1  1443 176 DIFFERENTIAL RESPONSES OF HEALTHY AND CHRONIC OBSTRUCTIVE PULMONARY DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(4). WHILE THE KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS IS STILL INCOMPLETE, DETAILED IN VITRO STUDIES ARE HIGHLY NEEDED. WITH THE AIM OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS AND BETTER INTEGRATING A NUMBER OF FACTORS RELATED TO PRE-EXISTING CHRONIC PULMONARY INFLAMMATORY, WE SOUGHT TO DEVELOP PRIMARY CULTURES OF NORMAL HUMAN BRONCHIAL EPITHELIAL (NHBE) CELLS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED HUMAN BRONCHIAL EPITHELIAL (DHBE) CELLS, GROWN AT THE AIR-LIQUID INTERFACE. PAN-CYTOKERATIN AND MUC5AC IMMUNOSTAINING CONFIRMED THE SPECIFIC CELL-TYPES OF BOTH THESE HEALTHY AND DISEASED CELL MODELS AND SHOWED THEY ARE CLOSED TO HUMAN BRONCHIAL EPITHELIA. THEREAFTER, HEALTHY AND DISEASED CELLS WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(4) AT THE NON-CYTOTOXIC CONCENTRATION OF 5 MUG/CM(2). THE DIFFERENCES BETWEEN THE OXIDATIVE AND INFLAMMATORY STATES IN NON-EXPOSED NHBE AND COPD-DHBE CELLS INDICATED THAT DISEASED CELLS CONSERVED THEIR SPECIFIC PHYSIOPATHOLOGICAL CHARACTERISTICS. INCREASES IN BOTH OXIDATIVE DAMAGE AND CYTOKINE SECRETION WERE REPORTED IN REPEATEDLY EXPOSED NHBE CELLS AND PARTICULARLY IN COPD-DHBE CELLS. DISEASED CELLS REPEATEDLY EXPOSED HAD LOWER CAPACITIES TO METABOLIZE THE ORGANIC CHEMICALS-COATED ONTO THE AIR-POLLUTION-DERIVED PM(4), SUCH AS BENZO[A]PYRENE (B[A]P), BUT SHOWED HIGHER SENSIBILITY TO THE FORMATION OF OH-B[A]P DNA ADDUCTS, BECAUSE THEIR DISEASED STATE POSSIBLY AFFECTED THEIR DEFENSES. DIFFERENTIAL PROFILES OF EPIGENETIC HALLMARKS (I.E., GLOBAL DNA HYPOMETHYLATION, P16 PROMOTER HYPERMETHYLATION, TELOMERE LENGTH SHORTENING, TELOMERASE ACTIVATION, AND HISTONE H3 MODIFICATIONS) OCCURRED IN REPEATEDLY EXPOSED NHBE AND PARTICULARLY IN COPD-DHBE CELLS. TAKEN TOGETHER, THESE RESULTS CLOSELY SUPPORTED THE HIGHEST RESPONSIVENESS OF COPD-DHBE CELLS TO A REPEATED EXPOSURE TO AIR POLLUTION-DERIVED PM(4). THE USE OF THESE INNOVATIVE IN VITRO EXPOSURE SYSTEMS SUCH AS NHBE AND COPD-DHBE CELLS COULD THEREFORE BE CONSIDER AS A VERY USEFUL AND POWERFUL PROMISING TOOL IN THE FIELD OF THE RESPIRATORY TOXICOLOGY, TAKING INTO ACCOUNT SENSITIVE INDIVIDUALS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                 
2  6528  26 TRANSCRIPTIONAL CORRELATES OF CHRONIC ALCOHOL NEUROADAPTATION IN DROSOPHILA LARVAE. WHEN PRESENTED WITH THE CHOICE, DROSOPHILA MELANOGASTER FEMALES WILL OFTEN PREFER TO LAY EGGS ON FOOD CONTAINING A SIGNIFICANT AMOUNT OF ALCOHOL. WHILE, IN SOME CASES, THIS BEHAVIORAL DECISION CAN PROVIDE A SURVIVAL ADVANTAGE TO THE DEVELOPING LARVAE, IT CAN ALSO LEAD TO DEVELOPMENTAL AND COGNITIVE PROBLEMS. ALCOHOL CONSUMPTION CAN AFFECT EXECUTIVE FUNCTIONS, EPISODIC MEMORY, AND OTHER BRAIN FUNCTION CAPACITIES. HOWEVER, IN THE FRUIT FLY, THE INITIAL COGNITIVE EFFECTS OF ALCOHOL CONSUMPTION HAVE BEEN SHOWN TO REVERSE UPON PERSISTENT EXPOSURE TO ALCOHOL. USING AN OLFACTORY CONDITIONING ASSAY WHERE AN ODORANT IS IMPLEMENTED AS A CONDITIONED STIMULUS AND PAIRED WITH A HEAT SHOCK AS AN UNCONDITIONED STIMULUS, A PREVIOUS STUDY HAS SHOWN THAT WHEN EXPOSED TO A SHORT ACUTE DOSE OF ALCOHOL, DROSOPHILA LARVAE CAN NO LONGER LEARN THIS ASSOCIATION. INTERESTINGLY, UPON PROLONGED CHRONIC ALCOHOL EXPOSURE, LARVAE SEEM TO SUCCESSFULLY AVOID THE CONDITIONED STIMULUS JUST AS WELL AS CONTROL ALCOHOL-NAIVE LARVAE, SUGGESTIVE OF ALCOHOL-INDUCED NEUROADAPTATIONS. HOWEVER, THE MECHANISMS BY WHICH DROSOPHILA ADAPT TO THE PRESENCE OF ALCOHOL REMAINS UNKNOWN. IN THIS STUDY, WE EXPLORE THE TRANSCRIPTIONAL CORRELATES OF NEUROADAPTATION IN DROSOPHILA LARVAE EXPOSED TO CHRONIC ALCOHOL TO UNDERSTAND THE GENETIC AND CELLULAR COMPONENTS RESPONSIBLE FOR THIS ADAPTATION. FOR THIS, WE EMPLOYED RNA SEQUENCING TECHNOLOGY TO EVALUATE DIFFERENCES IN GENE EXPRESSION IN THE BRAIN OF LARVAE CHRONICALLY EXPOSED TO ALCOHOL. OUR RESULTS SUGGEST THAT ALCOHOL-INDUCED NEUROADAPTATIONS ARE MODULATED BY A DIVERSE ARRAY OF SYNAPTIC GENES WITHIN THE LARVAL BRAIN THROUGH A SERIES OF EPIGENETIC MODULATORS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
3   683  26 BRAIN PLASTICITY AND COGNITIVE FUNCTIONS AFTER ETHANOL CONSUMPTION IN C57BL/6J MICE. ACUTE OR CHRONIC ADMINISTRATIONS OF HIGH DOSES OF ETHANOL IN MICE ARE KNOWN TO PRODUCE SEVERE COGNITIVE DEFICITS LINKED TO HIPPOCAMPAL DAMAGE. HOWEVER, WE RECENTLY REPORTED THAT CHRONIC AND MODERATE ETHANOL INTAKE IN C57BL/6J MICE INDUCED CHROMATIN REMODELING WITHIN THE BDNF PROMOTERS, LEADING TO BOTH ENHANCED BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND HIPPOCAMPAL NEUROGENESIS UNDER FREE-CHOICE PROTOCOL. WE PERFORMED HERE A SERIES OF CELLULAR AND BEHAVIORAL STUDIES TO ANALYZE THE CONSEQUENCES OF THESE MODIFICATIONS. WE SHOWED THAT A 3-WEEK CHRONIC FREE-CHOICE ETHANOL CONSUMPTION IN C57BL/6J MICE LED TO A DECREASE IN DNA METHYLATION OF THE BDNF GENE WITHIN THE CA1 AND CA3 SUBFIELDS OF THE HIPPOCAMPUS, AND UPREGULATED HIPPOCAMPAL BDNF SIGNALING PATHWAYS MEDIATED BY ERK, AKT AND CREB. HOWEVER, THIS ACTIVATION DID NOT AFFECT LONG-TERM POTENTIATION IN THE CA1. CONVERSELY, ETHANOL INTAKE IMPAIRED LEARNING AND MEMORY CAPACITIES ANALYZED IN THE CONTEXTUAL FEAR CONDITIONING TEST AND THE NOVEL OBJECT RECOGNITION TASK. IN ADDITION, ETHANOL INCREASED BEHAVIORAL PERSEVERATION IN THE BARNES MAZE TEST BUT DID NOT ALTER THE MOUSE OVERALL SPATIAL CAPACITIES. THESE DATA SUGGESTED THAT IN CONDITIONS OF CHRONIC AND MODERATE ETHANOL INTAKE, THE CHROMATIN REMODELING LEADING TO BDNF SIGNALING UPREGULATION IS PROBABLY AN ADAPTIVE PROCESS, ENGAGED VIA EPIGENETIC REGULATIONS, TO COUNTERACT THE COGNITIVE DEFICITS INDUCED BY ETHANOL.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4   440  30 ANTIOXIDATIVE EFFECTS OF RHODIOLA GENUS: PHYTOCHEMISTRY AND PHARMACOLOGICAL MECHANISMS AGAINST THE DISEASES. RHODIOLA AS ONE OF TRADITIONAL MEDICINES HAS BEEN USED FOR CLINICAL TREATMENTS DUE TO ITS STRONG ANTIOXIDANT PROPERTIES. PHYTOCHEMICAL ANALYSIS REVEALED THE PRESENCE OF FLAVONOIDS, PHENYLPROPANOIDS, PHENYLETHANOL/BENZYL ALCOHOL DERIVATIVES, CYANOGENIC GLYCOSIDES AND TERPENOIDS. THE BIOACTIVE COMPOUNDS HAD BEEN DEMONSTRATED TO BE EFFECTIVE AT SCAVENGING REACTIVE OXYGEN SPECIES (ROS). THE STRUCTURES CONTAIN PHENOLIC HYDROXYL GROUPS AND UNSATURATED BONDS. THIS ARTICLE REVIEWS ANTIOXIDANT CAPACITIES OF THE EXTRACTS AND BIOACTIVE COMPONENTS DERIVED FROM RHODIOLA PLANTS. AS THE MAJOR PHARMACOLOGICAL INGREDIENT, SALIDROSIDE IS RIGOROUSLY INVESTIGATED AND USED IN SCIENTIFIC RESEARCHES AND CLINICAL PRACTICES. ACCUMULATED EVIDENCES INDICATED THAT EXTRACTS OF RHODIOLA PLANTS OR SALIDROSIDE COULD BE ABLE TO REVERSE DNA DAMAGE AND ALTER EXPRESSION OF CYTOKINES AND ANTIOXIDATIVE ENZYMES INDUCED BY ROS. THE UNDERLYING MECHANISMS FOR THE ANTIOXIDATIVE EFFECTS OF THE HERB HAVE BEEN INVESTIGATED IN THE LAST TWO DECADES. WE SUMMARIZE THE POSSIBLE EFFECTS AND ACTING PATHWAYS FOR THE HERB INVOLVED IN SEVERAL CHRONIC DISEASES IN CARDIOVASCULAR, RESPIRATORY, AND NERVOUS SYSTEMS, AS WELL AS POTENTIAL EPIGENETIC INFLUENCES. THE INFORMATION GENERATED FROM EXPERIMENTAL AND CLINICAL STUDIES OFFERED VALUABLE INSIGHTS FOR FURTHER INVESTIGATIONS OF MEDICAL POTENTIALS OF RHODIOLA PLANTS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5  4831  30 OLIGOMERIC S100A4 IS ASSOCIATED WITH MONOCYTE INNATE IMMUNE MEMORY AND BYPASS OF TOLERANCE TO SUBSEQUENT STIMULATION WITH LIPOPOLYSACCHARIDES. OBJECTIVES: MOST DAMPS IN INFLAMMATORY DISEASES ARE TLR2- AND TLR4-LIGANDS AND ACCORDING TO THE CURRENT CONCEPT, REPEATED STIMULI WOULD RESULT IN TOLERANCE. AIMS OF THE STUDY WERE TO VERIFY THIS ASSUMPTION, TO INVESTIGATE WHETHER EPIGENETIC EFFECTORS ARE INVOLVED AND TO EXPLORE THE SITUATION IN RHEUMATOID ARTHRITIS (RA). METHODS: A TRAINED IMMUNITY (TI) AND TOLERANCE PROTOCOL WAS ESTABLISHED USING PERIPHERAL BLOOD MONOCYTES FROM HEALTHY DONORS, BETA-GLUCAN AND LIPOPOLYSACCHARIDE (LPS). THE TRAINING OR TOLERANCE CAPACITIES OF RA-RELEVANT DAMPS WERE TESTED. RESULTS: BETA-GLUCAN-, OS100A4-, HMBG1-, AND HSP90-PRETREATED MONOCYTES SHOWED INCREASED IL-6 RESPONSES TO LPS RE-STIMULATION. BETA-GLUCAN, OS100A AND TENASCIN C INDUCED TRAINING OF MONOCYTES TO RELEASE MORE TNFALPHA. IN COMPARISON TO BETA-GLUCAN, MOST DAMPS TESTED INDUCED LESS TI, WITH EXCEPTION OF OS100A4. MONOCYTES EXPOSED TO OS100A4 SHOWED INCREASED IL-1BETA, IL-6, AND TNFALPHA IN RESPONSE TO LPS, IN SPITE THAT BOTH STIMULATE TLR4. RNASEQ UPON BETA-GLUCAN OR OS100A4 REVEALED SIMILAR CHANGES IN CHEMOKINES/CYTOKINES AND EPIGENETIC EFFECTORS; 17 EPIGENETIC EFFECTORS CORRELATED WITH CHEMOKINE/CYTOKINE GENE EXPRESSION; PRDM8 WAS ASSOCIATED WITH MORE CHEMOKINE AND CYTOKINE TRANSCRIPTS. KNOCKDOWN OF PRDM8 ABOLISHED TI INDUCED BY OS100A4. IN RA, PLASMA S100A4 CORRELATED WITH INCREASED CSF2, AND INCREASED PRDM8 TRANSCRIPTION IN RA MONOCYTES WAS ASSOCIATED WITH INCREASED PLASMA CCL5 AND IL-6, AS WELL AS THERAPY-RESISTANCE. CONCLUSION: BYPASS OF TOLERANCE BY DAMPS MIGHT BE A PHENOMENON AS IMPORTANT AS TI, SINCE IT COULD EXPLAIN HOW CHRONIC INFLAMMATION CAN BE MAINTAINED IN SPITE OF AN ENVIRONMENT WITH MULTIPLE TLR2/TLR4-LIGANDS. IN RA MONOCYTES, A PRDM8-DEPENDENT TI MECHANISM COULD BE RESPONSIBLE FOR SUSTAINED CHEMOKINE/CYTOKINES LEVELS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6  5671  27 SHARED AND DISTINCT BIOLOGICAL CIRCUITS IN EFFECTOR, MEMORY AND EXHAUSTED CD8(+) T CELLS REVEALED BY TEMPORAL SINGLE-CELL TRANSCRIPTOMICS AND EPIGENETICS. NAIVE CD8(+) T CELLS CAN DIFFERENTIATE INTO EFFECTOR (T(EFF)), MEMORY (T(MEM)) OR EXHAUSTED (T(EX)) T CELLS. THESE DEVELOPMENTAL PATHWAYS ARE ASSOCIATED WITH DISTINCT TRANSCRIPTIONAL AND EPIGENETIC CHANGES THAT ENDOW CELLS WITH DIFFERENT FUNCTIONAL CAPACITIES AND THEREFORE THERAPEUTIC POTENTIAL. THE MOLECULAR CIRCUITRY UNDERLYING THESE DEVELOPMENTAL TRAJECTORIES AND THE EXTENT OF HETEROGENEITY WITHIN T(EFF), T(MEM) AND T(EX) POPULATIONS REMAIN POORLY UNDERSTOOD. HERE, WE USED THE LYMPHOCYTIC CHORIOMENINGITIS VIRUS MODEL OF ACUTE-RESOLVING AND CHRONIC INFECTION TO ADDRESS THESE GAPS BY APPLYING LONGITUDINAL SINGLE-CELL RNA-SEQUENCING (SCRNA-SEQ) AND SINGLE-CELL ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN SEQUENCING (SCATAC-SEQ) ANALYSES. THESE ANALYSES UNCOVERED NEW SUBSETS, INCLUDING A SUBPOPULATION OF T(EX) CELLS EXPRESSING NATURAL KILLER CELL-ASSOCIATED GENES THAT IS DEPENDENT ON THE TRANSCRIPTION FACTOR ZEB2, AS WELL AS MULTIPLE DISTINCT TCF-1(+) STEM/PROGENITOR-LIKE SUBSETS IN ACUTE AND CHRONIC INFECTION. THESE DATA ALSO REVEALED INSIGHTS INTO THE RESHAPING OF T(EX) SUBSETS FOLLOWING PROGRAMMED DEATH 1 (PD-1) PATHWAY BLOCKADE AND IDENTIFIED A KEY ROLE FOR THE CELL STRESS REGULATOR, BTG1, IN ESTABLISHING THE T(EX) POPULATION. FINALLY, THESE RESULTS HIGHLIGHTED HOW THE SAME BIOLOGICAL CIRCUITS SUCH AS CYTOTOXICITY OR STEM/PROGENITOR PATHWAYS CAN BE USED BY CD8(+) T CELL SUBSETS WITH HIGHLY DIVERGENT UNDERLYING CHROMATIN LANDSCAPES GENERATED DURING DIFFERENT INFECTIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7  2397  30 EPIGENETIC REPROGRAMMING OF AIRWAY MACROPHAGES PROMOTES POLARIZATION AND INFLAMMATION IN MUCO-OBSTRUCTIVE LUNG DISEASE. LUNG DISEASES, SUCH AS CYSTIC FIBROSIS AND COPD, ARE CHARACTERIZED BY MUCUS OBSTRUCTION AND CHRONIC AIRWAY INFLAMMATION, BUT THEIR MECHANISTIC LINK REMAINS POORLY UNDERSTOOD. HERE, WE FOCUS ON THE FUNCTION OF THE MUCOSTATIC AIRWAY MICROENVIRONMENT ON EPIGENETIC REPROGRAMMING OF AIRWAY MACROPHAGES (AM) AND RESULTING TRANSCRIPTOMIC AND PHENOTYPICAL CHANGES. USING A MOUSE MODEL OF MUCO-OBSTRUCTIVE LUNG DISEASE (SCNN1B-TRANSGENIC), WE IDENTIFY EPIGENETICALLY CONTROLLED, DIFFERENTIALLY REGULATED PATHWAYS AND TRANSCRIPTION FACTORS INVOLVED IN INFLAMMATORY RESPONSES AND MACROPHAGE POLARIZATION. FUNCTIONALLY, AMS FROM SCNN1B-TRANSGENIC MICE HAVE REDUCED EFFEROCYTOSIS AND PHAGOCYTOSIS, AND EXCESSIVE INFLAMMATORY RESPONSES UPON LIPOPOLYSACCHARIDE CHALLENGE, MEDIATED THROUGH ENHANCED IRF1 FUNCTION AND EXPRESSION. EX VIVO STIMULATION OF WILD-TYPE AMS WITH NATIVE MUCUS IMPAIRS EFFEROCYTOSIS AND PHAGOCYTOSIS CAPACITIES. IN ADDITION, MUCUS INDUCES GENE EXPRESSION CHANGES, COMPARABLE WITH THOSE OBSERVED IN AMS FROM SCNN1B-TRANSGENIC MICE. OUR DATA SHOW THAT MUCOSTASIS INDUCES EPIGENETIC REPROGRAMMING OF AMS, LEADING TO CHANGES FAVORING TISSUE DAMAGE AND DISEASE PROGRESSION. TARGETING THESE ALTERED AMS MAY SUPPORT THERAPEUTIC APPROACHES IN PATIENTS WITH MUCO-OBSTRUCTIVE LUNG DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
8  4544  30 MUSCLE HYPERTROPHY IN HYPOXIA WITH INFLAMMATION IS CONTROLLED BY BROMODOMAIN AND EXTRA-TERMINAL DOMAIN PROTEINS. SOME OF THE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS ENGAGED IN EXERCISE-BASED MUSCLE REHABILITATION PROGRAMS ARE UNRESPONSIVE. TO UNRAVEL THE RESPECTIVE ROLE OF CHRONIC HYPOXIA AND PULMONARY INFLAMMATION ON SOLEUS MUSCLE HYPERTROPHIC CAPACITIES, WE CHALLENGED MALE WISTAR RATS TO REPEATED LIPOPOLYSACCHARIDE INSTILLATIONS, ASSOCIATED OR NOT WITH A CHRONIC HYPOXIA EXPOSURE. MUSCLE HYPERTROPHY WAS INITIATED BY BILATERAL ABLATION OF SOLEUS AGONISTS 1 WEEK BEFORE SACRIFICE. TO UNDERSTAND THE ROLE PLAYED BY THE HISTONE ACETYLATION, WE ALSO TREATED OUR ANIMALS WITH AN INHIBITOR OF BROMODOMAINS AND EXTRA TERMINAL PROTEINS (I-BET) DURING THE WEEK AFTER SURGERY. PULMONARY INFLAMMATION TOTALLY INHIBITED THIS HYPERTROPHY RESPONSE UNDER BOTH NORMOXIC AND HYPOXIC CONDITIONS (26% LOWER THAN CONTROL SURGERY, P < 0.05), CONSISTENT WITH THE S6K1 AND MYOGENIN MEASUREMENTS. CHANGES IN HISTONE ACETYLATION AND CLASS IIA HISTONE DEACETYLASES EXPRESSION, FOLLOWING PULMONARY INFLAMMATION, SUGGESTED A PUTATIVE ROLE FOR HISTONE ACETYLATION SIGNALING IN THE ALTERED HYPERTROPHY RESPONSE. THE I-BET DRUG RESTORED THE HYPERTROPHY RESPONSE SUGGESTING THAT THE NON-RESPONSE OF MUSCLE TO A HYPERTROPHIC STIMULUS COULD BE MODULATED BY EPIGENETIC MECHANISMS, INCLUDING HISTONE-ACETYLATION DEPENDANT PATHWAYS. DRUGS TARGETING SUCH EPIGENETIC MECHANISMS MAY OPEN THERAPEUTIC PERSPECTIVES FOR COPD PATIENTS WITH SYSTEMIC INFLAMMATION WHO ARE UNRESPONSIVE TO REHABILITATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9  6520  37 TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF MONOCYTE AND MACROPHAGE DYSFUNCTION BY CHRONIC ALCOHOL CONSUMPTION. DRINKING ALCOHOL, EVEN IN MODERATION, CAN AFFECT THE IMMUNE SYSTEM. STUDIES HAVE SHOWN DISPROPORTIONATE EFFECTS OF ALCOHOL ON CIRCULATING AND TISSUE-RESIDENT MYELOID CELLS (GRANULOCYTES, MONOCYTES, MACROPHAGES, DENDRITIC CELLS). THESE CELLS ORCHESTRATE THE BODY'S FIRST LINE OF DEFENSE AGAINST MICROBIAL CHALLENGES AS WELL AS MAINTAIN TISSUE HOMEOSTASIS AND REPAIR. ALCOHOL'S EFFECTS ON THESE CELLS ARE DEPENDENT ON EXPOSURE PATTERN, WITH ACUTE DRINKING DAMPENING BUT CHRONIC DRINKING ENHANCING PRODUCTION OF INFLAMMATORY MEDIATORS. ALTHOUGH CHRONIC DRINKING IS ASSOCIATED WITH HEIGHTENED SYSTEMIC INFLAMMATION, STUDIES ON TISSUE RESIDENT MACROPHAGE POPULATIONS IN SEVERAL ORGANS INCLUDING THE SPLEEN, LIVER, BRAIN, AND LUNG HAVE ALSO SHOWN COMPROMISED FUNCTIONAL AND METABOLIC CAPACITIES OF THESE CELLS. MANY OF THESE EFFECTS ARE THOUGHT TO BE MEDIATED BY OXIDATIVE STRESS CAUSED BY ALCOHOL AND ITS METABOLITES WHICH CAN DIRECTLY IMPACT THE CELLULAR EPIGENETIC LANDSCAPES. IN ADDITION, SINCE MYELOID CELLS ARE RELATIVELY SHORT-LIVED IN CIRCULATION AND ARE UNDER CONSTANT REPOPULATION FROM THE BONE MARROW COMPARTMENT, ALCOHOL'S EFFECTS ON BONE MARROW PROGENITORS AND HEMATOPOIESIS ARE IMPORTANT FOR UNDERSTANDING THE IMPACT OF ALCOHOL SYSTEMICALLY ON THESE MYELOID POPULATIONS. ALCOHOL-INDUCED DISRUPTION OF PROGENITOR, CIRCULATING, AND TISSUE RESIDENT MYELOID POPULATIONS CONTRIBUTE TO THE INCREASED SUSCEPTIBILITY OF PATIENTS WITH ALCOHOL USE DISORDERS TO VIRAL AND BACTERIAL INFECTIONS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE IMPACT OF CHRONIC ALCOHOL CONSUMPTION ON THE FUNCTION OF MONOCYTES AND MACROPHAGES IN HOST DEFENSE, TISSUE REPAIR AND INFLAMMATION. WE THEN SUMMARIZE OUR CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING ALCOHOL-INDUCED DISRUPTION AND EXAMINE CHANGES IN TRANSCRIPTOME AND EPIGENOME OF MONOCYTES AND MCROPHAGES. OVERALL, CHRONIC ALCOHOL CONSUMPTION LEADS TO HYPER-INFLAMMATION CONCOMITANT WITH DECREASED MICROBIAL AND WOUND HEALING RESPONSES BY MONOCYTES/MACROPHAGES DUE TO A REWIRING OF THE EPIGENTIC AND TRANSCRIPTIONAL LANDSCAPE. HOWEVER, IN ADVANCED ALCOHOLIC LIVER DISEASE, MYELOID CELLS BECOME IMMUNOSUPPRESSED AS A RESPONSE TO THE SURROUNDING HYPER-INFLAMMATORY MILIEU. THEREFORE, THE EFFECT OF CHRONIC ALCOHOL ON THE INFLAMMATORY RESPONSE DEPENDS ON DISEASE STATE AND THE IMMUNE CELL POPULATION.	2022	
                                                                                                                                                                                                                                                                                                                                                 
10  2671  31 ETHANOL CONSUMPTION INDUCES NONSPECIFIC INFLAMMATION AND FUNCTIONAL DEFECTS IN ALVEOLAR MACROPHAGES. CHRONIC ALCOHOL DRINKING IS ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO VIRAL AND BACTERIAL RESPIRATORY PATHOGENS. IN THIS STUDY, WE USE A RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION TO STUDY THE EFFECTS OF LONG-TERM ALCOHOL DRINKING ON THE IMMUNOLOGICAL LANDSCAPE OF THE LUNG. WE REPORT A HEIGHTENED INFLAMMATORY STATE IN ALVEOLAR MACROPHAGES (AMS) OBTAINED FROM ETHANOL (ETOH)-DRINKING ANIMALS THAT IS ACCOMPANIED BY INCREASED CHROMATIN ACCESSIBILITY IN INTERGENIC REGIONS THAT REGULATE INFLAMMATORY GENES AND CONTAIN BINDING MOTIFS FOR TRANSCRIPTION FACTORS AP-1, IRF8, AND NFKB P-65. IN LINE WITH THESE TRANSCRIPTIONAL AND EPIGENETIC CHANGES AT THE BASAL STATE, AMS FROM ETOH-DRINKING ANIMALS GENERATE ELEVATED INFLAMMATORY MEDIATOR RESPONSES TO LIPOPOLYSACCHARIDES AND RESPIRATORY SYNCYTIAL VIRUS. HOWEVER, THE TRANSCRIPTIONAL ANALYSIS REVEALED AN INEFFICIENT INDUCTION OF INTERFERON-STIMULATED GENES WITH ETOH IN RESPONSE TO THE RESPIRATORY SYNCYTIAL VIRUS, SUGGESTING DISRUPTION OF ANTIMICROBIAL DEFENSES. CORRESPONDINGLY, AMS FROM ETOH-DRINKING ANIMALS EXHIBITED TRANSCRIPTIONAL SHIFTS INDICATIVE OF INCREASED OXIDATIVE STRESS AND OXIDATIVE PHOSPHORYLATION, WHICH WAS COUPLED WITH HIGHER CYTOSOLIC REACTIVE OXYGEN SPECIES AND MITOCHONDRIAL POTENTIAL. THIS HEIGHTENED OXIDATIVE STRESS STATE WAS ACCOMPANIED BY DECREASED ABILITY TO PHAGOCYTOSE BACTERIA. BULK RNA AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN SEQUENCING DATA FURTHER REVEALED REDUCED EXPRESSION AND CHROMATIN ACCESSIBILITY OF LOCI ASSOCIATED WITH TISSUE REPAIR AND MAINTENANCE WITH CHRONIC ETOH DRINKING. SIMILARLY, ANALYSIS OF SINGLE-CELL RNA SEQUENCING DATA REVEALED SHIFTS IN CELL STATES FROM TISSUE MAINTENANCE TO INFLAMMATORY RESPONSES WITH ETOH. COLLECTIVELY, THESE DATA PROVIDE NOVEL INSIGHT INTO MECHANISMS BY WHICH CHRONIC ETOH DRINKING INCREASES SUSCEPTIBILITY TO INFECTION IN PATIENTS WITH ALCOHOL USE DISORDERS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11  5808  33 STRATIFICATION OF COMPANION ANIMAL LIFE STAGES FROM ELECTRONIC MEDICAL RECORD DIAGNOSIS DATA. AGING IS A COMPLEX, MULTIFACTORIAL PROCESS, WHERE DIFFERENT LIFE STAGES REFLECT CHANGES IN METABOLIC PROCESSES, IMMUNE CAPACITIES, AND GENETIC/EPIGENETIC REPERTOIRES. WITH ACCUMULATING EXPOSURE TO ENVIRONMENTAL STRESSES AND DETERIORATION OF PHYSIOLOGICAL FUNCTIONS, BODY SYSTEMS BECOME MORE PRONE TO LOW-GRADE CHRONIC INFLAMMATION AND AN INCREASING RANGE OF PATHOLOGIES. WE HYPOTHESIZED THAT DIFFERENTIAL SUSCEPTIBILITY TO DISEASES ACROSS LIFE SPAN REFLECTS PHASED CHANGES IN AN ORGANISM'S PHYSIOLOGICAL CAPACITY THAT MAY HIGHLIGHT WHEN INTERVENTIONS MAY BE APPROPRIATELY USED. FURTHERMORE, THE NUMBER OF LIFE STAGES MAY VARY BETWEEN SPECIES AND BE IMPACTED BY SIGNALMENT SUCH AS BREED. WE TESTED THIS HYPOTHESIS USING DISEASE DIAGNOSES DATA FROM VETERINARY ELECTRONIC MEDICAL RECORDS CONTAINING ALMOST 2 MILLION CATS AND OVER 4 MILLION DOGS. BI-CLUSTERING (ON RATES OF DISEASE DIAGNOSES) AND ADAPTIVE BRANCH PRUNING WERE USED TO IDENTIFY AGE CLUSTERS THAT COULD BE USED TO DEFINE ADULT LIFE STAGES. CLUSTERING AMONG DIAGNOSES WERE THEN INTERPRETED WITHIN THE CONTEXT OF EACH DEFINED LIFE STAGE. THE ANALYSES IDENTIFIED 5 AGE CLUSTERS IN CATS AND 4 AGE CLUSTERS WITHIN EACH OF THE 4 CANINE BREED SIZE CATEGORIES USED. THIS STUDY, USING POPULATION SCALE DATA FOR TWO SPECIES, ONE WITH DIFFERENTIAL SIZE AND LIFE EXPECTANCIES, IS THE FIRST TO OUR KNOWLEDGE TO USE DISEASE DIAGNOSIS DATA TO DEFINE ADULT LIFE STAGES. THE LIFE STAGES PRESENTED HERE ARE A RESULT OF A DATA-DRIVEN APPROACH TO AGE AND DISEASE STRATIFICATION AND ARE INTENDED TO SUPPORT CONVERSATIONS BETWEEN CLINICIANS AND CLIENTS ABOUT APPROPRIATE HEALTH CARE RECOMMENDATIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12  2940  92 GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL AND SENSITIVE COPD-DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5). EVEN THOUGH CLINICAL, EPIDEMIOLOGICAL AND TOXICOLOGICAL STUDIES HAVE PROGRESSIVELY PROVIDED A BETTER KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS, FURTHER IN VITRO STUDIES ON RELEVANT CELL SYSTEMS ARE STILL NEEDED. HENCE, AIMING OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS, PRIMARY HUMAN BRONCHIAL EPITHELIAL CELLS DERIVED FROM NORMAL SUBJECTS (NHBE) OR SENSITIVE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED PATIENTS (DHBE) WERE DIFFERENTIATED AT THE AIR-LIQUID INTERFACE. THEREAFTER, THEY WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) TO STUDY THE OCCURRENCE OF SOME RELEVANT GENETIC AND/OR EPIGENETIC ENDPOINTS. CONCENTRATION-, EXPOSURE- AND SEASON-DEPENDENT INCREASES OF OH-B[A]P METABOLITES IN NHBE, AND TO A LESSER EXTENT, COPD-DHBE CELLS WERE REPORTED; HOWEVER, THERE WERE MORE TETRA-OH-B[A]P AND 8-OHDG DNA ADDUCTS IN COPD-DHBE CELLS. NO INCREASE IN PRIMARY DNA STRAND BREAK NOR CHROMOSOMAL ABERRATION WAS OBSERVED IN REPEATEDLY EXPOSED CELLS. TELOMERE LENGTH AND TELOMERASE ACTIVITY WERE MODIFIED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN NHBE AND PARTICULARLY COPD-DHBE CELLS. THERE WERE A GLOBAL DNA HYPOMETHYLATION, A P16 GENE PROMOTER HYPERMETHYLATION, AND A DECREASING DNA METHYLTRANSFERASE ACTIVITY IN NHBE AND NOTABLY COPD-DHBE CELLS REPEATEDLY EXPOSED. CHANGES IN SITE-SPECIFIC METHYLATION, ACETYLATION, AND PHOSPHORYLATION OF HISTONE H3 (I.E., H3K4ME3, H3K9AC, H3K27AC, AND H3S10PH) AND RELATED ENZYME ACTIVITIES OCCURRED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN ALL THE REPEATEDLY EXPOSED CELLS. COLLECTIVELY, THESE RESULTS HIGHLIGHTED THE KEY ROLE PLAYED BY GENETIC AND EVEN EPIGENETIC EVENTS IN NHBE AND PARTICULARLY SENSITIVE COPD-DHBE CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) AND THEIR DIFFERENT RESPONSIVENESS. WHILE THESE SPECIFIC EPIGENETIC CHANGES HAVE BEEN ALREADY DESCRIBED IN COPD AND EVEN LUNG CANCER PHENOTYPES, OUR FINDINGS SUPPORTED THAT, TOGETHER WITH GENETIC EVENTS, THESE EPIGENETIC EVENTS COULD DRAMATICALLY CONTRIBUTE TO THE SHIFT FROM HEALTHY TO DISEASED PHENOTYPES FOLLOWING REPEATED EXPOSURE TO RELATIVELY LOW DOSES OF AIR POLLUTION-DERIVED PM(2.5).	2017	
                                                                                                                                                                                                                                                                                                                                                                                                      
13   744  41 CANNABINOID WIN55,212-2 REPROGRAMS MONOCYTES AND MACROPHAGES TO INHIBIT LPS-INDUCED INFLAMMATION. INTRODUCTION: CHRONIC OR UNCONTROLLED ACTIVATION OF MYELOID CELLS INCLUDING MONOCYTES, MACROPHAGES AND DENDRITIC CELLS (DCS) IS A HALLMARK OF IMMUNE-MEDIATED INFLAMMATORY DISORDERS. THERE IS AN URGENT NEED FOR THE DEVELOPMENT OF NOVEL DRUGS WITH THE CAPACITY TO IMPAIR INNATE IMMUNE CELL OVERACTIVATION UNDER INFLAMMATORY CONDITIONS. COMPELLING EVIDENCE POINTED OUT CANNABINOIDS AS POTENTIAL THERAPEUTIC TOOLS WITH ANTI-INFLAMMATORY AND IMMUNOMODULATORY CAPACITY. WIN55,212-2, A NON-SELECTIVE SYNTHETIC CANNABINOID AGONIST, DISPLAYS PROTECTIVE EFFECTS IN SEVERAL INFLAMMATORY CONDITIONS BY MECHANISMS PARTIALLY DEPENDING ON THE GENERATION OF TOLEROGENIC DCS ABLE TO INDUCE FUNCTIONAL REGULATORY T CELLS (TREGS). HOWEVER, ITS IMMUNOMODULATORY CAPACITY ON OTHER MYELOID CELLS SUCH AS MONOCYTES AND MACROPHAGES REMAINS INCOMPLETELY UNDERSTOOD. METHODS: HUMAN MONOCYTE-DERIVED DCS (HMODCS) WERE DIFFERENTIATED IN THE ABSENCE (CONVENTIONAL HMODCS) OR PRESENCE OF WIN55,212-2 (WIN-HMODCS). CELLS WERE STIMULATED WITH LPS, COCULTURED WITH NAIVE T LYMPHOCYTES AND THEIR CYTOKINE PRODUCTION AND ABILITY TO INDUCE T CELL RESPONSES WERE ANALYSED BY ELISA OR FLOW CYTOMETRY. TO EVALUATE THE EFFECT OF WIN55,212-2 IN MACROPHAGE POLARIZATION, HUMAN AND MURINE MACROPHAGES WERE ACTIVATED WITH LPS OR LPS/IFNGAMMA, IN THE PRESENCE OR ABSENCE OF THE CANNABINOID. CYTOKINE, COSTIMULATORY MOLECULES AND INFLAMMASOME MARKERS WERE ASSAYED. METABOLIC AND CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE ALSO PERFORMED. FINALLY, THE PROTECTIVE CAPACITY OF WIN55,212-2 WAS STUDIED IN VIVO IN BALB/C MICE AFTER INTRAPERITONEAL INJECTION WITH LPS. RESULTS: WE SHOW FOR THE FIRST TIME THAT THE DIFFERENTIATION OF HMODCS IN THE PRESENCE OF WIN55,212-2 GENERATES TOLEROGENIC WIN-HMODCS THAT ARE LESS RESPONSIVE TO LPS STIMULATION AND ABLE TO PRIME TREGS. WIN55,212-2 ALSO IMPAIRS THE PRO-INFLAMMATORY POLARIZATION OF HUMAN MACROPHAGES BY INHIBITING CYTOKINE PRODUCTION, INFLAMMASOME ACTIVATION AND RESCUING MACROPHAGES FROM PYROPTOTIC CELL DEATH. MECHANISTICALLY, WIN55,212-2 INDUCED A METABOLIC AND EPIGENETIC SHIFT IN MACROPHAGES BY DECREASING LPS-INDUCED MTORC1 SIGNALING, COMMITMENT TO GLYCOLYSIS AND ACTIVE HISTONE MARKS IN PRO-INFLAMMATORY CYTOKINE PROMOTERS. WE CONFIRMED THESE DATA IN EX VIVO LPS-STIMULATED PERITONEAL MACROPHAGES (PMPHIS), WHICH WERE ALSO SUPPORTED BY THE IN VIVO ANTI-INFLAMMATORY CAPACITY OF WIN55,212-2 IN A LPS-INDUCED SEPSIS MOUSE MODEL. CONCLUSION: OVERALL, WE SHED LIGHT INTO THE MOLECULAR MECHANISMS BY WHICH CANNABINOIDS EXERT ANTI-INFLAMMATORY PROPERTIES IN MYELOID CELLS, WHICH MIGHT WELL CONTRIBUTE TO THE FUTURE RATIONAL DESIGN OF NOVEL THERAPEUTIC STRATEGIES FOR INFLAMMATORY DISORDERS.	2023	

14  6493  32 TRAINED IMMUNITY AND REACTIVITY OF MACROPHAGES AND ENDOTHELIAL CELLS. INNATE IMMUNE CELLS CAN DEVELOP EXACERBATED IMMUNOLOGIC RESPONSE AND LONG-TERM INFLAMMATORY PHENOTYPE FOLLOWING BRIEF EXPOSURE TO ENDOGENOUS OR EXOGENOUS INSULTS, WHICH LEADS TO AN ALTERED RESPONSE TOWARDS A SECOND CHALLENGE AFTER THE RETURN TO A NONACTIVATED STATE. THIS PHENOMENON IS KNOWN AS TRAINED IMMUNITY (TI). TI IS NOT ONLY IMPORTANT FOR HOST DEFENSE AND VACCINE RESPONSE BUT ALSO FOR CHRONIC INFLAMMATIONS SUCH AS CARDIOVASCULAR AND METABOLIC DISEASES SUCH AS ATHEROSCLEROSIS. TI CAN OCCUR IN INNATE IMMUNE CELLS SUCH AS MONOCYTES/MACROPHAGES, NATURAL KILLER CELLS, ENDOTHELIAL CELLS (ECS), AND NONIMMUNE CELLS, SUCH AS FIBROBLAST. IN THIS BRIEF REVIEW, WE ANALYZE THE SIGNIFICANCE OF TI IN ECS, WHICH ARE ALSO CONSIDERED AS INNATE IMMUNE CELLS IN ADDITION TO MACROPHAGES. TI CAN BE INDUCED BY A VARIETY OF STIMULI, INCLUDING LIPOPOLYSACCHARIDES, BCG (BACILLUS CALMETTE-GUERIN), AND OXLDL (OXIDIZED LOW-DENSITY LIPOPROTEIN), WHICH ARE DEFINED AS RISK FACTORS FOR CARDIOVASCULAR AND METABOLIC DISEASES. FURTHERMORE, TI IN ECS IS FUNCTIONAL FOR INFLAMMATION EFFECTIVENESS AND TRANSITION TO CHRONIC INFLAMMATION. REWIRING OF CELLULAR METABOLISM OF THE TRAINED CELLS TAKES PLACE DURING INDUCTION OF TI, INCLUDING INCREASED GLYCOLYSIS, GLUTAMINOLYSIS, INCREASED ACCUMULATION OF TRICARBOXYLIC ACID CYCLE METABOLITES AND ACETYL-COENZYME A PRODUCTION, AS WELL AS INCREASED MEVALONATE SYNTHESIS. SUBSEQUENTLY, THIS LEADS TO EPIGENETIC REMODELING, RESULTING IN IMPORTANT CHANGES IN CHROMATIN ARCHITECTURE THAT ENABLES INCREASED GENE TRANSCRIPTION AND ENHANCED PROINFLAMMATORY IMMUNE RESPONSE. HOWEVER, TI PATHWAYS AND INFLAMMATORY PATHWAYS ARE SEPARATED TO ENSURE MEMORY STAYS WHEN INFLAMMATION UNDERGOES RESOLUTION. ADDITIONALLY, REACTIVE OXYGEN SPECIES PLAY CONTEXT-DEPENDENT ROLES IN TI. THEREFORE, TI PLAYS SIGNIFICANT ROLES IN EC AND MACROPHAGE PATHOLOGY AND CHRONIC INFLAMMATION. HOWEVER, FURTHER CHARACTERIZATION OF TI IN ECS AND MACROPHAGES WOULD PROVIDE NOVEL INSIGHTS INTO CARDIOVASCULAR DISEASE PATHOGENESIS AND NEW THERAPEUTIC TARGETS. GRAPHIC ABSTRACT: A GRAPHIC ABSTRACT IS AVAILABLE FOR THIS ARTICLE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15  6292  22 THE PRIMACY OF PSYCHOANALYTIC INTERVENTION IN RECOVERY FROM THE PSYCHOSES AND SCHIZOPHRENIAS. FUNCTIONAL CAPACITIES, SUCH AS ATTACHMENT AND AFFECT REGULATION, OBJECT RELATIONS CAPACITY, SYMBOLIC FUNCTION AND LANGUAGE DEVELOPMENT, NOW DOCUMENTED BY NEUROSCIENTIFIC RESEARCH AND EPIGENETICS, ARE REVIEWED. RESULTS FROM THIS RESEARCH, TOGETHER WITH OTHER FACTORS, ARE POSITED TO HAVE CONTRIBUTED TO EFFECTIVE CONTEMPORARY PSYCHOANALYTIC AND PSYCHOTHERAPEUTIC TREATMENTS FOR THE PSYCHOSES AND SCHIZOPHRENIAS. ETIOLOGICAL FACTORS INVOLVING THE SCHIZOPHRENIAS AND OTHER PSYCHOSES ARE CONSIDERED BOTH IN TERMS OF AN EPIGENETIC MODEL, AND IN TERMS OF HOW ETIOLOGY MAY, OR MAY NOT, AFFECT CLINICAL TREATMENT. THE LACANIAN 388 PROGRAM IS REVIEWED IN SOME DETAIL, AS ARE SEVERAL PSYCHOANALYTIC AND PSYCHOTHERAPEUTIC CLINICAL APPROACHES USED WITH THIS POPULATION OVER THE LAST SIX DECADES. ALL TREATMENTS FOCUS ON THE PRIMACY OF PSYCHOTHERAPEUTIC INTERVENTION, AND USE MEDICATIONS MINIMALLY, NOT AT ALL, OR ONLY AS INFORMED BY AN OVER-ARCHING PSYCHODYNAMIC MODEL OF TREATMENT. THE AUTHOR ARGUES THAT THERE IS NOW SUBSTANTIAL RESEARCH AND OUTCOME DATA SUGGESTING THAT THE PSYCHOSES AND SCHIZOPHRENIAS ARE NOT CHRONIC DETERIORATING CONDITIONS. RECOVERY IS OBSERVED IN MANY PSYCHOTIC AND SCHIZOPHRENIC PATIENTS TREATED WITH APPROACHES THAT FOCUS ON THE PRIMACY OF PSYCHOTHERAPEUTIC INTERVENTION.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16  1011  27 CIGARETTE SMOKE CONDENSATE INDUCES DIFFERENTIAL EXPRESSION AND PROMOTER METHYLATION PROFILES OF CRITICAL GENES INVOLVED IN LUNG CANCER IN NL-20 LUNG CELLS IN VITRO: SHORT-TERM AND CHRONIC EXPOSURE. ESTABLISHING EARLY DIAGNOSTIC MARKERS OF HARM IS CRITICAL FOR EFFECTIVE PREVENTION PROGRAMS AND REGULATION OF TOBACCO PRODUCTS. THIS STUDY EXAMINED EFFECTS OF CIGARETTE SMOKE CONDENSATE (CSC) ON EXPRESSION AND PROMOTER METHYLATION PROFILE OF CRITICAL GENES (DAPK, ECAD, MGMT, AND RASSF1A) INVOLVED IN LUNG CANCER DEVELOPMENT IN DIFFERENT HUMAN LUNG CELL LINES. NL-20 CELLS WERE TREATED WITH 0.1-100 MUG/ML OF CSC FOR 24 TO 72 HRS FOR SHORT-TERM EXPOSURES. DAPK EXPRESSION OR METHYLATION STATUS WAS NOT SIGNIFICANTLY AFFECTED. HOWEVER, CSC TREATMENT RESULTED IN CHANGES IN EXPRESSION AND PROMOTER METHYLATION PROFILE OF ECAD, MGMT, AND RASSF1A. FOR CHRONIC STUDIES, CELLS WERE EXPOSED TO 1 OR 10 MUG/ML CSC UP TO 28 DAYS. CELLS SHOWED MORPHOLOGICAL CHANGES ASSOCIATED WITH TRANSFORMATION AND CHANGES IN INVASION CAPACITIES AND GLOBAL METHYLATION STATUS. THIS STUDY PROVIDES CRITICAL DATA SUGGESTING THAT EPIGENETIC CHANGES COULD SERVE AS AN EARLY BIOMARKER OF HARM DUE TO EXPOSURE TO CIGARETTE SMOKE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  4391  33 MODERATE EXERCISE INDUCES TRAINED IMMUNITY IN MACROPHAGES. DESPITE ITS IMPORTANCE IN PROTECTING THE HOST FROM INFECTIONS AND INJURY, EXCESSIVE INFLAMMATION MAY LEAD TO SERIOUS HUMAN DISEASES INCLUDING AUTOIMMUNE DISORDERS, CARDIOVASCULAR DISEASES, DIABETES, AND CANCER. EXERCISE IS A KNOWN IMMUNOMODULATOR; HOWEVER, WHETHER EXERCISE CAUSES LONG-TERM CHANGES IN INFLAMMATORY RESPONSES AND HOW THESE CHANGES OCCUR ARE LACKING. HERE, WE SHOW THAT CHRONIC MODERATE-INTENSITY TRAINING OF MICE LEADS TO PERSISTENT METABOLIC REWIRING AND CHANGES TO CHROMATIN ACCESSIBILITY IN BONE MARROW-DERIVED MACROPHAGES (BMDMS), WHICH, IN TURN, TEMPERS THEIR INFLAMMATORY RESPONSES. WE SHOW THAT BMDMS FROM EXERCISED MICE EXHIBITED A DECREASE IN LIPOPOLYSACCHARIDE (LPS)-INDUCED NF-KAPPAB ACTIVATION AND PROINFLAMMATORY GENE EXPRESSION ALONG WITH AN INCREASE IN M2-LIKE-ASSOCIATED GENES WHEN COMPARED WITH BMDMS FROM SEDENTARY MICE. THIS WAS ASSOCIATED WITH IMPROVED MITOCHONDRIAL QUALITY AND INCREASED RELIANCE ON OXIDATIVE PHOSPHORYLATION ACCOMPANIED WITH REDUCED MITOCHONDRIAL REACTIVE OXYGEN SPECIES (ROS) PRODUCTION. MECHANISTICALLY, ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN (ATAC)-SEQ ANALYSIS SHOWED CHANGES IN CHROMATIN ACCESSIBILITY OF GENES ASSOCIATED WITH INFLAMMATORY AND METABOLIC PATHWAYS. OVERALL, OUR DATA SUGGEST THAT CHRONIC MODERATE EXERCISE CAN INFLUENCE THE INFLAMMATORY RESPONSES OF MACROPHAGES BY REPROGRAMMING THEIR METABOLIC AND EPIGENETIC LANDSCAPE.NEW & NOTEWORTHY IN THIS STUDY, WE EXPLAIN HOW LONG-TERM MODERATE EXERCISE TRAINING CAN REDUCE INFLAMMATION IN MOUSE MACROPHAGES BY REPROGRAMMING THE WAY THEY SENSE AND RESPOND TO THE PRESENCE OF PATHOGENS. WE COMPLETED A THOROUGH ANALYSIS AND SHOWED THAT THESE CHANGES PERSIST IN MACROPHAGES BECAUSE EXERCISE IMPROVES THE ABILITY OF CELLS TO UTILIZE OXYGEN WITHOUT PRODUCING DAMAGING COMPOUNDS, AND CHANGES THE WAY THEY ACCESS THEIR DNA.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  5351  29 RATIONALE FOR DIETARY ANTIOXIDANT TREATMENT OF ADHD. INCREASING UNDERSTANDING ARISES REGARDING DISADVANTAGES OF STIMULANT MEDICATION IN CHILDREN WITH ADHD (ATTENTION-DEFICIT HYPERACTIVITY DISORDER). THIS REVIEW PRESENTS SCIENTIFIC FINDINGS SUPPORTING DIETARY ANTIOXIDANT TREATMENT OF ADHD AND DESCRIBES SUBSTANTIAL ALTERATIONS IN THE IMMUNE SYSTEM, EPIGENETIC REGULATION OF GENE EXPRESSION, AND OXIDATIVE STRESS REGULATION IN ADHD. AS A RESULT, CHRONIC INFLAMMATION AND OXIDATIVE STRESS COULD DEVELOP, WHICH CAN LEAD TO ADHD SYMPTOMS, FOR EXAMPLE BY CHRONIC T-CELL-MEDIATED NEUROINFLAMMATION, AS WELL AS BY NEURONAL OXIDATIVE DAMAGE AND LOSS OF NORMAL CEREBRAL FUNCTIONS. THEREFORE, MODULATION OF IMMUNE SYSTEM ACTIVITY AND OXIDANT-ANTIOXIDANT BALANCE USING NUTRITIONAL APPROACHES MIGHT HAVE POTENTIAL IN ADHD TREATMENT. THE USE OF NATURAL ANTIOXIDANTS AGAINST OXIDATIVE CONDITIONS IS AN EMERGING FIELD IN THE MANAGEMENT OF NEURODEGENERATIVE DISEASES. DIETARY POLYPHENOLS, FOR EXAMPLE, HAVE ANTIOXIDANT CAPACITIES AS WELL AS IMMUNOREGULATORY EFFECTS AND, THEREFORE, APPEAR APPROPRIATE IN ADHD THERAPY. THIS REVIEW CAN STIMULATE THE DEVELOPMENT AND INVESTIGATION OF DIETARY ANTIOXIDANT TREATMENT IN ADHD, WHICH IS HIGHLY DESIRED.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19  1357  36 DEVELOPMENT OF INNATE IMMUNE MEMORY BY NON-IMMUNE CELLS DURING STAPHYLOCOCCUS AUREUS INFECTION DEPENDS ON REACTIVE OXYGEN SPECIES. INTRODUCTION: THE MECHANISMS UNDERLYING INNATE IMMUNE MEMORY (TRAINED IMMUNITY) COMPRISE EPIGENETIC REPROGRAMMING OF TRANSCRIPTIONAL PATHWAYS ASSOCIATED WITH ALTERATIONS OF INTRACELLULAR METABOLISM. WHILE THE MECHANISMS OF INNATE IMMUNE MEMORY CARRIED OUT BY IMMUNE CELLS ARE WELL CHARACTERIZED, SUCH PROCESSES IN NON-IMMUNE CELLS, ARE POORLY UNDERSTOOD. THE OPPORTUNISTIC PATHOGEN, STAPHYLOCOCCUS AUREUS, IS RESPONSIBLE FOR A MULTITUDE OF HUMAN DISEASES, INCLUDING PNEUMONIA, ENDOCARDITIS AND OSTEOMYELITIS, AS WELL AS ANIMAL INFECTIONS, INCLUDING CHRONIC CATTLE MASTITIS THAT ARE EXTREMELY DIFFICULT TO TREAT. AN INDUCTION OF INNATE IMMUNE MEMORY MAY BE CONSIDERED AS A THERAPEUTIC ALTERNATIVE TO FIGHT S. AUREUS INFECTION. METHODS: IN THE CURRENT WORK, WE DEMONSTRATED THE DEVELOPMENT OF INNATE IMMUNE MEMORY IN NON-IMMUNE CELLS DURING S. AUREUS INFECTION EMPLOYING A COMBINATION OF TECHNIQUES INCLUDING ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), MICROSCOPIC ANALYSIS, AND CYTOMETRY. RESULTS: WE OBSERVED THAT TRAINING OF HUMAN OSTEOBLAST-LIKE MG-63 CELLS AND LUNG EPITHELIAL A549 CELLS WITH BETA-GLUCAN INCREASED IL-6 AND IL-8 PRODUCTION UPON A STIMULATION WITH S. AUREUS, CONCOMITANT WITH HISTONES MODIFICATIONS. IL-6 AND IL-8 PRODUCTION WAS POSITIVELY CORRELATED WITH AN ACETYLATION OF HISTONE 3 AT LYSINE 27 (H3K27), THUS SUGGESTING EPIGENETIC REPROGRAMMING IN THESE CELLS. AN ADDITION OF THE ROS SCAVENGER N-ACETYLCYSTEINE, NAC, PRIOR TO BETA-GLUCAN PRETREATMENT FOLLOWED BY AN EXPOSURE TO S. AUREUS, RESULTED IN DECREASED IL-6 AND IL-8 PRODUCTION, THEREBY SUPPORTING THE INVOLVEMENT OF ROS IN THE INDUCTION OF INNATE IMMUNE MEMORY. EXPOSURE OF CELLS TO LACTOCOCCUS LACTIS RESULTED IN INCREASED IL-6 AND IL-8 PRODUCTION BY MG-63 AND A549 CELLS UPON A STIMULATION WITH S. AUREUS THAT WAS CORRELATED WITH H3K27 ACETYLATION, SUGGESTING THE ABILITY OF THIS BENEFICIAL BACTERIUM TO INDUCE INNATE IMMUNE MEMORY. DISCUSSION: THIS WORK IMPROVES OUR UNDERSTANDING OF INNATE IMMUNE MEMORY IN NON-IMMUNE CELLS IN THE CONTEXT OF S. AUREUS INFECTION. IN ADDITION TO KNOWN INDUCERS, PROBIOTICS MAY REPRESENT GOOD CANDIDATES FOR THE INDUCTION OF INNATE IMMUNE MEMORY. OUR FINDINGS MAY HELP THE DEVELOPMENT OF ALTERNATIVE THERAPEUTIC APPROACHES FOR THE PREVENTION OF S. AUREUS INFECTION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                           
20  3171  34 GUT MICROBIAL GABAERGIC SIGNALING IMPROVES STRESS-ASSOCIATED INNATE IMMUNITY TO RESPIRATORY VIRAL INFECTION. INTRODUCTION: EPIDEMIOLOGICAL EVIDENCES REVEAL THAT POPULATIONS WITH PSYCHOLOGICAL STRESS HAVE AN INCREASED LIKELIHOOD OF RESPIRATORY VIRAL INFECTION INVOLVING INFLUENZA A VIRUS (IAV) AND SARS-COV-2. OBJECTIVES: THIS STUDY AIMS TO EXPLORE THE POTENTIAL CORRELATION BETWEEN PSYCHOLOGICAL STRESS AND INCREASED SUSCEPTIBILITY TO RESPIRATORY VIRAL INFECTIONS AND HOW THIS MAY CONTRIBUTE TO A MORE SEVERE DISEASE PROGRESSION. METHODS: A CHRONIC RESTRAINT STRESS (CRS) MOUSE MODEL WAS USED TO INFECT IAV AND ESTIMATE LUNG INFLAMMATION. ALVEOLAR MACROPHAGES (AMS) WERE OBSERVED IN THE NUMBERS, FUNCTION AND METABOLIC-EPIGENETIC PROPERTIES. TO CONFIRM THE CENTRAL IMPORTANCE OF THE GUT MICROBIOME IN STRESS-EXACERBATED VIRAL PNEUMONIA, MICE WERE CONDUCTED THROUGH MICROBIOME DEPLETION AND GUT MICROBIOME TRANSPLANTATION. RESULTS: STRESS EXPOSURE INDUCED A DECLINE IN LACTOBACILLACEAE ABUNDANCE AND HENCE GAMMA-AMINOBUTYRIC ACID (GABA) LEVEL IN MICE. MICROBIAL-DERIVED GABA WAS RELEASED IN THE PERIPHERAL AND SENSED BY AMS VIA GABA(A)R, LEADING TO ENHANCED MITOCHONDRIAL METABOLISM AND ALPHA-KETOGLUTARATE (ALPHAKG) GENERATION. THE METABOLIC INTERMEDIATOR IN TURN SERVED AS THE COFACTOR FOR THE EPIGENETIC REGULATOR TET2 TO CATALYZE DNA HYDROXYMETHYLATION AND PROMOTED THE PPARGAMMA-CENTERED GENE PROGRAM UNDERPINNING SURVIVAL, SELF-RENEWING, AND IMMUNOREGULATION OF AMS. THUS, WE UNCOVER AN UNAPPRECIATED GABA/TET2/PPARGAMMA REGULATORY CIRCUITRY INITIATED BY THE GUT MICROBIOME TO INSTRUCT DISTANT IMMUNE CELLS THROUGH A METABOLIC-EPIGENETIC PROGRAM. ACCORDINGLY, RECONSTITUTION WITH GABA-PRODUCING PROBIOTICS, ADOPTIVE TRANSFERRING OF GABA-CONDITIONED AMS, OR RESUMPTION OF PULMONARY ALPHAKG LEVEL REMARKABLY IMPROVED AMS HOMEOSTASIS AND ALLEVIATED SEVERE PNEUMONIA IN STRESSED MICE. CONCLUSION: TOGETHER, OUR STUDY IDENTIFIES MICROBIOME-DERIVED TONIC SIGNALING TUNED BY PSYCHOLOGICAL STRESS TO IMPRINT RESIDENT IMMUNE CELLS AND DEFENSIVE RESPONSE IN THE LUNGS. FURTHER STUDIES ARE WARRANTED TO TRANSLATE THESE FINDINGS, BASICALLY FROM MURINE MODELS, INTO THE INDIVIDUALS WITH PSYCHIATRIC STRESS DURING RESPIRATORY VIRAL INFECTION.	2023