1   214 160 ACUTE AND CHRONIC MOLECULAR SIGNATURES AND ASSOCIATED SYMPTOMS OF BLAST EXPOSURE IN MILITARY BREACHERS. INJURIES FROM EXPOSURE TO EXPLOSIONS ROSE DRAMATICALLY DURING THE IRAQ AND AFGHANISTAN WARS, WHICH MOTIVATED INVESTIGATIONS OF BLAST-RELATED NEUROTRAUMA AND OPERATIONAL BREACHING. IN THIS STUDY, MILITARY "BREACHERS" WERE EXPOSED TO CONTROLLED, LOW-LEVEL BLAST DURING A 10-DAY EXPLOSIVE BREACHING COURSE. USING AN OMICS APPROACH, WE ASSESSED EPIGENETIC, TRANSCRIPTIONAL, AND INFLAMMATORY PROFILE CHANGES IN BLOOD FROM OPERATIONAL BREACHING TRAINEES, WITH VARYING LEVELS OF LIFETIME BLAST EXPOSURE, ALONG WITH DAILY SELF-REPORTED SYMPTOMS (WITH TINNITUS, HEADACHES, AND SLEEP DISTURBANCES AS THE MOST FREQUENTLY REPORTED). ALTHOUGH ACUTE EXPOSURE TO BLAST DID NOT CONFER EPIGENETIC CHANGES, SPECIFICALLY IN DNA METHYLATION, DIFFERENTIALLY METHYLATED REGIONS (DMRS) WITH COORDINATED GENE EXPRESSION CHANGES ASSOCIATED WITH LIFETIME CUMULATIVE BLAST EXPOSURES WERE IDENTIFIED. THE ACCUMULATIVE EFFECT OF BLAST SHOWED INCREASED METHYLATION OF PAX8 ANTISENSE TRANSCRIPT WITH COORDINATED REPRESSION OF GENE EXPRESSION, WHICH HAS BEEN ASSOCIATED WITH SLEEP DISTURBANCE. DNA METHYLATION ANALYSES CONDUCTED IN CONJUNCTION WITH REPORTED SYMPTOMS OF TINNITUS IN THE LOW VERSUS HIGH BLAST INCIDENTS GROUPS IDENTIFIED DMRS IN KCNE1 AND CYP2E1 GENES. KCNE1 AND CYP2E1 SHOWED THE EXPECTED INVERSE CORRELATION BETWEEN DNA METHYLATION AND GENE EXPRESSION, WHICH HAVE BEEN PREVIOUSLY IMPLICATED IN NOISE-RELATED HEARING LOSS. ALTHOUGH NO SIGNIFICANT TRANSCRIPTIONAL CHANGES WERE OBSERVED IN SAMPLES OBTAINED AT THE ONSET OF THE TRAINING COURSE RELATIVE TO CHRONIC CUMULATIVE BLAST, WE IDENTIFIED A LARGE NUMBER OF TRANSCRIPTIONAL PERTURBATIONS ACUTELY PRE- VERSUS POST-BLAST EXPOSURE. ACUTELY, 67 ROBUSTLY DIFFERENTIALLY EXPRESSED GENES (FOLD CHANGE >/=1.5), INCLUDING UFC1 AND YOD1 UBIQUITIN-RELATED PROTEINS, WERE IDENTIFIED. INFLAMMATORY ANALYSES OF CYTOKINES AND CHEMOKINES REVEALED DYSREGULATION OF MCP-1, GCSF, HGF, MCSF, AND RANTES ACUTELY AFTER BLAST EXPOSURE. THESE DATA SHOW THE IMPORTANCE OF AN OMICS APPROACH, REVEALING THAT TRANSCRIPTIONAL AND INFLAMMATORY BIOMARKERS CAPTURE ACUTE LOW-LEVEL BLAST OVERPRESSURE EXPOSURE, WHEREAS DNA METHYLATION MARKS ENCAPSULATE CHRONIC LONG-TERM SYMPTOMS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                           
2  1997  22 EPIGENETIC AND INFLAMMATORY EVENTS IN EXPERIMENTAL PERIODONTITIS FOLLOWING SYSTEMIC MICROBIAL CHALLENGE. AIM: THE PURPOSE OF THIS STUDY WAS TO DETERMINE INFLAMMATORY AND EPIGENETIC FEATURES FOLLOWING INDUCTION OF ORAL AND GUT DYSBIOSIS IN EXPERIMENTAL PERIODONTITIS IN ORDER TO EXAMINE THE INTERPLAY BETWEEN ORAL AND SYSTEMIC INFECTION. MATERIALS AND METHODS: PERIODONTITIS WAS INDUCED IN 6- TO 8-WEEK-OLD C57BL/6 MICE BY (A) LIGATURE PLACEMENT (LIG GROUP) (ORAL CHALLENGE); (B) P. GINGIVALIS GAVAGE (PG GROUP) (SYSTEMIC CHALLENGE); AND (C) THE COMBINATION OF THE TWO MODELS ORAL AND SYSTEMIC CHALLENGE (PG + LIG). THE DURATION OF THE EXPERIMENT WAS 60 DAYS, AND THE ANIMALS WERE THEN SACRIFICED FOR ANALYSES. ALVEOLAR BONE LOSS WAS ASSESSED, AND A MULTIPLEX IMMUNOASSAY WAS PERFORMED. MAXILLAE AND GUT TISSUES WERE IMMUNOSTAINED FOR DNMT3B (DE NOVO METHYLATION MARKER), B AND T LYMPHOCYTE ATTENUATOR (BTLA) AND IL-18R1 (INFLAMMATION MARKERS). RESULTS: PG AND PG + LIG GROUPS EXHIBITED HIGHER BONE LOSS WHEN COMPARED TO SHAM. BAFF, VEGF, RANKL, RANTES AND IP-10 WERE SIGNIFICANTLY HIGHER WITH PG GAVAGE. LIKEWISE, DNMT3B WAS OVEREXPRESSED IN BOTH GUT AND MAXILLA AFTER THE PG ADMINISTRATION. THE SAME PATTERN WAS OBSERVED FOR BTLA AND IL-18R1 IN GUT TISSUES. CONCLUSIONS: THE SYSTEMIC MICROBIAL CHALLENGE EITHER ALONE OR IN COMBINATION WITH LOCAL CHALLENGE LEADS TO DISTINCT PATTERNS OF INFLAMMATORY AND EPIGENETIC FEATURES WHEN COMPARED TO SIMPLY LOCALLY INDUCED EXPERIMENTAL PERIODONTITIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3  1574  78 DNA METHYLATION PATTERNS OF CHRONIC EXPLOSIVE BREACHING IN U.S. MILITARY WARFIGHTERS. BACKGROUND: INJURIES FROM EXPOSURE TO EXPLOSIONS ROSE DRAMATICALLY DURING THE IRAQ AND AFGHANISTAN WARS, WHICH MOTIVATED INVESTIGATION OF BLAST-RELATED NEUROTRAUMA. WE HAVE UNDERTAKEN HUMAN STUDIES INVOLVING MILITARY "BREACHERS" -EXPOSED TO CONTROLLED, LOW-LEVEL BLAST DURING A 3-DAYS EXPLOSIVE BREACHING COURSE. METHODS: WE SCREENED EPIGENETIC PROFILES IN PERIPHERAL BLOOD SAMPLES FROM 59 SUBJECTS (IN TWO SEPARATE U.S. MILITARY TRAINING SESSIONS) USING INFINIUM METHYLATIONEPIC BEADCHIPS. PARTICIPANTS HAD VARYING NUMBERS OF EXPOSURES TO BLAST OVER THEIR MILITARY CAREERS (EMPIRICALLY DEFINED AS HIGH >/= 40, AND CONVERSELY, LOW < 39 BREACHING EXPOSURES). DAILY SELF-REPORTED PHYSIOLOGICAL SYMPTOMS WERE RECORDED. TINNITUS, MEMORY PROBLEMS, HEADACHES, AND SLEEP DISTURBANCES ARE MOST FREQUENTLY REPORTED. RESULTS: WE IDENTIFIED 14 SIGNIFICANTLY DIFFERENTIALLY METHYLATED REGIONS (DMRS) WITHIN GENES ASSOCIATED WITH CUMULATIVE BLAST EXPOSURE IN PARTICIPANTS WITH HIGH RELATIVE TO LOW CUMULATIVE BLAST EXPOSURE. NOTABLY, NTSR1 AND SPON1 WERE SIGNIFICANTLY DIFFERENTIALLY METHYLATED IN HIGH RELATIVE TO LOW BLAST EXPOSED GROUPS, SUGGESTING THAT SLEEP DYSREGULATION MAY BE ALTERED IN RESPONSE TO CHRONIC CUMULATIVE BLAST EXPOSURE. IN COMPARING LIFETIME BLAST EXPOSURE AT BASELINE (PRIOR TO EXPOSURE IN CURRENT TRAINING), AND TOP ASSOCIATED SYMPTOMS, WE IDENTIFIED SIGNIFICANT DMRS ASSOCIATED WITH TINNITUS, SLEEP DIFFICULTIES, AND HEADACHE. NOTABLY, WE IDENTIFIED KCNN3, SOD3, MUC4, GALR1, AND WDR45B, WHICH ARE IMPLICATED IN AUDITORY FUNCTION, AS DIFFERENTIALLY METHYLATED ASSOCIATED WITH SELF-REPORTED TINNITUS. THESE FINDINGS SUGGEST NEUROBIOLOGICAL MECHANISMS BEHIND AUDITORY INJURIES IN OUR MILITARY WARFIGHTERS AND ARE PARTICULARLY RELEVANT GIVEN TINNITUS IS NOT ONLY A PRIMARY DISABILITY AMONG VETERANS, BUT HAS ALSO BEEN DEMONSTRATED IN ACTIVE DUTY MEDICAL RECORDS FOR POPULATIONS EXPOSED TO BLAST IN TRAINING. ADDITIONALLY, WE FOUND THAT DIFFERENTIALLY METHYLATED REGIONS ASSOCIATED WITH THE GENES CCDC68 AND COMT TRACK WITH SLEEP DIFFICULTIES, AND THOSE WITHIN FMOD AND TNXB TRACK WITH PAIN AND HEADACHE. CONCLUSION: SLEEP DISTURBANCES, AS WELL AS TINNITUS AND CHRONIC PAIN, ARE WIDELY REPORTED IN U.S. MILITARY SERVICE MEMBERS AND VETERANS. AS WE HAVE PREVIOUSLY DEMONSTRATED, DNA METHYLATION ENCAPSULATES LIFETIME EXPOSURE TO BLAST. THE CURRENT DATA SUPPORT PREVIOUS FINDINGS AND RECAPITULATE TRANSCRIPTIONAL REGULATORY ALTERATIONS IN GENES INVOLVED IN SLEEP, AUDITORY FUNCTION, AND PAIN. THESE DATA UNCOVERED NOVEL EPIGENETIC AND TRANSCRIPTIONAL REGULATORY MECHANISM UNDERLYING THE ETIOLOGICAL BASIS OF THESE SYMPTOMS.	2020	

4  4735  32 NOVEL DETECTION OF POST-TRANSLATIONAL MODIFICATIONS IN HUMAN MONOCYTE-DERIVED DENDRITIC CELLS AFTER CHRONIC ALCOHOL EXPOSURE: ROLE OF INFLAMMATION REGULATOR H4K12AC. PREVIOUS REPORTS ON EPIGENETIC MECHANISMS INVOLVED IN ALCOHOL ABUSE HAVE FOCUS ON HEPATIC AND NEURONAL REGIONS, LEAVING THE IMMUNE SYSTEM AND SPECIFICALLY MONOCYTE-DERIVED DENDRITIC CELLS (MDDCS) UNDERSTUDIED. OUR LAB HAS PREVIOUSLY SHOWN HISTONE DEACETYLASES ARE MODULATED IN CELLS DERIVED FROM ALCOHOL USERS AND AFTER IN VITRO ACUTE ALCOHOL TREATMENT OF HUMAN MDDCS. IN THE CURRENT STUDY, WE DEVELOPED A NOVEL SCREENING TOOL USING MATRIX ASSISTED LASER DESORPTION IONIZATION-FOURIER TRANSFORM-ION CYCLOTRON RESONANCE MASS SPECTROMETRY (MALDI-FT-ICR MS) AND SINGLE CELL IMAGING FLOW CYTOMETRY TO DETECT POST-TRANSLATIONAL MODIFICATIONS (PTMS) IN HUMAN MDDCS DUE TO CHRONIC ALCOHOL EXPOSURE. OUR RESULTS DEMONSTRATE, FOR THE FIRST TIME, IN VITRO CHRONIC ALCOHOL EXPOSURE OF MDDCS MODULATES H3 AND H4 AND INDUCES A SIGNIFICANT INCREASE IN ACETYLATION AT H4K12 (H4K12AC). MOREOVER, THE TIP60/HAT INHIBITOR, NU9056, WAS ABLE TO BLOCK ETOH-INDUCED H4K12AC, ENHANCING THE EFFECT OF ETOH ON IL-15, RANTES, TGF-BETA1, AND TNF-ALPHA CYTOKINES WHILE RESTORING MCP-2 LEVELS, SUGGESTING THAT H4K12AC MAY BE PLAYING A MAJOR ROLE DURING INFLAMMATION AND MAY SERVE AS AN INFLAMMATION REGULATOR OR A CELLULAR STRESS RESPONSE MECHANISM UNDER CHRONIC ALCOHOL CONDITIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5   703  27 BTLA EXPRESSION IN CLL: EPIGENETIC REGULATION AND IMPACT ON CLL B CELL PROLIFERATION AND ABILITY TO IL-4 PRODUCTION. IN OUR PREVIOUS STUDY, WHILE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CASES SHOWED HIGHER LEVELS OF B AND T LYMPHOCYTE ATTENUATOR (BTLA) MRNA COMPARED TO CONTROLS, LOWER BTLA PROTEIN EXPRESSION WAS OBSERVED IN CASES COMPARED TO CONTROLS. HENCE WE HYPOTHESIZE THAT MICRO RNA (MIR) 155-5P REGULATES BTLA EXPRESSION IN CLL. IN LINE WITH EARLIER DATA, EXPRESSION OF BTLA MRNA AND MIR-155-5P IS ELEVATED IN CLL (P = 0.034 AND P = 0.0006, RESPECTIVELY) AS WELL AS IN MEC-1 CELL LINE (P = 0.009 AND 0.016, RESPECTIVELY). INHIBITION OF MIR-155-5P PARTIALLY RESTORED BTLA PROTEIN EXPRESSION IN CLL PATIENTS (P = 0.01) AND IN MEC-1 CELL LINES (P = 0.058). ADDITIONALLY, WE AIMED TO EVALUATE THE SIGNIFICANCE OF BTLA DEFICIENCY IN CLL CELLS ON PROLIFERATION AND IL-4 PRODUCTION OF B CELLS. WE FOUND THAT SECRETION OF IL-4 IS NOT DEPENDENT ON BTLA EXPRESSION, SINCE FRACTIONS OF BTLA POSITIVE AND BTLA NEGATIVE B CELLS EXPRESSING INTRACELLULAR IL-4 WERE SIMILAR IN CLL PATIENTS AND CONTROLS. WE DEMONSTRATED THAT IN CONTROLS THE FRACTION OF PROLIFERATING CELLS IS LOWER IN BTLA POSITIVE THAN IN BTLA NEGATIVE B CELLS (P = 0.059), WHICH WAS NOT OBSERVED IN CLL. HOWEVER, THE FREQUENCY OF BTLA POSITIVE KI67+ B CELLS IN CLL WAS HIGHER COMPARED TO CORRESPONDING CELLS FROM CONTROLS (P = 0.055) WHILE THERE WERE NO DIFFERENCES BETWEEN THE EXAMINED GROUPS REGARDING FREQUENCY OF BTLA NEGATIVE KI67+ B CELLS. OUR STUDIES SUGGEST THAT MIR-155-5P IS INVOLVED IN BTLA DEFICIENCY, AFFECTING PROLIFERATION OF CLL B CELLS, WHICH MAY BE ONE OF THE MECHANISMS RESPONSIBLE FOR CLL PATHOGENESIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6  5868  28 SUPPRESSIVE EFFECTS OF METFORMIN ON T-HELPER 1-RELATED CHEMOKINES EXPRESSION IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. PURPOSE OF THE STUDY: TYPE 1 AND TYPE 2 DIABETES MELLITUS (DM) ARE CHRONIC T-CELL-MEDIATED INFLAMMATORY DISEASES. METFORMIN IS A WIDELY USED DRUG FOR TYPE 2 DM THAT REDUCES THE NEED FOR INSULIN IN TYPE 1 DM. HOWEVER, WHETHER METFORMIN HAS AN ANTI-INFLAMMATORY EFFECT FOR TREATING DM IS UNKNOWN. WE INVESTIGATED THE ANTI-INFLAMMATORY MECHANISM OF METFORMIN IN THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1. MATERIALS AND METHODS: THE HUMAN MONOCYTIC LEUKEMIA CELL LINE THP-1 WAS PRETREATED WITH METFORMIN AND STIMULATED WITH LIPOPOLYSACCHARIDE (LPS). THE PRODUCTION OF T-HELPER (TH)-1-RELATED CHEMOKINES INCLUDING INTERFERON-GAMMA-INDUCED PROTEIN-10 (IP-10) AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), TH2-RELATED CHEMOKINE MACROPHAGE-DERIVED CHEMOKINE, AND THE PROINFLAMMATORY CHEMOKINE TUMOR NECROSIS FACTOR-ALPHA WAS MEASURED USING ENZYME-LINKED IMMUNOSORBENT ASSAY. INTRACELLULAR SIGNALING PATHWAYS WERE INVESTIGATED USING WESTERN BLOT ANALYSIS AND CHROMATIN IMMUNOPRECIPITATION ASSAY. RESULTS: METFORMIN SUPPRESSED LPS-INDUCED IP-10 AND MCP-1 PRODUCTION AS WELL AS LPS-INDUCED PHOSPHORYLATION OF C-JUN N-TERMINAL KINASE (JNK), P38, EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK), AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB). MOREOVER, METFORMIN SUPPRESSED LPS-INDUCED ACETYLATION OF HISTONES H3 AND H4 AT THE IP-10 PROMOTER. CONCLUSIONS: METFORMIN SUPPRESSED THE PRODUCTION OF TH1-RELATED CHEMOKINES IP-10 AND MCP-1 IN THP-1 CELLS. SUPPRESSIVE EFFECTS OF METFORMIN ON IP-10 PRODUCTION MIGHT BE ATTRIBUTED AT LEAST PARTIALLY TO THE JNK, P38, ERK, AND NF-KAPPAB PATHWAYS AS WELL AS TO EPIGENETIC REGULATION THROUGH THE ACETYLATION OF HISTONES H3 AND H4. THESE RESULTS INDICATED THE THERAPEUTIC ANTI-INFLAMMATORY POTENTIAL OF METFORMIN.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7  5305  43 PROTEOMICS ANALYSIS OF HUMAN OBESITY REVEALS THE EPIGENETIC FACTOR HDAC4 AS A POTENTIAL TARGET FOR OBESITY. SEDENTARY LIFESTYLE AND EXCESSIVE ENERGY INTAKE ARE PROMINENT CONTRIBUTORS TO OBESITY; A MAJOR RISK FACTORS FOR THE DEVELOPMENT OF INSULIN RESISTANCE, TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES. ELUCIDATING THE MOLECULAR MECHANISMS UNDERLYING THESE CHRONIC CONDITIONS IS OF RELEVANT IMPORTANCE AS IT MIGHT LEAD TO THE IDENTIFICATION OF NOVEL ANTI-OBESITY TARGETS. THE PURPOSE OF THE CURRENT STUDY IS TO INVESTIGATE DIFFERENTIALLY EXPRESSED PROTEINS BETWEEN LEAN AND OBESE SUBJECTS THROUGH A SHOT-GUN QUANTITATIVE PROTEOMICS APPROACH USING PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) EXTRACTS AS WELL AS POTENTIAL MODULATION OF THOSE PROTEINS BY PHYSICAL EXERCISE. USING THIS APPROACH, A TOTAL OF 47 PROTEINS SHOWED AT LEAST 1.5 FOLD CHANGE BETWEEN LEAN AND OBESE SUBJECTS. IN OBESE, THE PROTEOMIC PROFILING BEFORE AND AFTER 3 MONTHS OF PHYSICAL EXERCISE SHOWED DIFFERENTIAL EXPRESSION OF 38 PROTEINS. THROMBOSPONDIN 1 (TSP1) WAS AMONG THE PROTEINS THAT WERE UPREGULATED IN OBESE SUBJECTS AND THEN DECREASED BY PHYSICAL EXERCISE. CONVERSELY, THE HISTONE DEACETYLASE 4 (HDAC4) WAS DOWNREGULATED IN OBESE SUBJECTS AND THEN INDUCED BY PHYSICAL EXERCISE. THE PROTEOMIC DATA WAS FURTHER VALIDATED BY QRT-PCR, WESTERN BLOT AND IMMUNOHISTOCHEMISTRY IN BOTH PBMCS AND ADIPOSE TISSUE. WE ALSO SHOWED THAT HDAC4 LEVELS CORRELATED POSITIVELY WITH MAXIMUM OXYGEN CONSUMPTION (VO2 MAX) BUT NEGATIVELY WITH BODY MASS INDEX, PERCENT BODY FAT, AND THE INFLAMMATORY CHEMOKINE RANTES. IN FUNCTIONAL ASSAYS, OUR DATA INDICATED THAT ECTOPIC EXPRESSION OF HDAC4 SIGNIFICANTLY IMPAIRED TNF-ALPHA-DEPENDENT ACTIVATION OF NF-KAPPAB, ESTABLISHING THUS A LINK BETWEEN HDAC4 AND REGULATION OF THE IMMUNE SYSTEM. TOGETHER, THE EXPRESSION PATTERN OF HDAC4 IN OBESE SUBJECTS BEFORE AND AFTER PHYSICAL EXERCISE, ITS CORRELATION WITH VARIOUS PHYSICAL, CLINICAL AND METABOLIC PARAMETERS ALONG WITH ITS INHIBITORY EFFECT ON NF-KAPPAB ARE SUGGESTIVE OF A PROTECTIVE ROLE OF HDAC4 AGAINST OBESITY. HDAC4 COULD THEREFORE REPRESENT A POTENTIAL THERAPEUTIC TARGET FOR THE CONTROL AND MANAGEMENT OF OBESITY AND PRESUMABLY INSULIN RESISTANCE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9  3785  22 INTERGENERATIONAL EFFECTS OF PRE-PREGNANCY CHRONIC LIPOPOLYSACCHARIDE FROM PORPHYROMONAS GINGIVALIS ON THE LEARNING, MEMORY AND SEIZURE SUSCEPTIBILITY OF OFFSPRING. OBJECTIVE: THE AIM OF THIS STUDY WAS TO INVESTIGATE THE EFFECTS OF PRE-PREGNANCY CHRONIC EXPOSURE TO PORPHYROMONAS GINGIVALIS LPS (PG LPS) ON THE LEARNING, MEMORY, AND SEIZURE SUSCEPTIBILITY OF THE OFFSPRING. DESIGN: TO ACHIEVE PERIODONTITIS, PG LPS (5 MUG/KG) WAS INJECTED INTO THE GINGIVAL OF FIVE FEMALE RATS EVERY 48 H FOR THREE WEEKS. FIVE CONTROL FEMALE RATS RECEIVED SALINE (0.9 %) AND FIVE FEMALE WERE KEPT INTACT. THE CONCENTRATIONS OF TNF-ALPHA AND IL-6 WERE MEASURED IN THE BLOOD SAMPLES. ONE WEEK AFTER THE FINAL INJECTION, FEMALES WERE MATED WITH INTACT MALES. FOLLOWING BIRTH AND WEANING, TWO MALE AND TWO FEMALE OFFSPRING WERE RANDOMLY SELECTED FROM EACH MOTHER, AND NEW GROUPS OF MALE AND FEMALE OFFSPRING WERE DEFINED FOR BEHAVIORAL ASSESSMENTS. MORRIS WATER MAZE WAS USED TO EVALUATE SPATIAL MEMORY, SHUTTLE BOX WAS USED TO INVESTIGATE AVOIDANCE MEMORY AND A PENTYLENETETRAZOLE-INDUCED SEIZURE WAS USED TO EVALUATE SEIZURE SUSCEPTIBILITY IN THE OFFSPRING. RESULTS: SPATIAL LEARNING AND AVOIDANCE MEMORY SIGNIFICANTLY DECREASED IN BOTH MALE AND FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE RATS, COMPARED TO THE CONTROL OFFSPRING. LATENCY TO REACH SEIZURE STAGES 1 AND 2 SIGNIFICANTLY INCREASED IN THE MALE OFFSPRING, BUT NOT THE FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE, COMPARED TO THE CONTROL OFFSPRING. HOWEVER, NO SIGNIFICANT DIFFERENCE WAS FOUND IN LATENCY TO REACH STAGES 3-5. CONCLUSION: PRE-PREGNANCY EXPOSURE TO PG LPS COULD AFFECT SOME BEHAVIORAL FUNCTIONS IN BOTH MALE AND FEMALE OFFSPRING INTERGENERATIONALLY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
10  5189  33 PRENATAL ARSENIC EXPOSURE INDUCES IMMUNOMETABOLIC ALTERATION AND RENAL INJURY IN RATS. ARSENIC (AS) EXPOSURE IS PROGRESSIVELY ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), A LEADING PUBLIC HEALTH CONCERN PRESENT WORLDWIDE. THE ADVERSE EFFECT OF AS EXPOSURE ON THE KIDNEYS OF PEOPLE LIVING IN AS ENDEMIC AREAS HAVE NOT BEEN EXTENSIVELY STUDIED. FURTHERMORE, THE IMPACT OF ONLY PRENATAL EXPOSURE TO AS ON THE PROGRESSION OF CKD ALSO HAS NOT BEEN FULLY CHARACTERIZED. IN THE PRESENT STUDY, WE EXAMINED THE EFFECT OF PRENATAL EXPOSURE TO LOW DOSES OF AS 0.04 AND 0.4 MG/KG BODY WEIGHT (0.04 AND 0.4 PPM, RESPECTIVELY) ON THE PROGRESSION OF CKD IN MALE OFFSPRING USING A WISTAR RAT MODEL. INTERESTINGLY, ONLY PRENATAL AS EXPOSURE WAS SUFFICIENT TO ELEVATE THE EXPRESSION OF PROFIBROTIC (TGF-BETA1) AND PROINFLAMMATORY (IL-1ALPHA, MIP-2ALPHA, RANTES, AND TNF-ALPHA) CYTOKINES AT 2-DAY, 12- AND 38-WEEK TIME POINTS IN THE EXPOSED PROGENY. FURTHER, ALTERATION IN ADIPOGENIC FACTORS (GHRELIN, LEPTIN, AND GLUCAGON) WAS ALSO OBSERVED IN 12- AND 38-WEEK OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. AN ALTERED LEVEL OF THESE FACTORS COINCIDES WITH IMPAIRED GLUCOSE METABOLISM AND HOMEOSTASIS ACCOMPANIED BY PROGRESSIVE KIDNEY DAMAGE. WE OBSERVED A SIGNIFICANT INCREASE IN THE DEPOSITION OF EXTRACELLULAR MATRIX COMPONENTS AND GLOMERULAR AND TUBULAR DAMAGE IN THE KIDNEYS OF 38-WEEK-OLD MALE OFFSPRING PRENATALLY EXPOSED TO AS. FURTHERMORE, THE OVEREXPRESSION OF TGF-BETA1 IN KIDNEYS CORRESPONDS WITH HYPERMETHYLATION OF THE TGF-BETA1 GENE-BODY, INDICATING A POSSIBLE INVOLVEMENT OF PRENATAL AS EXPOSURE-DRIVEN EPIGENETIC MODULATIONS OF TGF-BETA1 EXPRESSION. OUR STUDY PROVIDES EVIDENCE THAT PRENATAL AS EXPOSURE TO MALES CAN ADVERSELY AFFECT THE IMMUNOMETABOLISM OF OFFSPRING WHICH CAN PROMOTE KIDNEY DAMAGE LATER IN LIFE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11  3456  33 HYPOMETHYLATION OF IL1RN AND NFKB1 GENES IS LINKED TO THE DYSBALANCE IN IL1BETA/IL-1RA AXIS IN FEMALE PATIENTS WITH TYPE 2 DIABETES MELLITUS. INFLAMMATION HAS RECEIVED CONSIDERABLE ATTENTION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS (T2DM). SUPPORTING THIS CONCEPT, ENHANCED EXPRESSION OF INTERLEUKIN (IL)-1BETA AND INCREASED INFILTRATION OF MACROPHAGES ARE OBSERVED IN PANCREATIC ISLETS OF PATIENTS WITH T2DM. ALTHOUGH IL-1 RECEPTOR ANTAGONIST (IL-1RA) PLAYS A MAJOR ROLE IN CONTROLLING OF IL-1BETA-MEDIATED INFLAMMATION, ITS COUNTERACTION EFFECTS AND EPIGENETIC ALTERATIONS IN T2DM ARE LESS STUDIED. THUS, WE AIMED TO ANALYZE THE DNA METHYLATION STATUS IN IL1RN, RELA (P65) AND NFKB1 (P50) GENES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM TREATED T2DM PATIENTS (N = 35) AND AGE-/SEX- MATCHED HEALTHY CONTROLS (N = 31). PRODUCTION OF IL-1BETA AND IL-1RA WAS ANALYZED IN PLASMA AND SUPERNATANTS FROM LPS-INDUCED PBMCS. IMMUNOMODULATORY EFFECTS OF IL-1BETA AND IL-1RA WERE STUDIED ON THP-1 CELLS. AVERAGE DNA METHYLATION LEVEL OF IL1RN AND NFKB1 GENE PROMOTERS WAS SIGNIFICANTLY DECREASED IN T2DM PATIENTS IN COMPARISON WITH HEALTHY CONTROLS (P< 0.05), WHICH WAS ASSOCIATED WITH THE INCREASED IL-1RA (P< 0.001) AND IL-1BETA (P = 0.039) PLASMA LEVELS IN T2DM PATIENTS. NEGATIVE ASSOCIATION BETWEEN AVERAGE METHYLATION OF IL1RN GENE AND IL-1RA PLASMA LEVELS WERE OBSERVED IN FEMALE T2DM PATIENTS. METHYLATION OF NFKB1 GENE WAS NEGATIVELY CORRELATED WITH IL-1RA LEVELS IN THE PATIENTS AND POSITIVELY WITH IL-1BETA LEVELS IN FEMALE PATIENTS. LPS-STIMULATED PBMCS FROM FEMALE PATIENTS FAILED TO RAISE IL-1BETA PRODUCTION, WHILE THE CELLS FROM HEALTHY FEMALES INCREASED IL-1BETA PRODUCTION IN COMPARISON WITH UNSTIMULATED CELLS (P< 0.001). TAKEN TOGETHER, THE FINDINGS SUGGEST THAT HYPOMETHYLATION OF IL1RN AND NFKB1 GENE PROMOTERS MAY PROMOTE THE INCREASED IL-1BETA/IL-1RA PRODUCTION AND REGULATE CHRONIC INFLAMMATION IN T2DM. FURTHER STUDIES ARE NECESSARY TO ELUCIDATE THE CAUSAL DIRECTION OF THESE ASSOCIATIONS AND POTENTIAL ROLE OF IL-1RA IN ANTI-INFLAMMATORY PROCESSES IN TREATED PATIENTS WITH T2DM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12  6085  28 THE EFFECTS OF ACARBOSE ON CHEMOKINE AND CYTOKINE PRODUCTION IN HUMAN MONOCYTIC THP-1 CELLS. BACKGROUND AND OBJECTIVES: CHRONIC INFLAMMATION INDUCED BY PROINFLAMMATORY CYTOKINES AND CHEMOKINES IS POSTULATED TO BE INVOLVED IN INSULIN RESISTANCE AND BETA-CELL DYSFUNCTION IN TYPE 2 DIABETES MELLITUS (T2DM). ACARBOSE, THE ALPHA-GLUCOSIDASE INHIBITOR, IS AN ORAL ANTIDIABETIC DRUG FOR T2DM. ACARBOSE SUPPRESSES INFLAMMATORY CYTOKINE PRODUCTION IN PATIENTS WITH T2DM, THOUGH THE UNDERLYING MECHANISMS ARE UNCLEAR. IN THE PRESENT STUDY, WE AIMED TO INVESTIGATE THE ANTI-INFLAMMATORY EFFECTS AND THE EXACT MECHANISMS OF ACARBOSE IN HUMAN MONOCYTIC THP-1 CELLS. METHODS: THP-1 CELLS WERE PRETREATED WITH ACARBOSE AND THEN STIMULATED WITH LIPOPOLYSACCHARIDE (LPS). THE LEVELS OF TH1-RELATED CHEMOKINES, INCLUDING INTERFERON-GAMMA-INDUCIBLE PROTEIN-10 (IP-10), MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1), TH2-RELATED CHEMOKINE MACROPHAGE-DERIVED CHEMOKINE (MDC), AND PROINFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), WERE DETERMINED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. INTRACELLULAR SIGNALING PATHWAYS WERE EXPLORED BY WESTERN BLOT ANALYSIS AND USING A CHROMATIN IMMUNOPRECIPITATION ASSAY. RESULTS: ACARBOSE SUPPRESSED THE LEVELS OF IP-10, MCP-1, MDC, AND TNF-ALPHA AND DOWNREGULATED PHOSPHORYLATION OF P38, C-JUN N-TERMINAL KINASE (JNK), EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK), AND NUCLEAR FACTOR-KAPPA B-P65 (NF-KAPPAB-P65) IN LPS-STIMULATED THP-1 CELLS. ACARBOSE SUPPRESSED LPS-INDUCED ACETYLATION OF HISTONES H3 (H3) AND H4 IN THE IP-10 AND MCP-1 PROMOTER REGIONS. THESE FINDINGS REVEALED THE SUPPRESSIVE EFFECTS OF ACARBOSE ON IP-10, MCP-1, MDC, AND TNF-ALPHA PRODUCTION IN THP-1 CELLS VIA, AT LEAST PARTIALLY, THE P38, JNK, ERK, AND NF-KAPPAB-P65 PATHWAYS, AS WELL AS THROUGH EPIGENETIC REGULATION VIA HISTONE H3 AND H4 ACETYLATION. CONCLUSION: OUR STUDY POINTS TO THE THERAPEUTIC ANTI-INFLAMMATORY POTENTIAL OF ACARBOSE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  3553  35 IMMUNOTOLERANCE OF DAIRY HEIFERS IN RESPONSE TO REPEATED EXPOSURE TO BACTERIAL LIPOPOLYSACCHARIDE ENDOTOXIN. DAIRY CATTLE FACE A VARIETY OF STRESSFUL EVENTS ON A DAILY BASIS. MORE SPECIFICALLY, CLIMATE CHANGE HAS RESULTED IN MORE FREQUENT HEAT STRESS EVENTS THAT INCREASE THE INCIDENCE OF CHRONIC BACTERIAL INFECTIONS BY INDUCING CONDITIONS LIKE LEAKY GUT SYNDROME, WHEREBY THE INTEGRITY OF THE INTESTINAL EPITHELIUM IS COMPROMISED ALLOWING FOR LUMINAL BACTERIAL LIPOPOLYSACCHARIDE (LPS) ENDOTOXIN TO INFILTRATE THE HOST'S BLOODSTREAM RESULTING IN ACUTE OR CHRONIC SYSTEMIC STIMULATION OF THE INNATE IMMUNE SYSTEM. REPEATED EXPOSURE TO LPS OVER A SHORT PERIOD OF TIME IS REPORTED TO INDUCE IMMUNOTOLERANCE WITHIN THE HOST. THIS LPS TOLERANCE IS AN ESSENTIAL IMMUNOHOMEOSTATIC RESPONSE THAT CAN PROTECT AGAINST OVER ACTIVATION OF THE INFLAMMATORY RESPONSE DURING SUBSEQUENT EXPOSURE TO LPS. IN THE PRESENT STUDY, HOLSTEIN CALVES (N = 20) WERE INITIALLY STRESS CHALLENGED WITH EITHER SALINE, OR 100, 200 OR 400 NG/KG OF LPS ADMINISTERED INTRAMUSCULAR, AND AGAIN RE-CHALLENGED WITH 200 NG/KG OF LPS 2-WEEKS LATER. SERUM WAS COLLECTED EVERY 2 HR FOR 6 HR TO PROFILE CHANGES IN CIRCULATORY STRESS BIOMARKERS AFTER THE REPEATED LPS EXPOSURES. HEIFERS THAT WERE INITIALLY CHALLENGED WITH 100, 200 AND 400 NG/KG OF LPS DEMONSTRATED SIGNIFICANTLY ATTENUATED CORTISOL RESPONSES IN THE SECOND CHALLENGE (P < 0.01, 0.01 AND 0.05, RESPECTIVELY), WHEREAS CONTROL ANIMALS WHO PREVIOUSLY RECEIVED SALINE DEMONSTRATED A STRONG CORTISOL RESPONSE AT 2 HR AFTER RECEIVING 200 NG/KG OF LPS (P < 0.05). THE CYTOKINE/CHEMOKINE (IL-6, CCL2, CCL3 AND CCL4) RESPONSES WERE ALSO ATTENUATED DURING THE LPS RECHALLENGE (P < 0.05). FINALLY, MICRORNA EXPRESSION PROFILES WERE DETERMINED TO ASSESS THE EPIGENETIC RESPONSE TO REPEATED LPS EXPOSURE. INTERESTINGLY, MIR-31 AND MIR-223 WERE DOWNREGULATED IN RESPONSE TO THE SECOND LPS CHALLENGE. THE PRESENT STUDY DEMONSTRATES THE DYNAMIC NATURE OF THE STRESS RESPONSE IN DAIRY CATTLE AS IT RELATES TO THE DEVELOPMENT OF LPS TOLERANCE. UNDERSTANDING THE ROLES OF VARIOUS STRESS BIOMARKERS IN THE CONTEXT OF INNATE IMMUNE CELL TOLERANCE IS ESSENTIAL FOR EVALUATING THEIR IMPACT ON IMMUNE SYSTEM HOMEOSTASIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  1795  35 EFFECT OF DIFFERENT COMBINATION OF MATERNAL AND POSTNATAL DIET ON ADIPOSE TISSUE MORPHOLOGY IN MALE RAT OFFSPRING. PURPOSE: ADIPOSE TISSUE EXPANSION CAN OCCUR THROUGH SEVERAL DIFFERENT WAYS AND, UNDER CERTAIN CONDITIONS, CAN BE CONNECTED WITH CHRONIC INFLAMMATION. TNF-ALPHA IS ONE OF THE IMPORTANT CYTOKINES INVOLVED IN THIS PROCESS. PROLONGED INFLAMMATION IN OBESITY CAN LEAD TO OBESITY-RELATED INSULIN RESISTANCE AND TISSUE DYSFUNCTION. THE AIM OF OUR STUDY WAS TO INVESTIGATE HOW DIFFERENT COMBINATION OF MATERNAL AND POSTNATAL DIET AFFECTS OFFSPRING ADIPOSE TISSUE MORPHOLOGY AND ADIPOSE TISSUE TNF-ALPHA EXPRESSION. METHODS: TEN FEMALE SPRAGUE DAWLEY RATS, 9 WEEKS OLD, WERE RANDOMLY DIVIDED INTO TWO GROUPS AND FED EITHER STANDARD LABORATORY CHOW OR FOOD RICH IN SATURATED FATTY ACIDS DURING 6 WEEKS AND THEN MATED WITH THE SAME MALE RAT. AFTER BIRTH AND LACTATION MALE RAT OFFSPRING FROM BOTH GROUPS WERE DIVIDED INTO FOUR SUBGROUPS DEPENDING ON THE DIET THEY WERE FED UNTIL 22 WEEKS OLD. SAMPLES OF WHITE ADIPOSE TISSUE WERE TAKEN FROM THE SUBCUTANEOUS, EPIDIDYMAL, AND PERIRENAL FAT PAD. ON TISSUE SECTIONS, HISTOMORPHOMETRIC ANALYSIS WAS CONDUCTED USING CELLPROFILER PROGRAM V 2.1.1, AND IMMUNOHISTOCHEMICAL STAINING FOR TNF-ALPHA WAS PERFORMED. RESULTS: GREATER MEAN SURFACE AREA OF SUBCUTANEOUS AND EPIDIDYMAL ADIPOCYTES WAS FOUND IN GROUPS OF MALE RAT OFFSPRING WITH ALTERED DIET. IN PERIRENAL ADIPOSE TISSUE, THE HIGHEST NUMBER OF ADIPOCYTES WAS MEASURED IN THE GROUP WHERE BOTH MOTHER AND OFFSPRING WERE FED A HIGH-FAT DIET. ADIPOCYTE STAINING INTENSITY FOR TNF-ALPHA DID NOT DIFFER SIGNIFICANTLY BETWEEN THE GROUPS. CONCLUSIONS: TOGETHER WITH OUR PREVIOUSLY PUBLISHED DATA, OUR RESULTS LEAD TO THE CONCLUSION THAT ALTERATION OF POSTNATAL DIET CAN LEAD TO TNF-ALPHA AND ADIPOCYTE MORPHOLOGY CHANGES.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
15  4081  27 MATERNAL MICRONUTRIENT SUPPLEMENTATION SUPPRESSES T CELL CHEMOKINE RECEPTOR EXPRESSION AND FUNCTION IN F1 MICE. PRENATAL ENVIRONMENTAL EXPOSURES PLAY A CRITICAL ROLE IN DETERMINING LATE-LIFE CHRONIC DISEASE SUSCEPTIBILITY. HOWEVER, THE MECHANISMS LINKING THE IN UTERO ENVIRONMENT AND DISEASE DEVELOPMENT IN THE OFFSPRING ARE POORLY UNDERSTOOD. RECENT INVESTIGATIONS HAVE CONFIRMED A CENTRAL PATHOGENIC ROLE OF T CELL CHEMOKINE RECEPTORS, PARTICULARLY C-C CHEMOKINE RECEPTOR (CCR) 2 AND CCR5, IN CHRONIC INFLAMMATORY CONDITIONS. THIS STUDY WAS DESIGNED TO DETERMINE THE EFFECT OF A SYNTHETIC PRENATAL MICRONUTRIENT SUPPLEMENTATION (MS) DIET RICH IN METHIONINE PATHWAY METABOLITES ON THE T CELL CHEMOKINE SYSTEM IN F1 C57BL/6 MICE. FEMALE MICE WERE FED EITHER AN MS OR CONTROL DIET 3 WK PRIOR TO MATING, DURING PREGNANCY, AND LACTATION. AT 4 WK OF AGE, F1 MICE WERE KILLED FOR EXPERIMENTS OR WERE FED THE STANDARD NIH-31 DIET AND ALLOWED TO AGE. FOOD CONSUMPTION, MATERNAL WEIGHT GAIN, AND LITTER SIZE WERE SIMILAR IN DAMS FED THE CONTROL AND MS DIETS. HOWEVER, THE F1 OFFSPRING OF DAMS FED THE MS DIET WERE SMALLER IN SIZE (P < 0.001). T CELLS FROM THE MS F1 OFFSPRING HAD GLOBAL HYPERMETHYLATION COMPARED WITH CONTROL F1 OFFSPRING (P < 0.005), CORRESPONDING TO LOWER T CELL CHEMOKINE RECEPTOR EXPRESSION [CCR2 (P < 0.001), CCR5 (P < 0.001), AND C-X-C CHEMOKINE RECEPTOR 3 (P < 0.01)] AND CYTOKINE EXPRESSION [TNFALPHA (P < 0.05), IL-2 (P < 0.001), AND IL-4 (P < 0.01)]. REDUCED T CELL CHEMOKINE RECEPTOR GENE EXPRESSION IN MS F1 MICE WAS ASSOCIATED WITH DECREASED CHEMOTAXIS IN VITRO TO C-C CHEMOKINE LIGAND (CCL) 2 AND C-X-C CHEMOKINE LIGAND 10 (P < 0.01) AND IN VIVO TO CCL2 (P < 0.01). TAKEN TOGETHER, THE RESULTS SUGGEST THAT EPIGENETIC ALTERATION THROUGH PRENATAL DIET MANIPULATION REDUCES THE RESPONSE TO PROINFLAMMATORY SIGNALS IN MICE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  4349  34 MIR-155 AND MIR-122 EXPRESSION OF SPERMATOZOA IN OBESE SUBJECTS. OBESITY IS CHARACTERIZED BY MILD CHRONIC INFLAMMATION THAT IS LINKED WITH IMPAIRED IRON HOMEOSTASIS. STUDIES IN HUMAN AND MURINE SHOW THAT THERE IS A TRANSGENERATIONAL EPIGENETIC INHERITANCE VIA THE GAMETES IN OBESITY; HOWEVER, THERE IS LITTLE INFORMATION ON CHANGES IN THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION AND IRON HOMEOSTASIS IN SPERMATOZOA FROM OBESE SUBJECTS. THE PRESENT STUDY INVESTIGATED THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION (MIR-21 Y MIR-155) AND IRON NUTRITION (MIR-122 AND MIR-200B) IN PLASMA, PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND SPERMATOZOA FROM NORMOZOOSPERMIC CONTROLS (CN; N = 17; BMI: 24.6 +/- 2.0) AND OBESE (OB; N = 17; BMI: 32.6 +/- 4.4) MEN. TO DETERMINE THE INFLAMMATION LEVELS, WE MEASURED IL-6, TNF-ALPHA, AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP1) BY MAGNETIC LUMINEX((R)) ASSAY. MRNA EXPRESSION OF IL6, TNF-ALPHA, AND HEPCIDIN (HAMP) IN PBMC WERE EVALUATED BY RT-QPCR. THE ANALYSIS OF MICRORNAS WAS PERFORMED USING THE TAQMAN((R)) ASSAYS. THE IRON CONTENT IN PBMC, SEMINAL PLASMA, AND SPERMATOZOA WAS DETERMINED BY INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY (ICP-MS). HIGH SERUM IL6, TNF-ALPHA, AND MCP1 LEVELS WERE OBSERVED IN OB GROUP (P < 0.05). GENE EXPRESSION ANALYSIS SHOWED AN INCREASED ABUNDANCE RELATIVE OF TNF-ALPHA (P = 0.018), HAMP (P = 0.03), AND IL6 (P = 0.02) IN PBMC FROM OBESE SUBJECTS. ALSO, WE OBSERVED HIGH LEVELS OF SERUM FERRITIN (P = 0.03), IRON CONTENT IN SEMINAL PLASMA (P = 0.04), AND SPERMATOZOA (P = 0.002), BUT LOWER SERUM FE (P = 0.007) IN OBESE SUBJECTS. IN THE OB GROUP, A HIGH EXPRESSION OF MIR-155 (P = 0.02) AND MIR-21 (P = 0.03) WAS OBSERVED IN PBMC AND MIR-122 (P = 0.03) IN PLASMA. IN SPERM, BOTH MIR-155 (P = 0.004) AND MIR-122 (P = 0.028) WERE HIGH IN THE OB GROUP. OUR RESULTS SHOWED THAT OBESE SUBJECTS HAVE INCREASED EXPRESSIONS OF MIR-155 AND MIR-122, TWO MICRORNAS THAT WERE PREVIOUSLY RELATED WITH INFLAMMATION AND IRON METABOLISM, RESPECTIVELY, AT BOTH THE SYSTEMIC AND SPERM LEVELS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17  5760  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  3124  29 GHRELIN TREATMENT IMPROVES PHYSICAL DECLINE IN SARCOPENIA MODEL MICE THROUGH MUSCULAR ENHANCEMENT AND MITOCHONDRIAL ACTIVATION. CHRONIC KIDNEY DISEASE (CKD) IMPAIRS PHYSICAL PERFORMANCE IN HUMANS, WHICH LEADS TO A RISK OF ALL-CAUSE MORTALITY. IN OUR PREVIOUS STUDY, WE DEMONSTRATED THAT A REDUCTION IN MUSCLE MITOCHONDRIA RATHER THAN MUSCLE MASS WAS A MAJOR CAUSE OF PHYSICAL DECLINE IN 5/6 NEPHRECTOMIZED CKD MODEL MICE. BECAUSE GHRELIN ADMINISTRATION HAS BEEN REPORTED TO ENHANCE OXYGEN UTILIZATION IN SKELETAL MUSCLE, WE EXAMINED THE USEFULNESS OF GHRELIN FOR A RECOVERY OF PHYSICAL DECLINE IN 5/6 NEPHRECTOMIZED C57BL/6 MICE, FOCUSING ON THE EPIGENETIC MODIFICATION OF PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR-1ALPHA (PGC-1ALPHA), A MASTER REGULATOR OF MITOCHONDRIAL BIOGENESIS. THE MICE WERE INTRAPERITONEALLY ADMINISTERED ACYLATED GHRELIN (0.1 NMOL/GBW; THREE TIMES PER WEEK) FOR A MONTH. MUSCLE STRENGTH AND EXERCISE ENDURANCE WERE MEASURED BY USING A DYNAMOMETER AND TREADMILL, RESPECTIVELY. MITOCHONDRIAL DNA COPY NUMBER WAS DETERMINED BY QUANTITATIVE PCR. THE METHYLATION LEVELS OF THE CYTOSINE RESIDUE AT 260 BASE PAIRS UPSTREAM OF THE TRANSLATION INITIATION POINT (C-260) OF PGC-1ALPHA, WHICH HAS BEEN DEMONSTRATED TO DECREASE THE EXPRESSION, WAS EVALUATED BY METHYLATION-SPECIFIC PCR AND BISULFITE GENOMIC SEQUENCING METHODS AFTER THE GHRELIN ADMINISTRATION. GHRELIN ADMINISTRATION IMPROVED BOTH MUSCLE STRENGTH AND EXERCISE ENDURANCE IN THE MICE AND WAS ASSOCIATED WITH AN INCREASE IN MUSCLE MASS AND MUSCLE MITOCHONDRIAL CONTENT. GHRELIN ADMINISTRATION DECREASED THE METHYLATION RATIO OF C-260 OF PGC-1ALPHA IN THE SKELETAL MUSCLE AND INCREASED THE EXPRESSION. THEREFORE, GHRELIN ADMINISTRATION EFFECTIVELY REDUCED THE PHYSICAL DECLINE IN 5/6 NEPHRECTOMIZED MICE AND WAS ACCOMPANIED WITH AN INCREASED MITOCHONDRIAL CONTENT THROUGH DE-METHYLATION OF THE PROMOTER REGION OF PGC-1ALPHA IN THE MUSCLE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
19   910  28 CHRONIC EXPOSURE TO ETHANOL OF MALE MICE BEFORE MATING PRODUCES ATTENTION DEFICIT HYPERACTIVITY DISORDER-LIKE PHENOTYPE ALONG WITH EPIGENETIC DYSREGULATION OF DOPAMINE TRANSPORTER EXPRESSION IN MOUSE OFFSPRING. PRECONCEPTION EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE MAY AFFECT NEUROBEHAVIORAL AND DEVELOPMENTAL FEATURES OF OFFSPRING. THIS STUDY INVESTIGATES THE EFFECTS OF PATERNAL EXPOSURE TO ETOH BEFORE CONCEPTION ON THE HYPERACTIVITY, INATTENTION, AND IMPULSIVITY BEHAVIOR OF MALE OFFSPRING IN MICE. SIRE MICE WERE TREATED WITH ETOH IN A CONCENTRATION RANGE APPROXIMATING HUMAN BINGE DRINKING (0-4 G/KG/DAY ETOH) FOR 7 WEEKS AND MATED WITH UNTREATED FEMALES MICE TO PRODUCE OFFSPRING. ETOH EXPOSURE TO SIRE MICE INDUCED ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)-LIKE HYPERACTIVE, INATTENTIVE, AND IMPULSIVE BEHAVIORS IN OFFSPRING. AS A MECHANISTIC LINK, BOTH PROTEIN AND MRNA EXPRESSION OF DOPAMINE TRANSPORTER (DAT), A KEY DETERMINANT OF ADHD-LIKE PHENOTYPES IN EXPERIMENTAL ANIMALS AND HUMANS, WERE SIGNIFICANTLY DECREASED BY PATERNAL ETOH EXPOSURE IN CEREBRAL CORTEX AND STRIATUM OF OFFSPRING MICE ALONG WITH INCREASED METHYLATION OF A CPG REGION OF THE DAT GENE PROMOTER. THE INCREASE IN METHYLATION OF DAT GENE PROMOTER WAS ALSO OBSERVED IN THE SPERM OF SIRE MICE, SUGGESTING GERMLINE CHANGES IN THE EPIGENETIC METHYLATION SIGNATURE OF DAT GENE BY ETOH EXPOSURE. IN ADDITION, THE EXPRESSION OF TWO KEY REGULATORS OF METHYLATION-DEPENDENT EPIGENETIC REGULATION OF FUNCTIONAL GENE EXPRESSION, NAMELY, MECP2 AND DNMT1, WAS MARKEDLY DECREASED IN OFFSPRING CORTEX AND STRIATUM SIRED BY ETOH-EXPOSED MICE. THESE RESULTS SUGGEST THAT PRECONCEPTIONAL EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE INDUCES BEHAVIORAL CHANGES IN OFFSPRING, POSSIBLY VIA EPIGENETIC CHANGES IN GENE EXPRESSION, WHICH IS ESSENTIAL FOR THE REGULATION OF ADHD-LIKE BEHAVIORS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  1030  44 CIRCULATING PLASMA MICRORNAS DYSREGULATION AND METABOLIC ENDOTOXEMIA INDUCED BY A HIGH-FAT HIGH-SATURATED DIET. HIGH-FAT DIET INCREASE TWO TO THREE TIMES THE PLASMA LIPOPOLYSACCHARIDE (LPS) LEVELS AND INDUCE SUBCLINICAL INFLAMMATION. DIET CAN MODIFY GENE EXPRESSION DUE TO EPIGENETIC PROCESSES RELATED TO MICRORNAS (MIRNAS). MICRORNAS (MIRNAS) PLAY IMPORTANT ROLE IN THE POST-TRANSCRIPTIONAL MECHANISMS INVOLVED IN REGULATION OF EXPRESSION OF GENES RELATED TO THE INFLAMMATORY RESPONSE. ALSO, DIET CAN INDIRECTLY INDUCE POST-TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION BY MIRNAS, WHICH MAY AFFECT THE RISK FOR THE DEVELOPMENT OF CHRONIC DISEASES. OBJECTIVE: THIS STUDY INVESTIGATED THE EFFECT OF HIGH-FAT HIGH-SATURATED MEAL INGESTION ON PLASMA MIRNA EXPRESSION AND LPS LEVELS DURING THE POSTPRANDIAL PERIOD IN HEALTHY WOMEN. METHODS: AN INTERVENTIONAL STUDY WAS CARRIED OUT IN WHICH A HIGH-FAT BREAKFAST (1067.45 KCAL), COMPOSED MAINLY OF SATURATED FATTY ACIDS (56 G), AND 500 ML OF WATER, WAS OFFERED. BLOOD SAMPLES WERE COLLECTED AT BASELINE AND 1, 3 AND 5 H AFTER MEAL INTAKE. THE STUDIED POPULATION CONSISTED OF HEALTHY WOMEN (N = 11), AGED BETWEEN 20 AND 40 YEARS, AND BODY MASS INDEX (BMI) BETWEEN 18.5 AND 25 KG/M(2). PLASMA LEVELS OF LIPID PROFILE, CYTOKINES, ADHESION MOLECULES, AND LPS WERE MEASURED AT THE 3 TIME POINTS. A PROFILE OF 752 HUMAN PLASMA MIRNA EXPRESSION WAS ANALYZED BY REAL-TIME PCR ASSAY. THESE ANALYZES WERE PERFORMED FOR ALL BLOOD COLLECTION TIME-POINTS. RESULTS: EXPRESSION PROFILE ANALYSIS REVEALED 33 DIFFERENTIALLY EXPRESSED PLASMA CIRCULATING MIRNAS COMPARED TO THAT OF THE CONTROL GROUP. MIR-145-5P AND MIR-200 WERE DIFFERENTIALLY MODULATED IN ALL TIME-POINTS POST MEAL CONSUMPTION. IN ADDITION, THERE WAS A SIGNIFICANT INCREASE IN PLASMA LPS, TRIGLYCERIDES, MYRISTIC AND PALMITIC SATURATED FATTY ACIDS LEVELS AT THE 3 TIME-POINTS IN COMPARISON WITH THE CONTROL BASAL LEVELS. WE ALSO OBSERVED INCREASED LEVELS OF THE PLASMA TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) CYTOKINE AND THE VASCULAR CELL ADHESION MOLECULE 1 (VCAM-1) LEVELS AFTER 5 H POST MEAL INGESTION. CONCLUSION: INGESTION OF HIGH-FAT HIGH-SATURATED MEAL WAS ABLE TO INDUCE METABOLIC ENDOTOXEMIA AND INCREASE THE EXPRESSION OF PRO-INFLAMMATORY MOLECULES SUCH AS TNF-ALPHA AND VCAM-1, AS WELL AS MODULATING CIRCULATING MIRNAS POSSIBLY CONTROLLING INFLAMMATORY AND LIPID METABOLISM PROTEINS AT THE POSTPRANDIAL PERIOD.	2020