1  5052 132 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2  6615  31 ULTRAVIOLET-A1 IRRADIATION THERAPY FOR SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (LUPUS, SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY THE PRODUCTION OF AUTOANTIBODIES, WHICH BIND TO ANTIGENS AND ARE DEPOSITED WITHIN TISSUES TO FIX COMPLEMENT, RESULTING IN WIDESPREAD SYSTEMIC INFLAMMATION. THE STUDIES PRESENTED HEREIN ARE CONSISTENT WITH HYPERPOLARIZED, ADENOSINE TRIPHOSPHATE (ATP)-DEFICIENT MITOCHONDRIA BEING CENTRAL TO THE DISEASE PROCESS. THESE HYPERPOLARIZED MITOCHONDRIA RESIST THE DEPOLARIZATION REQUIRED FOR ACTIVATION-INDUCED APOPTOSIS. THE MITOCHONDRIAL ATP DEFICITS ADD TO THIS RESISTANCE TO APOPTOSIS AND ALSO REDUCE THE MACROPHAGE ENERGY THAT IS NEEDED TO CLEAR APOPTOTIC BODIES. IN BOTH CASES, NECROSIS, THE ALTERNATIVE PATHWAY OF CELL DEATH, RESULTS. INTRACELLULAR CONSTITUENTS SPILL INTO THE BLOOD AND TISSUES, ELICITING INFLAMMATORY RESPONSES DIRECTED AT THEIR REMOVAL. WHAT RESULTS IS "AUTOIMMUNITY." ULTRAVIOLET (UV)-A1 PHOTONS HAVE THE CAPACITY TO REMEDIATE THIS ABERRANCY. EXOGENOUS EXPOSURE TO LOW-DOSE, FULL-BODY, UV-A1 RADIATION GENERATES SINGLET OXYGEN. SINGLET OXYGEN HAS TWO MAJOR PALLIATIVE ACTIONS IN PATIENTS WITH LUPUS AND THE UV-A1 PHOTONS THEMSELVES HAVE SEVERAL MORE. SINGLET OXYGEN DEPOLARIZES THE HYPERPOLARIZED MITOCHONDRION, TRIGGERING NON-ATP-DEPENDENT APOPTOSIS THAT DETERS NECROSIS. NEXT, SINGLET OXYGEN ACTIVATES THE GENE ENCODING HEME OXYGENASE (HO-1), A MAJOR GOVERNOR OF SYSTEMIC HOMEOSTASIS. HO-1 CATALYZES THE DEGRADATION OF THE OXIDANT HEME INTO BILIVERDIN (CONVERTED TO BILIRUBIN), FE, AND CARBON MONOXIDE (CO), THE FIRST THREE OF THESE EXERTING POWERFUL ANTIOXIDANT EFFECTS, AND IN CONJUNCTION WITH A FOURTH, CO, PROTECTING AGAINST INJURY TO THE CORONARY ARTERIES, THE CENTRAL NERVOUS SYSTEM, AND THE LUNGS. THE UV-A1 PHOTONS THEMSELVES DIRECTLY ATTENUATE DISEASE IN LUPUS BY REDUCING B CELL ACTIVITY, PREVENTING THE SUPPRESSION OF CELL-MEDIATED IMMUNITY, SLOWING AN EPIGENETIC PROGRESSION TOWARD SLE, AND AMELIORATING DISCOID AND SUBACUTE CUTANEOUS LUPUS. FINALLY, A COMBINATION OF THESE MECHANISMS REDUCES LEVELS OF ANTICARDIOLIPIN ANTIBODIES AND PROTECTS DURING LUPUS PREGNANCY. CAPPING ALL OF THIS IS THAT UV-A1 IRRADIATION IS AN ESSENTIALLY INNOCUOUS, HIGHLY MANAGEABLE, AND COMFORTABLE THERAPEUTIC AGENCY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3  6492  23 TRAFFIC-RELATED AIR POLLUTION AND GROUND-LEVEL OZONE ASSOCIATED GLOBAL DNA HYPOMETHYLATION AND BULKY DNA ADDUCT FORMATION. STUDIES HAVE INDICATED THAT AIR POLLUTION, INCLUDING SURFACE-LEVEL OZONE (O(3)), CAN SIGNIFICANTLY INFLUENCE THE RISK OF CHRONIC DISEASES. TO BETTER UNDERSTAND THE CARCINOGENIC MECHANISMS OF AIR POLLUTANTS AND IDENTIFY PREDICTIVE DISEASE BIOMARKERS, WE EXAMINED THE ASSOCIATION BETWEEN TRAFFIC-RELATED POLLUTANTS WITH DNA METHYLATION ALTERATIONS AND BULKY DNA ADDUCTS, TWO BIOMARKERS OF CARCINOGEN EXPOSURE AND CANCER RISK, IN THE PERIPHERAL BLOOD OF 140 VOLUNTEERS-95 TRAFFIC POLICE OFFICERS, AND 45 UNEXPOSED SUBJECTS. THE DNA METHYLATION AND ADDUCT MEASUREMENTS WERE PERFORMED BY BISULFITE-PCR AND PYROSEQUENCING AND (32)P-POSTLABELING ASSAY. AIRBORNE LEVELS OF BENZO(A)PYRENE [B(A)P], CARBON MONOXIDE, AND TROPOSPHERIC O(3) WERE DETERMINED BY PERSONAL EXPOSURE BIOMONITORING OR BY FIXED MONITORING STATIONS. OVERALL, AIR POLLUTION EXPOSURE WAS ASSOCIATED WITH A SIGNIFICANT REDUCTION (1.41 UNITS) IN GLOBAL DNA METHYLATION (95% C.I. -2.65-0.04, P = 0.026). THE DECREMENT IN ALU REPETITIVE ELEMENTS WAS GREATEST IN THE POLICEMEN WORKING DOWNTOWN (95% C.I. -3.23--0.49, P = 0.008). THE DNA ADDUCTS WERE FOUND TO BE SIGNIFICANTLY INCREASED (0.45 UNITS) IN THE MUNICIPAL OFFICERS WITH RESPECT TO UNEXPOSED SUBJECTS (95% C.I. 0.02-0.88, P = 0.039), MAINLY IN THOSE WHO WERE CONTROLLING TRAFFIC IN DOWNTOWN AREAS (95% C.I. 0.39-1.29, P < 0.001). REGRESSION MODELS INDICATED AN INCREMENT OF ALU METHYLATION AT HIGHER B(A)P CONCENTRATIONS (95% C.I. 0.03-0.60, P = 0.032). MOREOVER, STATISTICAL MODELS SHOWED A DECREMENT IN ALU METHYLATION AND AN INCREMENT OF DNA DAMAGE ONLY ABOVE THE CUT-OFF VALUE OF 30 MICROG/M(3) O(3). A SIGNIFICANT INCREMENT OF 0.73 UNITS OF IL-6 GENE METHYLATION WAS ALSO FOUND IN SMOKERS WITH RESPECT TO NON-SMOKERS. OUR RESULTS HIGHLIGHTED THE ROLE OF AIR POLLUTION ON EPIGENETIC ALTERATIONS AND GENOTOXIC EFFECTS, ESPECIALLY ABOVE THE TARGET VALUE OF 30 MICROG/M(3) SURFACE-LEVEL O(3), SUPPORTING THE NECESSITY FOR DEVELOPING PUBLIC HEALTH STRATEGIES AIMED TO REDUCE TRAFFIC-RELATED AIR POLLUTION MOLECULAR ALTERATIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  5209  31 PRENATAL XENOBIOTIC EXPOSURE AND INTRAUTERINE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS PROGRAMMING ALTERATION. THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IS ONE OF THE MOST IMPORTANT NEUROENDOCRINE AXES AND PLAYS AN IMPORTANT ROLE IN STRESS DEFENSE RESPONSES BEFORE AND AFTER BIRTH. PRENATAL EXPOSURE TO XENOBIOTICS, INCLUDING ENVIRONMENTAL TOXINS (SUCH AS SMOKE, SULFUR DIOXIDE AND CARBON MONOXIDE), DRUGS (SUCH AS SYNTHETIC GLUCOCORTICOIDS), AND FOODS AND BEVERAGE CATEGORIES (SUCH AS ETHANOL AND CAFFEINE), AFFECTS FETAL DEVELOPMENT INDIRECTLY BY CHANGING THE MATERNAL STATUS OR DAMAGING THE PLACENTA. CERTAIN XENOBIOTICS (SUCH AS CAFFEINE, ETHANOL AND DEXAMETHASONE) MAY ALSO AFFECT THE FETUS DIRECTLY BY CROSSING THE PLACENTA INTO THE FETUS DUE TO THEIR LIPOPHILIC PROPERTIES AND LOWER MOLECULAR WEIGHTS. ALL OF THESE FACTORS PROBABLY RESULT IN INTRAUTERINE PROGRAMMING ALTERATION OF THE HPA AXIS, WHICH SHOWED A LOW BASAL ACTIVITY BUT HYPERSENSITIVITY TO CHRONIC STRESS. THESE ALTERATIONS WILL, THEREFORE, INCREASE THE SUSCEPTIBILITY TO ADULT NEUROPSYCHIATRIC (SUCH AS DEPRESSION AND SCHIZOPHRENIA) AND METABOLIC DISEASES (SUCH AS HYPERTENSION, DIABETES AND NON-ALCOHOLIC FATTY LIVER DISEASE). THE "OVER-EXPOSURE OF FETUSES TO MATERNAL GLUCOCORTICOIDS" MAY BE THE MAIN INITIATION FACTOR BY WHICH THE FETAL HPA AXIS PROGRAMMING IS ALTERED. MEANTIME, XENOBIOTICS CAN DIRECTLY INDUCE ABNORMAL EPIGENETIC MODIFICATIONS AND EXPRESSION ON THE IMPORTANT FETAL GENES (SUCH AS HIPPOCAMPAL GLUCOCORTICOID RECEPTOR, ADRENAL STEROIDOGENIC ACUTE REGULATORY PROTEIN, ET AL) OR DAMAGE BY IN SITU OXIDATIVE METABOLISM OF FETAL ADRENALS, WHICH MAY ALSO BE CONTRIBUTED TO THE PROGRAMMING ALTERATION OF FETAL HPA AXIS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  4170  29 MEETING REPORT: ISN FOREFRONTS IN NEPHROLOGY ON ENDOTHELIAL BIOLOGY AND RENAL DISEASE: FROM BENCH TO PREVENTION. THIS ISN-SPONSORED FOREFRONT IN NEPHROLOGY MEETING, WHICH HAS BROUGHT TOGETHER 120 SCIENTISTS FROM 21 COUNTRIES, HAS BEEN CONCERNED WITH VARIOUS ASPECTS OF ENDOTHELIAL FUNCTION AND DYSFUNCTION AND THEIR CONTRIBUTION TO PROGRESSION OF CHRONIC KIDNEY DISEASE AND/OR ITS CARDIOVASCULAR COMPLICATIONS. THE FOLLOWING THEMES WERE DISCUSSED IN GREAT DEPTH: (1) PHENOTYPICAL CHANGES IN THE VASCULAR ENDOTHELIUM - PERMEABILITY, SENESCENCE, AND APOPTOSIS; (2) REGULATION OF ENDOTHELIAL NITRIC OXIDE (NO) SYNTHASE FUNCTION - CAVEOLAR AND SHEAR STRESS MECHANISMS, EPIGENETIC REGULATION, S-NITROSYLATION, AND RHO-KINASE REGULATION; (3) OXIDATIVE STRESS AND HYPOXIA-INDUCED CHANGES; (4) ORGANELLAR DYSFUNCTION - LYSOSOMES, MITOCHONDRIA, AND ENDOPLASMIC RETICULUM; (5) NO-INDEPENDENT MECHANISMS OF VASOMOTION - EPOXIDES, HEME OXYGENASE-1 AND CARBON MONOXIDE, THROMBOXANE, TUMOR NECROSIS FACTOR-ALPHA, AND URIC ACID; (6) ENDOTHELIAL CROSSTALK WITH PODOCYTES, MONOCYTES, SMOOTH MUSCLE CELLS, AND PLATELETS; (7) CANDIDATE CLINICAL BIOMARKERS OF ENDOTHELIAL DYSFUNCTION - FUNCTIONAL TESTING OF MACRO- AND MICRO-VASCULAR FUNCTIONS, SURROGATE MARKERS, CIRCULATING DETACHED ENDOTHELIAL CELLS, AND ENDOTHELIAL PRECURSOR CELLS; AND CULMINATED IN ROUND TABLE DISCUSSION ON THE DIAGNOSIS OF ENDOTHELIAL DYSFUNCTION AND ITS TREATMENT OPTIONS. IN CONCLUSION, THIS MEETING HAS FOCUSED ON SEVERAL KEY PROBLEMS OF ENDOTHELIAL CELL PATHOBIOLOGY RELEVANT TO CHRONIC KIDNEY DISEASE.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  5010  30 PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA DAMAGE AND CYTOGENETIC EFFECTS. IN THE PRESENT STUDY, THE POSSIBLE ROLE OF THE POLYUNSATURATED FATTY ACIDS LINOLEIC AND ARACHIDONIC ACID IN THE CHEMICAL INDUCTION OF CARCINOGENESIS HAS BEEN INVESTIGATED. ANALYSIS OF 7,8-DIHYDRO-8-OXO-2'-DEOXYGUANOSINE (8-OXODG) LEVELS IN 2'-DEOXYGUANOSINE (DG) AND ISOLATED DNA HAS DEMONSTRATED THAT LINOLEIC AND ARACHIDONIC ACID ARE CAPABLE OF INDUCING THIS SPECIFIC GENOTOXIC DAMAGE. THIS EFFECT APPEARS TO BE RELATED TO THE DEGREE OF FATTY ACID UNSATURATION, SINCE IT WAS NOT INDUCED BY MONOUNSATURATED OLEIC ACID. ENZYMATIC PEROXIDATION OF LINOLEIC AND ARACHIDONIC ACID RESULTED IN A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE. STUDIES ON THE INTERFERENCE OF RADICAL SCAVENGERS WITH THE INDUCTION OF 8-OXODG IN COMBINATION WITH ELECTRON SPIN RESONANCE SPECTROSCOPY DEMONSTRATED THAT THE SUPEROXIDE ANION WAS GENERATED DURING PEROXIDATION OF THESE FATTY ACIDS AND THAT SINGLET OXYGEN IS MOST LIKELY INVOLVED IN THE FORMATION OF OXIDATIVE DNA DAMAGE. THE LEVEL OF OXIDATIVE DAMAGE IN DG AND SINGLE-STRANDED DNA WAS HIGHER AS COMPARED TO THAT IN NATIVE DNA AFTER EQUIMOLAR TREATMENT. EXPOSURE OF HUMAN LYMPHOCYTES TO LINOLEIC OR ARACHIDONIC ACID DID NOT RESULT IN A SIGNIFICANT INCREASE IN LEVELS OF 8-OXODG. THIS MAY INDICATE THAT THE RATE OF INTRACELLULAR PEROXIDATION IS RELATIVELY LOW AND/OR THAT NUCLEAR DNA IN INTACT CELLS IS EFFECTIVELY PROTECTED AGAINST GENETIC DAMAGE INDUCED BY REACTIVE OXYGEN SPECIES. IT IS THEREFORE CONCLUDED THAT RELATIVELY SHORT PERIODS OF LINOLEIC OR ARACHIDONIC ACID ADMINISTRATION ARE NOT LIKELY TO IMPOSE A DIRECT GENOTOXIC RISK. IT CAN, HOWEVER, NOT BE EXCLUDED THAT CHRONIC EXPOSURE TO POLYUNSATURATED FATTY ACIDS INDUCES OXIDATIVE DNA DAMAGE OR IS RELATED TO CANCER RISK BY EPIGENETIC MECHANISMS, AS IS ALSO INDICATED BY THE OBSERVED CYTOTOXIC EFFECTS OF LINOLEIC AND ARACHIDONIC ACID.	1994	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7  6166  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8  6909  30 [TOXIC COMPONENTS OF PM(2.5) AND THEIR TOXICITY MECHANISMS-ON THE TOXICITY OF SULFATE AND CARBON COMPONENTS]. RECENTLY, THE MAIN AIR POLLUTANT HAS BEEN FINE PARTICULATE MATTER (PM(2.5)), WHICH IS TAKEN UP BY THE WHOLE BODY WITH SEVERE ADVERSE HEALTH EFFECTS. THE MAIN CHEMICAL COMPONENTS OF PM(2.5) ARE SALTS OF SULFATE (AND NITRATE) AND CARBONS. HOWEVER, IT REMAINS UNKNOWN WHICH COMPONENTS ARE TOXIC. HERE, THE AUTHOR REVIEWED THE LITERATURES TO DETERMINE WHICH COMPONENTS ARE TOXIC AND THE MAIN MECHANISMS UNDERLYING THEIR TOXICITY. MANY EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT SULFATE CONCENTRATION IS STRONGLY RELATED TO MORTALITY. HOWEVER, THERE IS NO EXPERIMENTAL EVIDENCE SHOWING THAT SULFATE AT ENVIRONMENTAL CONCENTRATIONS OF PM(2.5) CAUSES CARDIOVASCULAR DISEASE OR OTHER DISEASE. ON THE OTHER HAND, CARBON COMPONENTS SUCH AS ELEMENTARY CARBON (EC) PRODUCES HIGH CONCENTRATIONS OF REACTIVE OXYGEN SPECIES (ROS) VIA ITS PHAGOCYTOSIS BY MACROPHAGES, AND ORGANIC CARBON (OC) ALSO PRODUCES HIGH CONCENTRATIONS OF ROS DURING ITS METABOLIC PROCESSES, AND THE ROS CAUSE ACUTE AND CHRONIC INFLAMMATION. THEY CAUSE MANY DISEASES INCLUDING CARDIOVASCULAR DISEASE, ASTHMA AND CANCER. FURTHERMORE, THERE ARE MANY LINES OF EVIDENCE SHOWING THAT EPIGENETIC CHANGES SUCH AS DNA METHYLATION OR MICRORNA EXPRESSION INDUCED BY PARTICULATE MATTERS ALSO INDUCE THE DEVELOPMENT OF MANY DISEASES SUCH AS THOSE MENTIONED ABOVE. IT HAS BEEN REPORTED THAT CARBON COMPONENTS ARE INCORPORATED INTO THE BRAIN AND PRODUCE ROS, AND THAT THE ROS CAUSE DAMAGE TO BRAIN CELLS AND ALZHEIMER'S DISEASE AND COGNITIVE DISORDERS IN THE ELDERLY.FROM THESE LINES OF EVIDENCE, THE AUTHOR WOULD LIKE TO EMPHASIZE THAT THE MAIN TOXICITY OF PM(2.5) IS DUE TO CARBON COMPONENTS, AND IT IS IMPORTANT TO TAKE COUNTERMEASURES TO DECREASE THE CONCENTRATION OF CARBON COMPONENTS IN AMBIENT AIR.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9  1223  29 CRITICAL REVIEW ON EMERGING HEALTH EFFECTS ASSOCIATED WITH THE INDOOR AIR QUALITY AND ITS SUSTAINABLE MANAGEMENT. INDOOR AIR QUALITY (IAQ) IS ONE OF THE FUNDAMENTAL ELEMENTS AFFECTING PEOPLE'S HEALTH AND WELL-BEING. CURRENTLY, THERE IS A LACK OF AWARENESS AMONG PEOPLE ABOUT THE QUANTIFICATION, IDENTIFICATION, AND POSSIBLE HEALTH EFFECTS OF IAQ. AIRBORNE POLLUTANTS SUCH AS VOLATILE ORGANIC COMPOUNDS (VOCS), PARTICULATE MATTER (PM), SULFUR DIOXIDE (SO2), CARBON MONOXIDE (CO), NITROUS OXIDE (NO), POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) MICROBIAL SPORES, POLLEN, ALLERGENS, ETC. PRIMARILY CONTRIBUTE TO IAQ DETERIORATION. THIS REVIEW DISCUSSES THE SOURCES OF MAJOR INDOOR AIR POLLUTANTS, MOLECULAR TOXICITY MECHANISMS, AND THEIR EFFECTS ON CARDIOVASCULAR, OCULAR, NEUROLOGICAL, WOMEN, AND FOETAL HEALTH. ADDITIONALLY, CONTEMPORARY STRATEGIES AND SUSTAINABLE METHODS FOR REGULATING AND REDUCING POLLUTANT CONCENTRATIONS ARE EMPHASIZED, AND CURRENT INITIATIVES TO ADDRESS AND ENHANCE IAQ ARE EXPLORED, ALONG WITH THEIR UNIQUE ADVANTAGES AND POTENTIALS. DUE TO THEIR LONGER EXPOSURE TIMES AND PARTICULAR PHYSICAL CHARACTERISTICS, WOMEN AND CHILDREN ARE MORE AT RISK FOR POOR INDOOR AIR QUALITY. BY TRIGGERING MANY TOXICITY MECHANISMS, INCLUDING OXIDATIVE STRESS, DNA METHYLATION, EPIGENETIC MODIFICATIONS, AND GENE ACTIVATION, INDOOR AIR POLLUTION CAN CAUSE A RANGE OF HEALTH ISSUES. LOW BIRTH WEIGHT, ACUTE LOWER RESPIRATORY TRACT INFECTIONS, SICK BUILDING SYNDROMES (SBS), AND EARLY DEATH ARE MORE PREVALENT IN EXPOSED RESIDENTS. ON THE OTHER HAND, THE MAIN CAUSES OF INCAPACITY AND EARLY MORTALITY ARE LUNG CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND CARDIOVASCULAR DISORDERS. IT'S CRUCIAL TO ACKNOWLEDGE ANTICIPATED RESEARCH NEEDS AND IMPLEMENTED EFFICIENT INTERVENTIONS AND POLICIES TO LOWER HEALTH HAZARDS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10  3939  28 LNC-IL7R ALLEVIATES PM(2.5)-MEDIATED CELLULAR SENESCENCE AND APOPTOSIS THROUGH EZH2 RECRUITMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: LONG-TERM EXPOSURE TO PM(2.5) (PARTICULATE MATTER WITH AN AERODYNAMIC DIAMETER OF </= 2.5 MUM) IS ASSOCIATED WITH PULMONARY INJURY AND EMPHYSEMA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE INVESTIGATED MECHANISMS THROUGH WHICH THE LONG NONCODING RNA LNC-IL7R CONTRIBUTES TO CELLULAR DAMAGE BY INDUCING OXIDATIVE STRESS IN COPD PATIENTS EXPOSED TO PM(2.5). METHODS: ASSOCIATIONS OF SERUM LNC-IL7R LEVELS WITH LUNG FUNCTION, EMPHYSEMA, AND PREVIOUS PM(2.5) EXPOSURE IN COPD PATIENTS WERE ANALYZED. REACTIVE OXYGEN SPECIES AND LNC-IL7R LEVELS WERE MEASURED IN PM(2.5)-TREATED CELLS. THE LEVELS OF LNC-IL7R AND CELLULAR SENESCENCE-ASSOCIATED GENES, NAMELY P16(INK4A) AND P21(CIP1/WAF1), WERE DETERMINED THROUGH LUNG TISSUE SECTION STAINING. THE EFFECTS OF P16(INK4A) OR P21(CIP1/WAF1) REGULATION WERE EXAMINED BY PERFORMING LNC-IL7R OVEREXPRESSION AND KNOCKDOWN ASSAYS. THE FUNCTIONS OF LNC-IL7R-MEDIATED CELL PROLIFERATION, CELL CYCLE, SENESCENCE, COLONY FORMATION, AND APOPTOSIS WERE EXAMINED IN CELLS TREATED WITH PM(2.5). CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE CONDUCTED TO INVESTIGATE THE EPIGENETIC REGULATION OF P21(CIP1/WAF1). RESULTS: LNC-IL7R LEVELS DECREASED IN COPD PATIENTS AND WERE NEGATIVELY CORRELATED WITH EMPHYSEMA OR PM(2.5) EXPOSURE. LNC-IL7R LEVELS WERE UPREGULATED IN NORMAL LUNG EPITHELIAL CELLS BUT NOT IN COPD CELLS EXPOSED TO PM(2.5). LOWER LNC-IL7R EXPRESSION IN PM(2.5)-TREATED CELLS INDUCED P16(INK4A) AND P21(CIP1/WAF1) EXPRESSION BY INCREASING OXIDATIVE STRESS. HIGHER LNC-IL7R EXPRESSION PROTECTED AGAINST CELLULAR SENESCENCE AND APOPTOSIS, WHEREAS LOWER LNC-IL7R EXPRESSION AUGMENTED INJURY IN PM(2.5)-TREATED CELLS. LNC-IL7R AND THE ENHANCER OF ZESTE HOMOLOG 2 (EZH2) SYNERGISTICALLY SUPPRESSED P21(CIP1/WAF1) EXPRESSION THROUGH EPIGENETIC MODULATION. CONCLUSION: LNC-IL7R ATTENUATES PM(2.5)-MEDIATED P21(CIP1/WAF1) EXPRESSION THROUGH EZH2 RECRUITMENT, AND ITS DYSFUNCTION MAY AUGMENT CELLULAR INJURY IN COPD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11  3458  22 HYPOMETHYLATION OF LINE-1 REPEAT ELEMENTS AND GLOBAL LOSS OF DNA HYDROXYMETHYLATION IN VAPERS AND SMOKERS. THE OUTBREAK OF VAPING-RELATED SEVERE LUNG INJURIES AND DEATHS AND THE EPIDEMIC OF TEEN VAPING IN THE U.S. UNDERSCORE THE URGENT NEED FOR DETERMINING THE BIOLOGICAL CONSEQUENCES OF ELECTRONIC CIGARETTE (E-CIG) USE. WE HAVE INVESTIGATED THE ASSOCIATION BETWEEN VAPING AND EPIGENETIC CHANGES BY QUANTIFYING DNA METHYLATION LEVELS IN LONG INTERSPERSED NUCLEOTIDE ELEMENT 1 (LINE-1) AND GLOBAL DNA HYDROXYMETHYLATION (5-HMC) LEVELS AND MEASURING THE EXPRESSION LEVEL OF ENZYMES CATALYSING THE RESPECTIVE PROCESSES IN PERIPHERAL BLOOD OF EXCLUSIVE VAPERS, SMOKERS, AND CONTROLS, MATCHED FOR AGE, GENDER, AND RACE (N = 45). BOTH VAPERS AND SMOKERS SHOWED SIGNIFICANT LOSS OF METHYLATION IN LINE-1 REPEAT ELEMENTS IN COMPARISON TO CONTROLS (P = 0.00854 AND P = 0.03078, RESPECTIVELY). SIMILARLY, VAPERS AND SMOKERS HAD SIGNIFICANT REDUCTIONS IN 5-HMC LEVELS RELATIVE TO CONTROLS (P = 0.04884 AND P = 0.0035, RESPECTIVELY). NEITHER THE LINE-1 METHYLATION LEVELS NOR THE GLOBAL 5-HMC LEVELS WERE DIFFERENT BETWEEN VAPERS AND SMOKERS. THERE WAS A DIRECT CORRELATION BETWEEN METHYLATION LEVELS IN THE LINE-1 ELEMENTS AND GLOBAL 5-HMC LEVELS IN THE STUDY SUBJECTS (R = 0.31696, P = 0.03389). INVERSE AND STATISTICALLY SIGNIFICANT CORRELATIONS WERE FOUND BETWEEN BOTH THE LINE-1 METHYLATION LEVELS AND THE GLOBAL 5-HMC LEVELS AND VARIOUS VAPING/SMOKING METRICS IN THE STUDY SUBJECTS. THERE WERE MODEST BUT NOT STATISTICALLY SIGNIFICANT CHANGES IN TRANSCRIPTION OF DNA METHYLTRANSFERASES AND TEN-ELEVEN TRANSLOCATION ENZYMES IN BOTH VAPERS AND SMOKERS RELATIVE TO CONTROLS. OUR FINDINGS SUPPORT FOLLOW-UP GENOME-WIDE INVESTIGATIONS INTO THE EPIGENETIC EFFECTS OF VAPING, WHICH MAY FURTHER CLARIFY THE HEALTH CONSEQUENCES OF E-CIG USE. ABBREVIATIONS: 5-MC: 5-METHYLCYTOSINE; 5-HMC: 5-HYDROXYMETHYLCYTOSINE; 8-OHDG: 8-HYDROXY-2'-DEOXYGUANOSINE; ACTIN: ACTIN BETA; ANOVA: ANALYSIS OF VARIANCE; BER: BASE EXCISION REPAIR; BMI: BODY MASS INDEX; CO: CARBON MONOXIDE; COHB: CARBOXYHAEMOGLOBIN; COBRA: COMBINED BISULPHITE RESTRICTION ANALYSIS; COPD: CHRONIC OBSTRUCTIVE PULMONARY DISEASE; DNMT1: DNA METHYLTRANSFERASE 1; DNMT3A: DNA METHYLTRANSFERASE 3A; DNMT3B: DNA METHYLTRANSFERASE 3B; E-CIGS: ELECTRONIC CIGARETTES; ELISA: ENZYME-LINKED IMMUNOSORBENT ASSAY; ENDS: ELECTRONIC NICOTINE DELIVERY SYSTEMS; FDA: FOOD AND DRUG ADMINISTRATION; GAPDH; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; HPLC: HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; LINE-1: LONG INTERSPERSED NUCLEOTIDE ELEMENT 1; PBS: PHOSPHATE-BUFFERED SALINE; RFU: RELATIVE FLUORESCENCE UNITS; RT-QPCR: QUANTITATIVE REVERSE-TRANSCRIPTION POLYMERASE CHAIN REACTION; ROS: REACTIVE OXYGEN SPECIES; SAM, S-ADENOSYLMETHIONINE; SE: STANDARD ERROR; TET1: TEN-ELEVEN TRANSLOCATION 1; TET2: TEN-ELEVEN TRANSLOCATION 2; TET3: TEN-ELEVEN TRANSLOCATION 3.	2020	
                                                           
12  4117  32 MECHANISMS OF AUTOPHAGIC RESPONSES TO ALTERED NUTRITIONAL STATUS. AUTOPHAGY IS A DYNAMIC PROCESS AND CRITICAL FOR CELLULAR REMODELING AND ORGANELLE QUALITY CONTROL. IN RESPONSE TO ALTERED NUTRITIONAL STATUS (E.G., FASTING AND FEEDING), AUTOPHAGIC ACTIVITY IS FINELY TUNED BY TRANSCRIPTIONAL, POSTTRANSLATIONAL, AND EPIGENETIC REGULATIONS VIA VARIOUS SIGNALING PATHWAYS, INCLUDING ENERGY SENSORS (E.G., MECHANISTIC TARGET OF RAPAMYCIN (MTOR)/ AMP-ACTIVATED PROTEIN KINASE - UNC-51 LIKE AUTOPHAGY ACTIVATING KINASE 1, MTORC1- WD REPEAT DOMAIN, PHOSPHOINOSITIDE INTERACTING 2, MTORC1- TRANSCRIPTION FACTOR EB, PERILIPIN 5- SIRTUIN 1, AND SIRTUIN 1-MEDIATED DEACETYLATION OF AUTOPHAGY PROTEINS), FASTING OR FEEDING INDUCED HORMONES (E.G., FIBROBLAST GROWTH FACTOR [FGF21]- PROTEIN KINASE A - JUMONJI DOMAIN-CONTAINING PROTEIN D3, FGF21- DOWNSTREAM REGULATORY ELEMENT ANTAGONIST MODULATOR - E3 LIGASE MIDLINE-1- TRANSCRIPTION FACTOR EB, FGF19-SHP- LYSINE-SPECIFIC DEMETHYLASE, INSULIN- INSULIN RECEPTOR SUBSTRATE - PROTEIN KINASE B - FORKHEAD BOX O, GLUCAGON- PROTEIN KINASE A - CAMP RESPONSE BINDING PROTEIN), AND LYSOSOMAL ENZYMES (E.G., CATHEPSIN B AND CATHEPSIN L). IN CONTRAST TO FASTING THAT INDUCES AUTOPHAGY AND HEALTH BENEFITS, NUTRIENT OVERSUPPLY (OVERFEEDING OR FEEDING ON HIGH ENERGY DIETS) DYSREGULATES AUTOPHAGY, WHICH HAS BEEN INCREASINGLY OBSERVED IN ANIMAL MODELS OF HUMAN CHRONIC DISEASES SUCH AS OBESITY, DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, AND CARDIOVASCULAR DISEASE. STUDIES HAVE REVEALED MULTIFACETED EFFECTS OF HIGH ENERGY DIETS ON AUTOPHAGY, BEING EITHER AN INHIBITOR OR ENHANCER OF AUTOPHAGY. THE CONUNDRUM MAY ARISE FROM THE VARIATIONS IN METHODS FOR AUTOPHAGY ANALYSIS, COMPONENTS OF HIGH ENERGY DIETS AND CONTROL DIETS FOR TREATMENTS, TREATMENT DURATIONS, AND THE AGES OF GENETIC BACKGROUNDS OF LABORATORY ANIMALS. IN THIS ARTICLE, WE REVIEWED THE EVIDENCE FROM BOTH HUMAN AND ANIMAL STUDIES, PRESENTING THE MOLECULAR MECHANISM OF AUTOPHAGIC RESPONSE TO ALTERED NUTRITIONAL STATUS AND DISCUSSING THE CONTRIBUTING FACTORS OF AND POSSIBLE SOLUTION TO THE CURRENT CONUNDRUM CONCERNING THE EXACT ROLE OF HIGH ENERGY DIETS IN AUTOPHAGIC REGULATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13  5760  28 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14  4044  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  5227  29 PRMT6 MEDIATES INFLAMMATION VIA ACTIVATION OF THE NF-KAPPAB/P65 PATHWAY ON A CIGARETTE SMOKE EXTRACT-INDUCED MURINE EMPHYSEMA MODEL. INTRODUCTION: SMOKE-DRIVEN LUNG INFLAMMATION IS CONSIDERED TO BE THE MAJOR PATHOPHYSIOLOGY MECHANISM OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA. PROTEIN ARGININE METHYLTRANSFERASE 6 (PRMT6) IS A KEY EPIGENETIC ENZYME, WHICH IS RELATED TO PROTECTING THE TRI-METHYLATION OF H3K4 (H3K4ME3). WE HYPOTHESIZED THAT PTMT6 PROTECTS LUNG INFLAMMATION THROUGH THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY. METHODS: MICE WERE INJECTED WITH CIGARETTE SMOKE EXTRACT (CSE) OR PBS TO ESTABLISH A MICE MODEL, INTRATRACHEALLY INSTILLED WITH OVEREXPRESSED PRMT6 OR NEGATIVE CONTROL VECTOR. MORPHOMETRY OF LUNG SLIDES AND LUNG FUNCTION WERE MEASURED. WE DETERMINED THE PROTEIN EXPRESSION OF PRMT6 AND ITS RELATED HISTONE TARGETS, THE ACTIVATION OF NF-KAPPAB PATHWAY, THE LEVEL OF TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) AND INTERLEUKIN-1BETA (IL-1BETA). RESULTS: AFTER PRMT6 OVEREXPRESSION, THE MORPHOMETRY INDEXES AND LUNG FUNCTION WERE IMPROVED. ALSO, THE EXPRESSION OF H3K4ME3 WAS DECREASED. OVEREXPRESSED PRMT6 COULD SUPPRESS CSE-INDUCED NF-KAPPAB ACTIVATION AND PRO-INFLAMMATION GENES EXPRESSION. CONCLUSIONS: THE OVEREXPRESSED PRMT6 COULD SERVE AS AN INFLAMMATION INHIBITOR, POTENTIALLY THROUGH BLOCKING THE NF-KAPPAB/P65 PATHWAY IN THE MURINE EMPHYSEMA MODEL.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16  6669  27 URIC ACID IN METABOLIC SYNDROME: DOES URIC ACID HAVE A DEFINITIVE ROLE? INCREASED SERUM URIC ACID (SUA) LEVELS ARE COMMONLY SEEN IN PATIENTS WITH METABOLIC SYNDROME AND ARE WIDELY ACCEPTED AS RISK FACTORS FOR HYPERTENSION, GOUT, NON-ALCOHOLIC FATTY LIVER DISEASE, CHRONIC KIDNEY DISEASE (CKD), AND CARDIOVASCULAR DISEASES. ALTHOUGH SOME AMBIGUITY FOR THE EXACT ROLE OF URIC ACID (UA) IN THESE DISEASES IS STILL PRESENT, SEVERAL PATHOPHYSIOLOGICAL MECHANISMS HAVE BEEN IDENTIFIED SUCH AS INCREASED OXIDATIVE STRESS, INFLAMMATION, AND APOPTOSIS. ACCUMULATING EVIDENCE IN GENOMICS ENLIGHTENS GENETIC VARIABILITIES AND SOME EPIGENETIC CHANGES THAT CAN CONTRIBUTE TO HYPERURICEMIA. HERE WE DISCUSS THE ROLE OF UA WITHIN METABOLISM AND THE CONSEQUENCES OF ASYMPTOMATIC HYPERURICEMIA WHILE PROVIDING NEWFOUND EVIDENCE FOR THE ASSOCIATIONS BETWEEN UA AND GUT MICROBIOTA AND VITAMIN D. INCREASED SUA LEVELS AND BENEFICIAL EFFECTS OF LOWERING SUA LEVELS NEED TO BE ELUCIDATED MORE TO UNDERSTAND ITS COMPLICATED FUNCTION WITHIN DIFFERENT METABOLIC PATHWAYS AND SET OPTIMAL TARGET LEVELS FOR SUA FOR REDUCING RISKS FOR METABOLIC AND CARDIOVASCULAR DISEASES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17   298  31 AIR POLLUTION AND AIRWAY DISEASE. EPIDEMIOLOGICAL AND TOXICOLOGICAL RESEARCH CONTINUES TO SUPPORT A LINK BETWEEN URBAN AIR POLLUTION AND AN INCREASED INCIDENCE AND/OR SEVERITY OF AIRWAY DISEASE. DETRIMENTAL EFFECTS OF OZONE (O(3)), NITROGEN DIOXIDE (NO(2)) AND PARTICULATE MATTER (PM), AS WELL AS TRAFFIC-RELATED POLLUTION AS A WHOLE, ON RESPIRATORY SYMPTOMS AND FUNCTION ARE WELL DOCUMENTED. NOT ONLY DO WE HAVE STRONG EPIDEMIOLOGICAL EVIDENCE OF A RELATIONSHIP BETWEEN AIR POLLUTION AND EXACERBATION OF ASTHMA AND RESPIRATORY MORBIDITY AND MORTALITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BUT RECENT STUDIES, PARTICULARLY IN URBAN AREAS, HAVE SUGGESTED A ROLE FOR POLLUTANTS IN THE DEVELOPMENT OF BOTH ASTHMA AND COPD. SIMILARLY, WHILE PREVALENCE AND SEVERITY OF ATOPIC CONDITIONS APPEAR TO BE MORE COMMON IN URBAN COMPARED WITH RURAL COMMUNITIES, EVIDENCE IS EMERGING THAT TRAFFIC-RELATED POLLUTANTS MAY CONTRIBUTE TO THE DEVELOPMENT OF ALLERGY. FURTHERMORE, NUMEROUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES SUGGEST AN ASSOCIATION BETWEEN EXPOSURE TO NO(2) , O(3) , PM AND COMBUSTION PRODUCTS OF BIOMASS FUELS AND AN INCREASED SUSCEPTIBILITY TO AND MORBIDITY FROM RESPIRATORY INFECTION. GIVEN THE CONSIDERABLE CONTRIBUTION THAT TRAFFIC EMISSIONS MAKE TO URBAN AIR POLLUTION RESEARCHERS HAVE SOUGHT TO CHARACTERIZE THE RELATIVE TOXICITY OF TRAFFIC-RELATED PM POLLUTANTS. RECENT ADVANCES IN MECHANISMS IMPLICATED IN THE ASSOCIATION OF AIR POLLUTANTS AND AIRWAY DISEASE INCLUDE EPIGENETIC ALTERATION OF GENES BY COMBUSTION-RELATED POLLUTANTS AND HOW POLYMORPHISMS IN GENES INVOLVED IN ANTIOXIDANT PATHWAYS AND AIRWAY INFLAMMATION CAN MODIFY RESPONSES TO AIR POLLUTION EXPOSURES. OTHER INTERESTING EPIDEMIOLOGICAL OBSERVATIONS RELATED TO INCREASED HOST SUSCEPTIBILITY INCLUDE A POSSIBLE LINK BETWEEN CHRONIC PM EXPOSURE DURING CHILDHOOD AND VULNERABILITY TO COPD IN ADULTHOOD, AND THAT INFANTS SUBJECTED TO HIGHER PRENATAL LEVELS OF AIR POLLUTION MAY BE AT GREATER RISK OF DEVELOPING RESPIRATORY CONDITIONS. WHILE THE CHARACTERIZATION OF POLLUTANT COMPONENTS AND SOURCES PROMISE TO GUIDE POLLUTION CONTROL STRATEGIES, THE IDENTIFICATION OF SUSCEPTIBLE SUBPOPULATIONS WILL BE NECESSARY IF TARGETED THERAPY/PREVENTION OF POLLUTION-INDUCED RESPIRATORY DISEASES IS TO BE DEVELOPED.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18  4075  26 MATERNAL HIGH-FAT DIET IMPAIRS LEPTIN SIGNALING AND UP-REGULATES TYPE-1 CANNABINOID RECEPTOR WITH SEX-SPECIFIC EPIGENETIC CHANGES IN THE HYPOTHALAMUS OF NEWBORN RATS. MATERNAL NUTRITIONAL IMBALANCES TRIGGER DEVELOPMENTAL ADAPTATIONS INVOLVING EARLY EPIGENETIC MECHANISMS ASSOCIATED WITH ADULT CHRONIC DISEASE. MATERNAL HIGH-FAT (HF) DIET PROMOTES OBESITY AND HYPOTHALAMIC LEPTIN RESISTANCE IN MALE RAT OFFSPRING AT WEANING AND ADULTHOOD. LEPTIN RESISTANCE IS ASSOCIATED WITH OVER ACTIVATION OF THE ENDOCANNABINOID SYSTEM (ECS). THE ECS MAINLY CONSISTS OF ENDOCANNABINOIDS DERIVED FROM N-6 FATTY ACIDS AND CANNABINOID RECEPTORS (CB1 CODED BY CNR1 AND CB2 CODED BY CNR2). THE CB1 ACTIVATION IN HYPOTHALAMUS STIMULATES FEEDING AND APPETITE FOR FAT WHILE CB2 ACTIVATION SEEMS TO PLAY AN IMMUNOMODULATORY ROLE. WE DEMONSTRATED THAT MATERNAL HF DIET INCREASES HYPOTHALAMIC CB1 IN MALE OFFSPRING WHILE INCREASES CB2 IN FEMALE OFFSPRING AT BIRTH, PRIOR TO OBESITY DEVELOPMENT. HOWEVER, THE MOLECULAR MECHANISMS BEHIND THESE CHANGES REMAIN UNEXPLORED. WE HYPOTHESIZED THAT MATERNAL HF DIET WOULD DOWN-REGULATE LEPTIN SIGNALING AND UP-REGULATE CNR1 MRNA LEVELS IN THE HYPOTHALAMUS OF THE OFFSPRING AT BIRTH, ASSOCIATED WITH SEX-SPECIFIC CHANGES IN EPIGENETIC MARKERS AND SEX STEROID SIGNALING. TO TEST OUR HYPOTHESIS, WE USED PROGENITOR FEMALE RATS THAT RECEIVED CONTROL DIET (C, 9% FAT) OR ISOCALORIC HIGH-FAT DIET (HF, 28% FAT) FROM 8 WEEKS BEFORE MATING UNTIL DELIVERY. BLOOD, HYPOTHALAMUS AND CARCASS FROM C AND HF MALE AND FEMALE OFFSPRING WERE COLLECTED FOR BIOCHEMICAL AND MOLECULAR ANALYSES AT BIRTH. MATERNAL HF DIET DOWN-REGULATED THE TRANSCRIPTIONAL FACTOR STAT3 IN THE HYPOTHALAMUS OF MALE AND FEMALE OFFSPRING, BUT INDUCED HYPOLEPTINEMIA ONLY IN MALES AND DECREASED PHOSPHORYLATED STAT3 ONLY IN FEMALE OFFSPRING. BECAUSE LEPTIN ACTS THROUGH STAT3 PATHWAY TO INHIBIT CENTRAL ECS, OUR RESULTS SUGGEST THAT LEPTIN PATHWAY IMPAIRMENT MIGHT CONTRIBUTE TO INCREASED LEVELS OF CRN1 MRNA IN HYPOTHALAMUS OF BOTH SEX OFFSPRING. BESIDES, MATERNAL HF DIET INCREASED THE HISTONE ACETYLATION PERCENTAGE OF CNR1 PROMOTER IN MALE OFFSPRING AND INCREASED THE ANDROGEN RECEPTOR BINDING TO THE CNR1 PROMOTER, WHICH CAN CONTRIBUTE TO HIGHER EXPRESSION OF CNR1 IN NEWBORN HF OFFSPRING. MATERNAL HF DIET INCREASED PLASMA N6 TO N3 FATTY ACID RATIO IN MALE OFFSPRING, WHICH IS AN IMPORTANT RISK FACTOR TO METABOLIC DISEASES AND MIGHT INDICATE AN OVER ACTIVATION OF ENDOCANNABINOID SIGNALING. THUS, ALTHOUGH MATERNAL HF DIET PROGRAMS A SIMILAR PHENOTYPE IN ADULT OFFSPRING OF BOTH SEXES (OBESITY, HYPERPHAGIA AND HIGHER PREFERENCE FOR FAT), HERE WE SHOWED THAT MOLECULAR MECHANISMS INVOLVING LEPTIN SIGNALING, ECS, EPIGENETIC MARKERS AND SEX HORMONE SIGNALING WERE MODIFIED PRIOR TO OBESITY DEVELOPMENT AND CAN DIFFER BETWEEN NEWBORN MALE AND FEMALE OFFSPRING. THESE OBSERVATIONS MAY PROVIDE MOLECULAR INSIGHTS INTO SEX-SPECIFIC TARGETS FOR ANTI-OBESITY THERAPIES.	2019	

19  1201  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20  6456  25 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