXIDATIVE STRESS. HCV DIRECTLY INCREASES SUPEROXIDE AND H2O2 FORMATION IN HEPATOCYTES BY ELEVATING NOX PROTEIN EXPRESSION AND SENSITIZING MITOCHONDRIA TO REACTIVE OXYGEN SPECIES GENERATION WHILE DECREASING GLUTATHIONE. NITRIC OXIDE SYNTHESIS AND HEPATIC IRON ARE ALSO ELEVATED. FURTHERMORE, ACTIVATION OF PHAGOCYTIC NADPH OXIDASE (NOX) 2 OF HOST IMMUNE CELLS IS LIKELY TO EXACERBATE OXIDATIVE STRESS IN HCV-INFECTED PATIENTS. KEY MECHANISMS OF HCC INCLUDE GENOME INSTABILITY, EPIGENETIC REGULATION, INFLAMMATION WITH CHRONIC TISSUE INJURY AND SUSTAINED CELL PROLIFERATION, AND MODULATION OF CELL GROWTH AND DEATH. OXIDATIVE STRESS, OR NOX PROTEINS, PLAYS VARIOUS ROLES IN THESE MECHANISMS. NOX PROTEINS ALSO FUNCTION IN HEPATIC FIBROSIS, WHICH COMMONLY PRECEDES HCC, AND NOX4 ELEVATION BY HCV IS MEDIATED BY TRANSFORMING GROWTH FACTOR BETA. THIS REVIEW SUMMARIZES MECHANISMS OF ONCOGENESIS BY HCV, HIGHLIGHTING THE ROLES OF OXIDATIVE STRESS AND HEPATIC NOX ENZYMES IN HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5   449 28 APOCYNIN PREVENTS ANXIETY-LIKE BEHAVIOR AND HISTONE DEACETYLASES OVEREXPRESSION INDUCED BY SUB-CHRONIC STRESS IN MICE. ANXIETY DISORDERS ARE COMMON MENTAL HEALTH DISEASES AFFECTING UP TO 7% OF PEOPLE AROUND THE WORLD. STRESS IS CONSIDERED ONE OF THE MAJOR ENVIRONMENTAL RISK FACTORS TO PROMOTE ANXIETY DISORDERS THROUGH MECHANISMS INVOLVING EPIGENETIC CHANGES. MOREOVER, ALTERATION IN REDOX BALANCE AND INCREASED REACTIVE OXYGEN SPECIES (ROS) PRODUCTION HAVE BEEN DETECTED IN ANXIETY PATIENTS AND IN STRESSED-ANIMAL MODELS OF ANXIETY. HERE WE TESTED IF THE ADMINISTRATION OF APOCYNIN, A NATURAL ORIGIN ANTIOXIDANT, MAY PREVENT THE ANXIETY-LIKE PHENOTYPE AND REDUCTION OF HISTONE ACETYLATION INDUCED BY A SUBCHRONIC FORCED SWIMMING STRESS (FSS) PARADIGM. WE FOUND THAT APOCYNIN PREVENTED THE ENHANCED LATENCY TIME IN THE NOVELTY-SUPPRESSED FEEDING TEST, AND THE PRODUCTION OF MALONDIALDEHYDE INDUCED BY FSS. MOREOVER, APOCYNIN WAS ABLE TO BLOCK THE UPREGULATION OF P47PHOX, A KEY SUBUNIT OF THE NADPH OXIDASE COMPLEX. FINALLY, APOCYNIN PREVENTED THE RISE OF HIPPOCAMPAL HDAC1, HDAC4 AND HDAC5, AND THE REDUCTION OF HISTONE-3 ACETYLATION LEVELS PROMOTED BY FSS EXPOSURE. IN CONCLUSION, OUR RESULTS PROVIDE EVIDENCE THAT APOCYNIN REDUCES THE DELETERIOUS EFFECT OF STRESS AND SUGGESTS THAT OXIDATIVE STRESS MAY REGULATE EPIGENETIC MECHANISMS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  2892 28 GARDENIAE FRUCTUS ATTENUATES THIOACETAMIDE-INDUCED LIVER FIBROSIS IN MICE VIA BOTH AMPK/SIRT1/NF-KAPPAB PATHWAY AND NRF2 SIGNALING. LIVER FIBROSIS, WHICH MEANS A SORT OF THE EXCESSIVE ACCUMULATION OF EXTRACELLULAR MATRICES (ECMS) COMPONENTS THROUGH THE LIVER TISSUE, IS CONSIDERED AS TISSUE REPAIR OR WOUND-HEALING STATUS. THIS PATHOLOGICAL STAGE POTENTIALLY LEADS TO CIRRHOSIS, IF NOT CONTROLLED, IT PROGRESSIVELY RESULTS IN HEPATOCELLULAR CARCINOMA. HEREIN, WE INVESTIGATED THE PHARMACOLOGICAL PROPERTIES AND UNDERLYING MECHANISMS OF GARDENIAE FRUCTUS (GF) AGAINST THIOACETAMIDE (TAA)-INDUCED LIVER FIBROSIS OF MICE MODEL. GF NOT ONLY ATTENUATED HEPATIC TISSUE OXIDATION BUT ALSO IMPROVED HEPATIC INFLAMMATION. WE FURTHER CONFIRMED THAT GF LED TO AMELIORATING LIVER FIBROSIS BY ECMS DEGRADATIONS. REGARDING THE POSSIBLE UNDERLYING MECHANISM OF GF, WE OBSERVED GF REGULATED EPIGENETIC REGULATOR, SIRTUIN 1 (SIRT1), IN TAA-INJECTED LIVER TISSUE. THESE ALTERATIONS WERE WELL SUPPORTED BY SIRT1 RELATED SIGNALING PATHWAYS THROUGH REGULATIONS OF ITS DOWNSTREAM PROTEINS INCLUDING, AMP-ACTIVATED PROTEIN KINASE (AMPK), P47(PHOX), NADPH OXIDASE 2, NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 (NRF2), AND HEME OXYGENASE-1, RESPECTIVELY. TO VALIDATE THE POSSIBLE MECHANISM OF GF, WE USED HEPG2 CELLS WITH HYDROGEN PEROXIDE TREATED OXIDATIVE STRESS AND CHRONIC EXPOSURE CONDITIONS VIA DETERIORATIONS OF CELLULAR SIRT1. MOREOVER, GF REMARKABLY ATTENUATED ECMS ACCUMULATIONS IN TRANSFORMING GROWTH FACTOR-BETA1-INDUCED LX-2 CELLS RELYING ON THE SIRT1 EXISTENCE. TAKEN TOGETHER, GF ATTENUATED LIVER FIBROSIS THROUGH AMPK/SIRT1 PATHWAY AS WELL AS NRF2 SIGNALING CASCADES. THEREFORE, GF COULD BE A CLINICAL REMEDY FOR LIVER FIBROSIS PATIENTS IN THE FUTURE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  2950 14 GENETIC AND EPIGENETIC DAMAGE INDUCED BY REACTIVE NITROGEN SPECIES: IMPLICATIONS IN CARCINOGENESIS. CHRONIC INFECTION AND INFLAMMATION ARE RECOGNIZED RISK FACTORS FOR HUMAN CANCER AT VARIOUS SITES. INFECTION AND INFLAMMATION CAN ACTIVATE AND INDUCE A VARIETY OF OXIDANT-GENERATING ENZYMES, INCLUDING NADPH OXIDASE AND INDUCIBLE NITRIC OXIDE SYNTHASE. REACTIVE OXYGEN AND NITROGEN SPECIES PRODUCED BY SUCH ENZYMES REACT WITH EACH OTHER TO GENERATE NEW AND MORE POTENT REACTIVE SPECIES. THESE OXIDANTS NOT ONLY CAN DAMAGE DNA AND INDUCE MUTATIONS, BUT ALSO CAN ACTIVATE ONCOGENE PRODUCTS AND/OR INACTIVATE TUMOR-SUPPRESSOR PROTEINS, THUS CONTRIBUTING TO MOST PROCESSES OF CARCINOGENESIS. APPROPRIATE TREATMENT OF INFLAMMATION SHOULD BE FURTHER EXPLORED FOR CHEMOPREVENTION OF HUMAN CANCERS, ESPECIALLY THOSE ASSOCIATED WITH CHRONIC INFLAMMATION.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8  6456 19 THYMOSIN BETA4 PREVENTS OXIDATIVE STRESS, INFLAMMATION, AND FIBROSIS IN ETHANOL- AND LPS-INDUCED LIVER INJURY IN MICE. THYMOSIN BETA 4 (TBETA4), AN ACTIN-SEQUESTERING PROTEIN, IS INVOLVED IN TISSUE DEVELOPMENT AND REGENERATION. IT PREVENTS INFLAMMATION AND FIBROSIS IN SEVERAL TISSUES. WE INVESTIGATED THE ROLE OF TBETA4 IN CHRONIC ETHANOL- AND ACUTE LIPOPOLYSACCHARIDE- (LPS-) INDUCED MOUSE LIVER INJURY. C57BL/6 MICE WERE FED 5% ETHANOL IN LIQUID DIET FOR 4 WEEKS PLUS BINGE ETHANOL (5 G/KG, GAVAGE) WITH OR WITHOUT LPS (2 MG/KG, INTRAPERITONEAL) FOR 6 HOURS. TBETA4 (1 MG/KG, INTRAPERITONEAL) WAS ADMINISTERED FOR 1 WEEK. WE DEMONSTRATED THAT TBETA4 PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN LIVER INJURY MARKERS AS WELL AS CHANGES IN LIVER PATHOLOGY. IT ALSO PREVENTED ETHANOL- AND LPS-MEDIATED INCREASE IN OXIDATIVE STRESS BY DECREASING ROS AND LIPID PEROXIDATION AND INCREASING THE ANTIOXIDANTS, REDUCED GLUTATHIONE AND MANGANESE-DEPENDENT SUPEROXIDE DISMUTASE. IT ALSO PREVENTED THE ACTIVATION OF NUCLEAR FACTOR KAPPA B BY BLOCKING THE PHOSPHORYLATION OF THE INHIBITORY PROTEIN, IKAPPAB, THEREBY PREVENTED PROINFLAMMATORY CYTOKINE PRODUCTION. MOREOVER, TBETA4 PREVENTED FIBROGENESIS BY SUPPRESSING THE EPIGENETIC REPRESSOR, METHYL-CPG-BINDING PROTEIN 2, THAT COORDINATELY REVERSED THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND DOWNREGULATED FIBROGENIC GENES, PLATELET-DERIVED GROWTH FACTOR-BETA RECEPTOR, ALPHA-SMOOTH MUSCLE ACTIN, COLLAGEN 1, AND FIBRONECTIN, RESULTING IN REDUCED FIBROSIS. OUR DATA SUGGEST THAT TBETA4 HAS ANTIOXIDANT, ANTI-INFLAMMATORY, AND ANTIFIBROTIC POTENTIAL DURING ALCOHOLIC LIVER INJURY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9  5942 27 TARGETING OF CELLULAR REDOX METABOLISM FOR MITIGATION OF RADIATION INJURY. ACCIDENTAL EXPOSURE TO IONIZING RADIATION IS A SERIOUS CONCERN TO HUMAN LIFE. STUDIES ON THE MITIGATION OF SIDE EFFECTS FOLLOWING EXPOSURE TO ACCIDENTAL RADIATION EVENTS ARE ONGOING. RECENT STUDIES HAVE SHOWN THAT RADIATION CAN ACTIVATE SEVERAL SIGNALING PATHWAYS, LEADING TO CHANGES IN THE METABOLISM OF FREE RADICALS INCLUDING REACTIVE OXYGEN SPECIES (ROS) AND NITRIC OXIDE (NO). CELLULAR AND MOLECULAR MECHANISMS SHOW THAT RADIATION CAN CAUSE DISRUPTION OF NORMAL REDUCTION/OXIDATION (REDOX) SYSTEM. MITOCHONDRIA MALFUNCTION FOLLOWING EXPOSURE TO RADIATION AND MUTATIONS IN MITOCHONDRIA DNA (MTDNA) HAVE A KEY ROLE IN CHRONIC OXIDATIVE STRESS. FURTHERMORE, EXPOSURE TO RADIATION LEADS TO INFILTRATION OF INFLAMMATORY CELLS SUCH AS MACROPHAGES, LYMPHOCYTES AND MAST CELLS, WHICH ARE IMPORTANT SOURCES OF ROS AND NO. THESE CELLS GENERATE FREE RADICALS VIA UPREGULATION OF SOME PRO-OXIDANT ENZYMES SUCH AS NADPH OXIDASES, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) AND CYCLOOXYGENASE-2 (COX-2). EPIGENETIC CHANGES ALSO HAVE A KEY ROLE IN A SIMILAR WAY. OTHER MEDIATORS SUCH AS MAMMALIAN TARGET OF RAPAMYCIN (MTOR) AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR), WHICH ARE INVOLVED IN THE NORMAL METABOLISM OF CELLS HAVE ALSO BEEN SHOWN TO REGULATE CELL DEATH FOLLOWING EXPOSURE TO RADIATION. THESE MECHANISMS ARE TISSUE SPECIFIC. INHIBITION OR ACTIVATION OF EACH OF THESE TARGETS CAN BE SUGGESTED FOR MITIGATION OF RADIATION INJURY IN A SPECIFIC TISSUE. IN THE CURRENT PAPER, WE REVIEW THE CELLULAR AND MOLECULAR CHANGES IN THE METABOLISM OF CELLS AND ROS/NO FOLLOWING EXPOSURE TO RADIATION. FURTHERMORE, THE POSSIBLE STRATEGIES FOR MITIGATION OF RADIATION INJURY THROUGH MODULATION OF CELLULAR METABOLISM IN IRRADIATED ORGANS WILL BE DISCUSSED.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  4044 14 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11   604 21 BEYOND BROODING ON ONCOMETABOLIC HAVOC IN IDH-MUTANT GLIOMAS AND AML: CURRENT AND FUTURE THERAPEUTIC STRATEGIES. ISOCITRATE DEHYDROGENASES 1 AND 2 (IDH1,2), THE KEY KREBS CYCLE ENZYMES THAT GENERATE NADPH REDUCING EQUIVALENTS, UNDERGO HETEROZYGOUS MUTATIONS IN >70% OF LOW- TO MID-GRADE GLIOMAS AND ~20% OF ACUTE MYELOID LEUKEMIAS (AMLS) AND GAIN AN UNUSUAL NEW ACTIVITY OF REDUCING THE ALPHA-KETOGLUTARATE (ALPHA-KG) TO D-2 HYDROXYGLUTARATE (D-2HG) IN A NADPH-CONSUMING REACTION. THE ONCOMETABOLITE D-2HG, WHICH ACCUMULATES >35 MM, IS WIDELY ACCEPTED TO DRIVE A PROGRESSIVE ONCOGENESIS BESIDES EXACERBATING THE ALREADY INCREASED OXIDATIVE STRESS IN THESE CANCERS. MORE IMPORTANTLY, D-2HG COMPETES WITH ALPHA-KG AND INHIBITS A LARGE NUMBER OF ALPHA-KG-DEPENDENT DIOXYGENASES SUCH AS TET (TEN-ELEVEN TRANSLOCATION), JMJC DOMAIN-CONTAINING KDMS (HISTONE LYSINE DEMETHYLASES), AND THE ALKBH DNA REPAIR PROTEINS THAT ULTIMATELY LEAD TO HYPERMETHYLATION OF THE CPG ISLANDS IN THE GENOME. THE RESULTING CPG ISLAND METHYLATOR PHENOTYPE (CIMP) ACCOUNTS FOR MAJOR GENE EXPRESSION CHANGES INCLUDING THE SILENCING OF THE MGMT (O(6)-METHYLGUANINE DNA METHYLTRANSFERASE) REPAIR PROTEIN IN GLIOMAS. GLIOMA PATIENTS WITH IDH1 MUTATIONS ALSO SHOW BETTER THERAPEUTIC RESPONSES AND LONGER SURVIVAL, THE REASONS FOR WHICH ARE YET UNCLEAR. THERE HAS BEEN A GREAT SURGE IN DRUG DISCOVERY FOR CURTAILING THE MUTANT IDH ACTIVITIES, AND ARRESTING TUMOR PROLIFERATION; HOWEVER, GIVEN THE UNIQUE AND CHRONIC METABOLIC EFFECTS OF D-2HG, THE PROMISE OF THESE COMPOUNDS FOR GLIOMA TREATMENT IS UNCERTAIN. THIS COMPREHENSIVE REVIEW DISCUSSES THE BIOLOGY, CURRENT DRUG DESIGN AND OPPORTUNITIES FOR IMPROVED THERAPIES THROUGH EXPLOITABLE SYNTHETIC LETHALITY PATHWAYS, AND AN INTRIGUING ONCOMETABOLITE-INSPIRED STRATEGY FOR PRIMARY GLIOBLASTOMA.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12  5297 22 PROTEIN ARGININE METHYLTRANSFERASE 5 CONTRIBUTES TO PACLITAXEL-INDUCED NEUROPATHIC PAIN BY ACTIVATING TRANSIENT RECEPTOR POTENTIAL VANILLOID 1 EPIGENETIC MODIFICATION IN DORSAL ROOT GANGLION. BACKGROUND: PACLITAXEL (PTX), WHICH IS A FIRST-LINE CHEMOTHERAPY DRUG USED TO TREAT VARIOUS TYPES OF CANCERS, EXHIBITS PERIPHERAL NEUROPATHY AS A COMMON SIDE EFFECT THAT IS DIFFICULT TO TREAT. PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT 5) IS A KEY REGULATOR OF THE CHEMOTHERAPY RESPONSE, AS CHEMOTHERAPY DRUGS INDUCE PRMT5 EXPRESSION. HOWEVER, LITTLE IS KNOWN ABOUT THE PRMT5-MEDIATED EPIGENETIC MECHANISMS INVOLVED IN PTX-INDUCED NEUROPATHIC ALLODYNIA. METHODS: SPRAGUE-DAWLEY RATS WERE INTRAPERITONEALLY GIVEN PTX TO INDUCE NEUROPATHIC PAIN. BIOCHEMICAL ANALYSES WERE CONDUCTED TO MEASURE THE PROTEIN EXPRESSION LEVELS IN THE DORSAL ROOT GANGLION (DRG) OF THE ANIMALS. THE VON FREY TEST AND HOT PLATE TEST WERE USED TO EVALUATE NOCICEPTIVE BEHAVIORS. RESULTS: PTX INCREASED THE PRMT5 (MEAN DIFFERENCE [MD]: 0.68, 95% CONFIDENCE INTERVAL [CI], 0.88-0.48; P < .001 FOR VEHICLE)-MEDIATED DEPOSITION OF HISTONE H3R2 DIMETHYL SYMMETRIC (H3R2ME2S) AT THE TRANSIENT RECEPTOR POTENTIAL VANILLOID 1 (TRPV1) PROMOTER IN THE DRG. PRMT5-INDUCED H3R2ME2S RECRUITED WD REPEAT DOMAIN 5 (WDR5) TO INCREASE TRIMETHYLATION OF LYSINE 4 ON HISTONE H3 (H3K4ME3) AT TRPV1 PROMOTERS, THUS RESULTING IN TRPV1 TRANSCRIPTIONAL ACTIVATION (MD: 0.65, 95% CI, 0.82-0.49; P < .001 FOR VEHICLE) IN DRG IN PTX-INDUCED NEUROPATHIC PAIN. MOREOVER, PTX INCREASED THE ACTIVITY OF NADPH OXIDASE 4 (NOX4) (MD: 0.66, 95% CI, 0.81-0.51; P < .001 FOR VEHICLE), PRMT5-INDUCED H3R2ME2S, AND WDR5-MEDIATED H3K4ME3 IN THE DRG IN PTX-INDUCED NEUROPATHIC PAIN. PHARMACOLOGICAL ANTAGONISM AND THE SELECTIVE KNOCKDOWN OF PRMT5 IN DRG NEURONS COMPLETELY BLOCKED PRMT5-MEDIATED H3R2ME2S, WDR5-MEDIATED H3K4ME3, OR TRPV1 EXPRESSION AND NEUROPATHIC PAIN DEVELOPMENT AFTER PTX INJECTION. REMARKABLY, NOX4 INHIBITION NOT ONLY ATTENUATED ALLODYNIA BEHAVIOR AND REVERSED THE ABOVE-MENTIONED SIGNALING BUT ALSO REVERSED NOX4 UPREGULATION VIA PTX. CONCLUSIONS: THUS, THE NOX4/PRMT5-ASSOCIATED EPIGENETIC MECHANISM IN DRG HAS A DOMINANT FUNCTION IN THE TRANSCRIPTIONAL ACTIVATION OF TRPV1 IN PTX-INDUCED NEUROPATHIC PAIN.	2023	
                                                                                                                                                                                                                                      
13  5052 19 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
14  6166 22 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	
                                                                                                                                                                                                                                                                                                      
15  1201 23 CORTICOTROPIN-RELEASING FACTOR RECEPTOR-1 MODULATES BIOMARKERS OF DNA OXIDATION IN ALZHEIMER'S DISEASE MICE. INCREASED PRODUCTION OF HYDROXYL RADICAL IS THE MAIN SOURCE OF OXIDATIVE DAMAGE IN MAMMALIAN DNA THAT ACCUMULATES IN ALZHEIMER'S DISEASE (AD). REACTIVE OXYGEN SPECIES (ROS) REACT WITH BOTH NUCLEAR DNA (NDNA) AND MITOCHONDRIAL DNA (MTDNA) TO GENERATE 8-HYDROXY-2'-DEOXYGUANOSINE (8-OHDG), BOTH OF WHICH CAN BE MEASURED IN THE URINE. KNOWLEDGE OF THIS PATHWAY HAS POSITIONED MEASUREMENT OF URINE 8-OHDG AS A RELIABLE INDEX OF DNA OXIDATION AND A POTENTIAL BIOMARKER TARGET FOR TRACKING EARLY CELLULAR DYSFUNCTION IN AD. FURTHERMORE, EPIGENETIC STUDIES DEMONSTRATE DECREASED GLOBAL DNA METHYLATION LEVELS (E.G. 5-METHYL-2'-DEOXYCYTIDINE, 5-MDC) IN AD TISSUES. MOREOVER, STRESS HORMONES CAN ACTIVATE NEURONAL OXIDATIVE STRESS WHICH WILL STIMULATE THE RELEASE OF ADDITIONAL STRESS HORMONES AND RESULT IN DAMAGES TO HIPPOCAMPAL NEURONS IN THE AD BRAIN. OUR PREVIOUS WORK SUGGESTS THAT TREATING AD TRANSGENIC MICE THE TYPE-1 CORTICOTROPIN-RELEASING FACTOR RECEPTOR (CRFR1) ANTAGONIST, R121919, TO REDUCE STRESS SIGNALING, PREVENTED ONSET OF COGNITIVE IMPAIRMENT, SYNAPTIC/DENDRITIC LOSS AND ABETA PLAQUE ACCUMULATION. THEREFORE, TO INVESTIGATE WHETHER LEVELS OF DNA OXIDATION CAN BE IMPACTED BY THE SAME THERAPEUTIC APPROACH, URINE LEVELS OF HYDROGEN PEROXIDE, 8-OHDG, 5-MDC AND TOTAL ANTIOXIDANT CAPACITY (TAC) WERE ANALYZED USING AN AD TG MOUSE MODEL. WE FOUND THAT TG ANIMALS HAD AN 80% INCREASE IN HYDROGEN PEROXIDE LEVELS COMPARED TO WILD TYPE (WT) COUNTERPARTS, AN EFFECT THAT COULD BE DRAMATICALLY REVERSED BY THE CHRONIC ADMINISTRATION WITH R121919. A SIGNIFICANT DECREASE OF 8-OHDG LEVELS WAS OBSERVED IN TG MICE TREATED WITH CRFR1 ANTAGONIST. COLLECTIVELY OUR DATA SUGGEST THAT THE BENEFICIAL EFFECTS OF CRFR1 ANTAGONISM SEEN IN TG MICE MAY BE MECHANISTICALLY LINKED TO THE MODULATION OF OXIDATIVE STRESS PATHWAYS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16  4427 22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                 
17   616 21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  5860 27 SULFORAPHANE PREVENTS ANGIOTENSIN II-INDUCED CARDIOMYOPATHY BY ACTIVATION OF NRF2 THROUGH EPIGENETIC MODIFICATION. NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR (NRF2) IS AN IMPORTANT REGULATOR OF CELLULAR ANTIOXIDANT DEFENCE. WE PREVIOUSLY SHOWED THAT SFN PREVENTED ANG II-INDUCED CARDIAC DAMAGE VIA ACTIVATION OF NRF2. HOWEVER, THE UNDERLYING MECHANISM OF SFN'S PERSISTENT CARDIAC PROTECTION REMAINS UNCLEAR. THIS STUDY AIMED TO EXPLORE THE POTENTIAL OF SFN IN ACTIVATING CARDIAC NRF2 THROUGH EPIGENETIC MECHANISMS. WILD-TYPE MICE WERE INJECTED SUBCUTANEOUSLY WITH ANG II, WITH OR WITHOUT SFN. ADMINISTRATION OF CHRONIC ANG II-INDUCED CARDIAC INFLAMMATORY FACTOR EXPRESSION, OXIDATIVE DAMAGE, FIBROSIS AND CARDIAC REMODELLING AND DYSFUNCTION, ALL OF WHICH WERE EFFECTIVELY IMPROVED BY SFN TREATMENT, COUPLED WITH AN UP-REGULATION OF NRF2 AND DOWNSTREAM GENES. BISULFITE GENOME SEQUENCING AND CHROMATIN IMMUNOPRECIPITATION (CHIP) WERE PERFORMED TO DETECT THE METHYLATION LEVEL OF THE FIRST 15 CPGS AND HISTONE H3 ACETYLATION (AC-H3) STATUS IN THE NRF2 PROMOTER REGION, RESPECTIVELY. THE RESULTS SHOWED THAT SFN REDUCED ANG II-INDUCED CPG HYPERMETHYLATION AND PROMOTED AC-H3 ACCUMULATION IN THE NRF2 PROMOTER REGION, ACCOMPANIED BY THE INHIBITION OF GLOBAL DNMT AND HDAC ACTIVITY, AND A DECREASED PROTEIN EXPRESSION OF KEY DNMT AND HDAC ENZYMES. TAKEN TOGETHER, SFN EXERTS ITS CARDIOPROTECTIVE EFFECT THROUGH EPIGENETIC MODIFICATION OF NRF2, WHICH MAY PARTIALLY CONTRIBUTE TO LONG-TERM ACTIVATION OF CARDIAC NRF2.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19   594 18 BET PROTEIN INHIBITOR JQ1 MODULATES MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS INDUCED BY CHRONIC KIDNEY DISEASE. AMONG THE MECHANISMS INVOLVED IN THE PROGRESSION OF KIDNEY DISEASE, MITOCHONDRIAL DYSFUNCTION HAS SPECIAL RELEVANCE. EPIGENETIC DRUGS SUCH AS INHIBITORS OF EXTRA-TERMINAL DOMAIN PROTEINS (IBET) HAVE SHOWN BENEFICIAL EFFECTS IN EXPERIMENTAL KIDNEY DISEASE, MAINLY BY INHIBITING PROLIFERATIVE AND INFLAMMATORY RESPONSES. THE IMPACT OF IBET ON MITOCHONDRIAL DAMAGE WAS EXPLORED IN IN VITRO STUDIES IN RENAL CELLS STIMULATED WITH TGF-BETA1 AND IN VIVO IN MURINE UNILATERAL URETERAL OBSTRUCTION (UUO) MODEL OF PROGRESSIVE KIDNEY DAMAGE. IN VITRO, JQ1 PRETREATMENT PREVENTED THE TGF-BETA1-INDUCED DOWNREGULATION OF COMPONENTS OF THE OXIDATIVE PHOSPHORYLATION CHAIN (OXPHOS), SUCH AS CYTOCHROME C AND CV-ATP5A IN HUMAN PROXIMAL TUBULAR CELLS. IN ADDITION, JQ1 ALSO PREVENTED THE ALTERED MITOCHONDRIAL DYNAMICS BY AVOIDING THE INCREASE IN THE DRP-1 FISSION FACTOR. IN UUO MODEL, RENAL GENE EXPRESSION LEVELS OF CYTOCHROME C AND CV-ATP5A AS WELL AS PROTEIN LEVELS OF CYTOCHROME C WERE REDUCED THESE CHANGES WERE PREVENTED BY JQ1 ADMINISTRATION. IN ADDITION, JQ1 DECREASED PROTEIN LEVELS OF THE DRP1 FISSION PROTEIN AND INCREASED THE OPA-1 FUSION PROTEIN, RESTORING MITOCHONDRIAL DYNAMICS. MITOCHONDRIA ALSO PARTICIPATE IN THE MAINTENANCE OF REDOX BALANCE. JQ1 RESTORED THE GENE EXPRESSION OF ANTIOXIDANT PROTEINS, SUCH AS CATALASE AND HEME OXYGENASE 1 IN TGF-BETA1-STIMULATED HUMAN PROXIMAL TUBULAR CELLS AND IN MURINE OBSTRUCTED KIDNEYS. INDEED, IN TUBULAR CELLS, JQ1 DECREASED ROS PRODUCTION INDUCED BY STIMULATION WITH TGF-BETA1, AS EVALUATED BY MITOSOXTM. IBETS, SUCH AS JQ1, IMPROVE MITOCHONDRIAL DYNAMICS, FUNCTIONALITY, AND OXIDATIVE STRESS IN KIDNEY DISEASE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  4510 30 MTOR-DEPENDENT OXIDATIVE STRESS REGULATES OXLDL-INDUCED TRAINED INNATE IMMUNITY IN HUMAN MONOCYTES. INTRODUCTION: CELLS OF THE INNATE IMMUNE SYSTEM PARTICULARLY MONOCYTES AND MACROPHAGES HAVE BEEN RECOGNIZED AS PIVOTAL PLAYERS BOTH DURING THE INITIAL INSULT AS WELL AS THE CHRONIC PHASE OF ATHEROSCLEROSIS. IT HAS RECENTLY BEEN SHOWN THAT OXIDIZED LOW-DENSITY LIPOPROTEIN (OXLDL) INDUCES A LONG-TERM PRO-INFLAMMATORY RESPONSE IN MONOCYTES DUE TO EPIGENETIC AND METABOLIC REPROGRAMMING, AN EMERGING NEW CONCEPT CALLED TRAINED INNATE IMMUNITY. CHANGES IN THE CELLULAR REDOX STATE ARE CRUCIAL EVENTS IN THE REGULATION OF MANY PHYSIOLOGIC FUNCTIONS IN MACROPHAGES INCLUDING TRANSCRIPTION, DIFFERENTIATION AND INFLAMMATORY RESPONSE. HERE WE HAVE ANALYZED THE ROLE OF REACTIVE OXYGEN SPECIES (ROS) IN REGULATING THIS PROINFLAMMATORY MONOCYTE PRIMING IN RESPONSE TO OXLDL-TREATMENT. METHODS AND RESULTS: HUMAN MONOCYTES WERE ISOLATED AND INCUBATED WITH OXLDL FOR 24 H. AFTER 5 DAYS OF RESTING, OXLDL TREATED CELLS PRODUCED SIGNIFICANTLY MORE INFLAMMATORY CYTOKINES UPON RESTIMULATION WITH THE TLR2-AGONIST PAM3CYS. FURTHERMORE, OXLDL INCUBATION INDUCED PERSISTENT MTOR ACTIVATION, ROS FORMATION, HIF1ALPHA ACCUMULATION AND HIF1ALPHA TARGET GENE EXPRESSION, WHILE PHARMACOLOGIC MTOR INHIBITION OR SIRNA MEDIATED INHIBITION OF THE MTORC1 SUBUNIT RAPTOR PREVENTED ROS FORMATION AND PROINFLAMMATORY PRIMING. MTOR DEPENDENT ROS FORMATION WAS ASSOCIATED WITH INCREASED EXPRESSION OF NAPDH OXIDASES AND NECESSARY FOR THE EMERGENCE OF THE PRIMED PHENOTYPE AS ANTIOXIDANT TREATMENT BLOCKED OXLDL PRIMING. INHIBITION OF CYTOSOLIC ROS FORMATION COULD ALSO BLOCK MTOR ACTIVATION AND HIF1ALPHA ACCUMULATION SUGGESTING A POSITIVE FEEDBACK LOOP BETWEEN MTOR AND CYTOSOLIC ROS. ALTHOUGH MITOCHONDRIAL ROS SCAVENGING DID NOT BLOCK HIF1ALPHA-ACCUMULATION AT AN EARLY TIME POINT (24 H), IT WAS PERSISTENTLY REDUCED ON DAY 6. THEREFORE, MITOCHONDRIAL ROS FORMATION APPEARS TO OCCUR INITIALLY DOWNSTREAM OF THE MTOR-CYTOROS-HIF1ALPHA FEEDBACK LOOP BUT SEEMS TO BE A CRUCIAL FACTOR THAT CONTROLS THE LONG-TERM ACTIVATION OF THE MTOR-HIF1ALPHA-AXIS. CONCLUSION: IN SUMMARY, OUR DATA DEMONSTRATE THAT MTOR DEPENDENT ROS PRODUCTION CONTROLS THE OXLDL-INDUCED TRAINED INNATE IMMUNITY PHENOTYPE IN HUMAN MONOCYTE DERIVED MACROPHAGES. PHARMACOLOGIC MODULATION OF THESE PATHWAYS MIGHT PROVIDE A POTENTIAL APPROACH TO MODULATE INFLAMMATION, ASSOCIATED WITH ABERRANT MONOCYTE ACTIVATION, DURING ATHEROSCLEROSIS DEVELOPMENT.	2018