1 1401 128 DIETARY AND PHARMACOLOGICAL TREATMENT OF ABDOMINAL PAIN IN IBS. THIS REVIEW INTRODUCES THE PRINCIPLES OF VISCERAL SENSATION AND APPRAISES THE CURRENT APPROACHES TO MANAGEMENT OF VISCERAL PAIN IN FUNCTIONAL GI DISEASES, PRINCIPALLY IBS. THESE APPROACHES INCLUDE DIETARY MEASURES INCLUDING FIBRE SUPPLEMENTATION, LOW FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES AND POLYOLS DIET, AND PHARMACOLOGICAL APPROACHES SUCH AS ANTISPASMODICS, PEPPERMINT OIL, ANTIDEPRESSANTS (TRICYCLIC AGENTS, SELECTIVE SEROTONIN REUPTAKE INHIBITORS), 5-HT(3) RECEPTOR ANTAGONISTS (ALOSETRON, ONDANSETRON, RAMOSETRON), NON-ABSORBED ANTIBIOTIC (RIFAXIMIN), SECRETAGOGUES (LUBIPROSTONE, LINACLOTIDE), MU-OPIOID RECEPTOR (OR) AND KAPPA-OR AGONIST, DELTA-OR ANTAGONIST (ELUXADOLINE), HISTAMINE H1 RECEPTOR ANTAGONIST (EBASTINE), NEUROKININ-2 RECEPTOR ANTAGONIST (IBODUTANT) AND GABAERGIC AGENTS (GABAPENTIN AND PREGABALIN). EFFICACY AND SAFETY ARE DISCUSSED BASED ON PIVOTAL TRIALS OR PUBLISHED SYSTEMATIC REVIEWS AND META-ANALYSIS, EXPRESSING ORS OR RELATIVE RISKS AND THEIR 95% CIS. POTENTIAL NEW APPROACHES MAY BE BASED ON RECENT INSIGHTS ON MUCOSAL EXPRESSION OF GENES, AND MICRORNA AND EPIGENETIC MARKERS IN HUMAN BIOPSIES AND IN ANIMAL MODELS OF VISCERAL HYPERSENSITIVITY.THE OBJECTIVES OF THIS REVIEW ARE TO APPRAISE THE PHYSIOLOGY AND ANATOMY OF GUT SENSATION AND THE EFFICACY IN THE RELIEF OF VISCERAL PAIN (TYPICALLY IN IBS) OF SEVERAL CLASSES OF THERAPIES. THESE INCLUDE FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES AND POLYOLS (FODMAPS) AND DIFFERENT CLASSES OF MEDICATIONS (BOX 1). BOX 1CLASSES OF PHARMACOLOGICAL AGENTS FOR VISCERAL PAINANTIDEPRESSANTS (TRICYCLIC AGENTS, SELECTIVE SEROTONIN REUPTAKE INHIBITORS)PEPPERMINT OIL5-HT(3) RECEPTOR ANTAGONISTS (ALOSETRON, ONDANSETRON, RAMOSETRON)NON-ABSORBED ANTIBIOTIC (RIFAXIMIN)SECRETAGOGUES (LUBIPROSTONE, LINACLOTIDE)MU-OPIOID RECEPTOR (OR) AND KAPPA-OR AGONIST AND DELTA-OR ANTAGONIST (ELUXADOLINE)HISTAMINE H1 RECEPTOR ANTAGONIST (EBASTINE)NEUROKININ-2 RECEPTOR ANTAGONIST (IBODUTANT)GABAERGIC AGENTS (GABAPENTIN AND PREGABALIN).	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2 5763  12 SOME COMMENTS ON MASOCHISM AND THE DELUSION OF OMNIPOTENCE FROM A DEVELOPMENTAL PERSPECTIVE. THIS PAPER EXPLORES THE RELATION OF THE DELUSION OF OMNIPOTENCE TO MASOCHISM AND SUGGESTS THAT THIS FANTASY CONSTITUTES A MAJOR COMPONENT OF THE RESISTANCE SO PROMINENT IN WORK WITH MASOCHISTIC PATIENTS. THE CONNECTIONS AMONG MASOCHISM, OMNIPOTENCE, NEGATIVE THERAPEUTIC REACTION, AND CLINGING TO PAIN ARE DISCUSSED. THE CLASSICAL VIEW HAS BEEN THAT THE FAILURE OF INFANTILE OMNIPOTENCE FORCES THE CHILD TO TURN TO REALITY. OUR EXPERIENCE WITH MASOCHISTIC PATIENTS SUGGESTS THAT IT IS THE REAL FAILURE TO ACHIEVE COMPETENT INTERACTIONS WITH OTHERS THAT FORCES THE CHILD TO TURN TO OMNIPOTENT SOLUTIONS. THE DISTINCTION IS MADE BETWEEN FANTASIES THAT ENHANCE THE REAL CAPACITIES OF THE SELF AND THOSE AIMED AT DENYING AND TRANSFORMING THE PAIN AND INADEQUACY OF THE MOTHER-CHILD RELATIONSHIP. THE EPIGENETIC TRANSFORMATIONS OF OMNIPOTENT FANTASIES THROUGH ALL LEVELS OF DEVELOPMENT ARE DESCRIBED. THE PATIENT'S NEED TO PROTECT THE OMNIPOTENT FANTASY IS DISCUSSED IN RELATION TO RESISTANCE AT EACH PHASE OF ANALYSIS.	1991	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3 3626  21 IN-SILICO DISCOVERY OF DUAL ACTIVE MOLECULE TO RESTORE SYNAPTIC WIRING AGAINST AUTISM SPECTRUM DISORDER VIA HDAC2 AND H3R INHIBITION. METAL-DEPENDENT HISTONE DEACETYLASES (HDACS) ARE ESSENTIAL EPIGENETIC REGULATORS; THEIR MOLECULAR AND PHARMACOLOGICAL ROLES IN MEDICALLY CRITICAL DISEASES SUCH AS NEUROPSYCHIATRIC DISORDERS, NEURODEGENERATION, AND CANCER ARE BEING STUDIED GLOBALLY. HDAC2'S DIFFERENTIAL EXPRESSION IN THE CENTRAL NERVOUS SYSTEM MAKES IT AN APPEALING THERAPEUTIC TARGET FOR CHRONIC NEUROLOGICAL DISEASES LIKE AUTISM SPECTRUM DISORDER. IN THIS STUDY, WE IDENTIFIED H3R INHIBITOR MOLECULES THAT ARE COMPUTATIONALLY EFFECTIVE AT BINDING TO THE HDAC2 METAL-COORDINATED BINDING SITE. THE STUDY HIGHLIGHTS THE IMPORTANCE OF PITOLISANT IN SCREENING THE POTENTIAL H3R INHIBITORS BY USING A HYBRID WORKFLOW OF LIGAND AND RECEPTOR-BASED DRUG DISCOVERY. THE SCREENED LEAD COMPOUNDS WITH PUBCHEM SIDS 103179850, 103185945, AND 103362074 SHOW VIABLE BINDING WITH HDAC2 IN SILICO. THE IMPORTANCE OF LIGAND CONTACTS WITH THE ZN2+ ION IN THE HDAC2 CATALYTIC SITE IS ALSO DISCUSSED AND INVESTIGATED FOR A SIGNIFICANT ROLE IN ENZYME INHIBITION. THE PROPOSED H3R INHIBITORS 103179850, 103185945, AND 103362074 ARE ESTIMATED AS DUAL-ACTIVE MOLECULES TO BLOCK THE HDAC2-MEDIATED DEACETYLATION OF THE EAAT2 GENE (SLC1A2) AND H3R-MEDIATED SYNAPTIC TRANSMISSION IRREGULARITY AND ARE, THEREFORE, OPEN FOR EXPERIMENTAL VALIDATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  582  20 BEHAVIORAL AND PHYSIOLOGICAL EFFECTS OF ACUTE AND CHRONIC KAVA EXPOSURE IN ADULT ZEBRAFISH. KAVA KAVA (PIPER METHYSTICUM) IS A MEDICINAL PLANT CONTAINING KAVALACTONES THAT EXERT POTENT SEDATIVE, ANALGESIC AND ANTI-STRESS ACTION. HOWEVER, THEIR PHARMACOLOGICAL EFFECTS AND MOLECULAR TARGETS REMAIN POORLY UNDERSTOOD. THE ZEBRAFISH (DANIO RERIO) HAS RECENTLY EMERGED AS A POWERFUL NEW MODEL ORGANISM FOR NEUROSCIENCE RESEARCH AND DRUG DISCOVERY. HERE, WE EVALUATE THE EFFECTS OF ACUTE AND CHRONIC EXPOSURE TO KAVA AND KAVALACTONES ON ADULT ZEBRAFISH ANXIETY, AGGRESSION AND SOCIALITY, AS WELL AS ON THEIR NEUROCHEMICAL, NEUROENDOCRINE AND GENOMIC RESPONSES. SUPPORTING EVOLUTIONARILY CONSERVED MOLECULAR TARGETS, ACUTE KAVA AND KAVALACTONES EVOKED DOSE-DEPENDENT BEHAVIORAL INHIBITION, UPREGULATED BRAIN EXPRESSION OF EARLY PROTOONCOGENES C-FOS AND C-JUN, ELEVATED BRAIN MONOAMINES AND LOWERED WHOLE-BODY CORTISOL. CHRONIC 7-DAY KAVA EXPOSURE EVOKED SIMILAR BEHAVIORAL EFFECTS, DID NOT ALTER CORTISOL LEVELS, AND FAILED TO EVOKE WITHDRAWAL-LIKE STATES UPON DISCONTINUATION. HOWEVER, CHRONIC KAVA UPREGULATED SEVERAL MICROGLIAL (INOS, EGR-2, CD11B), ASTROCYTAL (C3, C4B, S100A), EPIGENETIC (NCOA-1) AND PRO-INFLAMMATORY (IL-1BETA, IL-6, TNFA) BIOMARKER GENES, DOWNREGULATED CD206 AND IL-4, AND DID NOT AFFECT MAJOR APOPTOTIC GENES IN THE BRAIN. COLLECTIVELY, THIS STUDY SUPPORTS ROBUST, EVOLUTIONARILY CONSERVED BEHAVIORAL AND PHYSIOLOGICAL EFFECTS OF KAVA AND KAVALACTONES IN ZEBRAFISH, IMPLICATES BRAIN MONOAMINES IN THEIR ACUTE EFFECTS, AND PROVIDES NOVEL IMPORTANT INSIGHTS INTO POTENTIAL ROLE OF NEUROGLIAL AND EPIGENETIC MECHANISMS IN LONG-TERM KAVA USE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
5  238  26 ADENOSINE KINASE: A KEY REGULATOR OF PURINERGIC PHYSIOLOGY. ADENOSINE (ADO) IS AN ESSENTIAL BIOMOLECULE FOR LIFE THAT PROVIDES CRITICAL REGULATION OF ENERGY UTILIZATION AND HOMEOSTASIS. ADENOSINE KINASE (ADK) IS AN EVOLUTIONARY ANCIENT RIBOKINASE DERIVED FROM BACTERIAL SUGAR KINASES THAT IS WIDELY EXPRESSED IN ALL FORMS OF LIFE, TISSUES AND ORGAN SYSTEMS THAT TIGHTLY REGULATES INTRACELLULAR AND EXTRACELLULAR ADO CONCENTRATIONS. THE FACILE ABILITY OF ADK TO ALTER ADO AVAILABILITY PROVIDES A "SITE AND EVENT" SPECIFICITY TO THE ENDOGENOUS PROTECTIVE EFFECTS OF ADO IN SITUATIONS OF CELLULAR STRESS. IN ADDITION TO MODULATING THE ABILITY OF ADO TO ACTIVATE ITS COGNATE RECEPTORS (P1 RECEPTORS), NUCLEAR ADK ISOFORM ACTIVITY HAS BEEN LINKED TO EPIGENETIC MECHANISMS BASED ON TRANSMETHYLATION PATHWAYS. PREVIOUS DRUG DISCOVERY RESEARCH HAS TARGETED ADK INHIBITION AS A THERAPEUTIC APPROACH TO MANAGE EPILEPSY, PAIN, AND INFLAMMATION. THESE EFFORTS GENERATED MULTIPLE CLASSES OF HIGHLY POTENT AND SELECTIVE INHIBITORS. HOWEVER, CLINICAL DEVELOPMENT OF EARLY ADK INHIBITORS WAS STOPPED DUE TO APPARENT MECHANISTIC TOXICITY AND THE LACK OF SUITABLE TRANSLATIONAL MARKERS. NEW INSIGHTS REGARDING THE POTENTIAL ROLE OF THE NUCLEAR ADK ISOFORM (ADK-LONG) IN THE EPIGENETIC MODULATION OF MALADAPTIVE DNA METHYLATION OFFERS THE POSSIBILITY OF IDENTIFYING NOVEL ADK-ISOFORM SELECTIVE INHIBITORS AND NEW INTERVENTIONAL STRATEGIES THAT ARE INDEPENDENT OF ADO RECEPTOR ACTIVATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6 3479  21 IDENTIFICATION OF BIOACTIVE METABOLITES AND EVALUATION OF IN VITRO ANTI-INFLAMMATORY AND IN VIVO ANTINOCICEPTIVE AND ANTIARTHRITIC ACTIVITIES OF ENDOPHYTE FUNGI ISOLATED FROM ELAEOCARPUS FLORIBUNDUS BLUME. ETHNOPHARMACOLOGICAL RELEVANCE: FUNCTIONAL DISABILITY ASSOCIATED WITH RHEUMATOID ARTHRITIS (RA), A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE IS A CHALLENGING CONCERN IN HEALTHCARE SYSTEMS. ALONG WITH ENVIRONMENTAL FACTORS AND EPIGENETIC DISORDERS, MULTIPLE PATHWAYS ARE REPORTED AS PROMINENT MECHANISM FOR THE PROGRESSION OF RA SYMPTOMS INCLUDING; PAIN, SWELLING AND STIFFNESS OF JOINTS. ELAEOCARPUS FLORIBUNDUS BLUME HAS BEEN USED AS A FOLKLORE MEDICINE FOR RA FROM ANCIENT TIMES. THIS PLANT HARBOURS A SUITE OF ENDOPHYTIC FUNGI THAT PRODUCE A RANGE OF METABOLITES OF POTENTIAL INTEREST. THUS, FOR THE ESTABLISHMENT OF A SCIENTIFIC BASIS FOR THIS FOLKLORE USE, IT IS ESSENTIAL TO FIND OUT THE INVOLVEMENT, IF ANY, OF THE ENDOPHYTIC FUNGI LIVING IN THIS PLANT AND THE METABOLITES THEY ELABORATE, FOR THE MANAGEMENT OF RA. AIM OF THE STUDY: THIS STUDY WAS DESIGNED TO ISOLATE, IDENTIFY AND EVALUATE THE IN VITRO ANTI-INFLAMMATORY AND IN VIVO ANTINOCICEPTIVE AND ANTIARTHRITIC ACTIVITIES OF THE COMPOUNDS PRODUCED BY THE ENDOPHYTIC FUNGI LIVING IN DIFFERENT PARTS OF ELAEOCARPUS FLORIBUNDUS BLUME. MATERIALS AND METHODS: ENDOPHYTIC FUNGI FROM DIFFERENT PARTS OF THE PLANT WERE ISOLATED AND CULTURED FOR THE PRODUCTION OF SECONDARY METABOLITES. CHROMATOGRAPHICALLY FRACTIONATED FUNGAL EXTRACTS WERE ASSESSED FOR ANTI-INFLAMMATORY AND ANTINOCICEPTIVE ACTIVITIES. FOR THE EVALUATION OF ANTI-INFLAMMATORY ACTIVITY, IN VITRO CYCLOOXYGENASE (COX1/COX2) AND 5-LIPOXYGENASE (5-LOX) INHIBITORY ASSAYS WERE PERFORMED. FOR THE EVALUATION OF IN VIVO ANTINOCICEPTIVE ACTIVITY, HOT PLATE ACETIC ACID INDUCED WRITHING, AND FORMALIN INDUCED PAW LICKING METHODS WERE ADOPTED, WHEREAS COMPLETE FREUND'S ADJUVANT (CFA) INDUCED POLY-ARTHRITIC METHOD WAS ADOPTED FOR THE EVALUATION OF ANTIARTHRITIC ACTIVITY. THE MOST EFFECTIVE FRACTION WAS ANALYZED BY LIQUID CHROMATOGRAPHY-MASS SPECTROSCOPY (LC-MS) IN SEARCH OF THE BIOACTIVE EXTRACELLULAR METABOLITES. RESULTS: FIVE ENDOPHYTIC FUNGI VIZ. ASPERGILLUS FUMIGATUS, ASPERGILLUS NIGER, RHIZOCTONIA ORYZAE, RHIZOPUS ORYZAE, AND SYNCEPHALASTRUM RACEMOSUM WERE ISOLATED. COX1/COX2 AND 5-LOX INHIBITORY ASSAYS STATE THAT THE ASPERGILLUS NIGER FRACTION POSSESSES THE GREATEST ACTIVITY AGAINST THESE ENZYMES OF INFLAMMATORY PROCESS. IN VIVO ANTINOCICEPTIVE SHOWED SIGNIFICANT (***P<0.001) REDUCTION OF PAIN IN A DOSE DEPENDENT MANNER. AS WELL, SIGNIFICANT (***P<0.001) REDUCTION OF PAW VOLUME WAS OBSERVED IN CFA INDUCE POLY-ARTHRITIC TEST. LC/MS ANALYSIS OF THE ASPERGILLUS NIGER FRACTION REVEALED THE PRESENCE OF BIOACTIVE COMPOUNDS INCLUDING TENSYUIC ACID, HEXYLITACONIC ACID, CHLOROGENIC ACID, NIGRAGILLIN, TMC-256C1, ASNIPYRONE B, ASPERENONE, FUMARIC ACID AND FUSARUBIN, ALL HAVING REPORTED PHARMACOLOGICAL ACTIVITIES. CONCLUSION: THE PRESENT STUDY DEMONSTRATES THAT SECONDARY METABOLITES PRODUCED BY ENDOPHYTIC FUNGI LIVING IN VARIOUS PARTS OF ELAEOCARPUS FLORIBUNDUS BLUME HAD POTENTIAL TO RELIEF PAIN AND INFLAMMATION. THE ENDOPHYTES WERE FOUND TO CONTAIN MULTIPLE BIOMOLECULES EFFECTIVE IN RHEUMATOID ARTHRITIS. THESE FINDINGS PROVIDE A RATIONALE FOR THE FOLKLORE USE OF THE PLANT IN THE MANAGEMENT OF RHEUMATOID ARTHRITIS.	2021	

7  760  21 CASZ1: CURRENT IMPLICATIONS IN CARDIOVASCULAR DISEASES AND CANCERS. CASTOR ZINC FINGER 1 (CASZ1) IS A C2H2 ZINC FINGER FAMILY PROTEIN THAT HAS TWO SPLICING VARIANTS, CASZ1A AND CASZ1B. IT IS INVOLVED IN MULTIPLE PHYSIOLOGICAL PROCESSES, SUCH AS TISSUE DIFFERENTIATION AND ALDOSTERONE ANTAGONISM. GENETIC AND EPIGENETIC ALTERNATIONS OF CASZ1 HAVE BEEN CHARACTERIZED IN MULTIPLE CARDIOVASCULAR DISORDERS, SUCH AS CONGENITAL HEART DISEASES, CHRONIC VENOUS DISEASES, AND HYPERTENSION. HOWEVER, LITTLE IS KNOWN ABOUT HOW CASZ1 MECHANICALLY PARTICIPATES IN THE PATHOGENESIS OF THESE DISEASES. OVER THE PAST DECADES, AT FIRST GLANCE, PARADOXICAL INFLUENCES ON CELL BEHAVIORS AND PROGRESSIONS OF DIFFERENT CANCER TYPES HAVE BEEN DISCOVERED FOR CASZ1, WHICH MAY BE EXPLAINED BY A "DOUBLE-AGENT" ROLE FOR CASZ1. IN THIS REVIEW, WE DISCUSS THE PHYSIOLOGICAL FUNCTION OF CASZ1, AND FOCUS ON THE ASSOCIATION OF CASZ1 ABERRATIONS WITH THE PATHOGENESIS OF CARDIOVASCULAR DISEASES AND CANCERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8 1679  19 DRUG RESISTANCE IN GIARDIA DUODENALIS. GIARDIA DUODENALIS IS A MICROAEROPHILIC PARASITE OF THE HUMAN GASTROINTESTINAL TRACT AND A MAJOR CONTRIBUTOR TO DIARRHEAL AND POST-INFECTIOUS CHRONIC GASTROINTESTINAL DISEASE WORLD-WIDE. TREATMENT OF G. DUODENALIS INFECTION CURRENTLY RELIES ON A SMALL NUMBER OF DRUG CLASSES. NITROHETEROCYCLICS, IN PARTICULAR METRONIDAZOLE, HAVE REPRESENTED THE FRONT LINE TREATMENT FOR THE LAST 40 YEARS. NITROHETEROCYCLIC-RESISTANT G. DUODENALIS HAVE BEEN ISOLATED FROM PATIENTS AND CREATED IN VITRO, PROMPTING CONSIDERABLE RESEARCH INTO THE BIOMOLECULAR MECHANISMS OF RESISTANCE. THESE COMPOUNDS ARE REDOX-ACTIVE AND ARE BELIEVED TO DAMAGE PROTEINS AND DNA AFTER BEING ACTIVATED BY OXIDOREDUCTASE ENZYMES IN METABOLICALLY ACTIVE CELLS. IN THIS REVIEW, WE EXPLORE THE MOLECULAR PHENOTYPES OF NITROHETEROCYCLIC-RESISTANT G. DUODENALIS DESCRIBED TO DATE IN THE CONTEXT OF THE PROTIST'S UNUSUAL GLYCOLYTIC AND ANTIOXIDANT SYSTEMS. WE PROPOSE THAT RESISTANCE MECHANISMS ARE LIKELY TO EXTEND WELL BEYOND CURRENTLY DESCRIBED RESISTANCE-ASSOCIATED ENZYMES (I.E., PYRUVATE FERREDOXIN OXIDOREDUCTASES AND NITROREDUCTASES), TO INCLUDE NAD(P)H- AND FLAVIN-GENERATING PATHWAYS, AND POSSIBLY REDOX-SENSITIVE EPIGENETIC REGULATION. MECHANISMS THAT ALLOW G. DUODENALIS TO TOLERATE OXIDATIVE STRESS MAY LEAD TO RESISTANCE AGAINST BOTH OXYGEN AND NITROHETEROCYCLICS, WITH IMPLICATIONS FOR CLINICAL CONTROL. THE PRESENT REVIEW HIGHLIGHTS THE POTENTIAL FOR SYSTEMS BIOLOGY TOOLS AND ADVANCED BIOINFORMATICS TO FURTHER INVESTIGATE THE MULTIFACETED MECHANISMS OF NITROHETEROCYCLIC RESISTANCE IN THIS IMPORTANT PATHOGEN.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  681  19 BRAIN LIPOTOXICITY OF PHYTANIC ACID AND VERY LONG-CHAIN FATTY ACIDS. HARMFUL CELLULAR/MITOCHONDRIAL ACTIVITIES IN REFSUM DISEASE AND X-LINKED ADRENOLEUKODYSTROPHY. IT IS INCREASINGLY UNDERSTOOD THAT IN THE AGING BRAIN, ESPECIALLY IN THE CASE OF PATIENTS SUFFERING FROM NEURODEGENERATIVE DISEASES, SOME FATTY ACIDS AT PATHOLOGICALLY HIGH CONCENTRATIONS EXERT DETRIMENTAL ACTIVITIES. TO STUDY SUCH ACTIVITIES, WE HERE ANALYZE GENETIC DISEASES, WHICH ARE DUE TO COMPROMISED METABOLISM OF SPECIFIC FATTY ACIDS, EITHER THE BRANCHED-CHAIN PHYTANIC ACID OR VERY LONG-CHAIN FATTY ACIDS (VLCFAS). MICROMOLAR CONCENTRATIONS OF PHYTANIC ACID OR OF VLCFAS DISTURB THE INTEGRITY OF NEURAL CELLS BY IMPAIRING CA(2+) HOMEOSTASIS, ENHANCING OXIDATIVE STRESS OR DE-ENERGIZING MITOCHONDRIA. FINALLY, THESE COMBINED HARMFUL ACTIVITIES ACCELERATE CELL DEATH. MITOCHONDRIA ARE MORE SEVERELY TARGETED BY PHYTANIC ACID THAN BY VLCFAS. THE INSERTION OF VLCFAS INTO THE INNER MEMBRANE DISTORTS THE ARRANGEMENT OF MEMBRANE CONSTITUENTS AND THEIR FUNCTIONAL INTERACTIONS. PHYTANIC ACID EXERTS SPECIFIC PROTONOPHORIC ACTIVITY, INDUCES REACTIVE OXYGEN SPECIES (ROS) GENERATION, AND REDUCES ATP GENERATION. A CLEAR INHIBITION OF THE NA(+), K(+)-ATPASE ACTIVITY BY PHYTANIC ACID HAS ALSO BEEN REPORTED. IN ADDITION TO THE INSTANTANEOUS EFFECTS, A CHRONIC EXPOSURE OF BRAIN CELLS TO LOW MICROMOLAR CONCENTRATIONS OF PHYTANIC ACID MAY PRODUCE NEURONAL DAMAGE IN REFSUM DISEASE BY ALTERING EPIGENETIC TRANSCRIPTIONAL REGULATION. MYELIN-PRODUCING OLIGODENDROCYTES RESPOND WITH PARTICULAR SENSITIVITY TO VLCFAS. DELETERIOUS ACTIVITY OF VLCFAS ON ENERGY-DEPENDENT MITOCHONDRIAL FUNCTIONS DECLINES WITH INCREASING THE HYDROCARBON CHAIN LENGTH (C22:0 > C24:0 > C26:0). IN CONTRAST, THE REVERSE SEQUENCE HOLDS TRUE FOR CELL DEATH INDUCTION BY VLCFAS (C22:0 < C24:0 < C26:0). IN ADRENOLEUKODYSTROPHY, THE UPTAKE OF VLCFAS BY PEROXISOMES IS IMPAIRED BY DEFECTS OF THE ABCD1 TRANSPORTER. STUDYING MITOCHONDRIA FROM ABCD1-DEFICIENT AND WILD-TYPE MICE PROVES THAT THE ENERGY-DEPENDENT FUNCTIONS ARE NOT ALTERED IN THE DISEASE MODEL. THUS, A DEFECTIVE ABCD1 APPARENTLY EXERTS NO OBVIOUS ADAPTIVE PRESSURE ON MITOCHONDRIA. FURTHER RESEARCH HAS TO ELUCIDATE THE DETAILED MECHANISTIC BASIS FOR THE FAILURES CAUSING FATTY ACID-MEDIATED NEURODEGENERATION AND SHOULD HELP TO PROVIDE POSSIBLE THERAPEUTIC INTERVENTIONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10  608  22 BEYOND HOMEOSTASIS: UNDERSTANDING THE IMPACT OF PSYCHOSOCIAL FACTORS ON APPETITE USING NONHUMAN PRIMATE MODELS. ANIMAL MODELS HAVE PROVEN TO BE EXCEPTIONALLY INFORMATIVE IN DEFINING NEUROPEPTIDE REGULATION OF APPETITE AND ENERGY HOMEOSTASIS (GAO AND HORVATH 2007, BERTHOUD 2012, WILLIAMS AND ELMQUIST 2012). MORE RECENT STUDIES USING A RANGE OF ANIMAL MODELS AND MOLECULAR TOOLS ARE ELUCIDATING HOW EPIGENETIC CHANGES RESULTING FROM SPECIFIC PRENATAL AND POSTNATAL DIETARY ENVIRONMENTS OR EXPERIENCES AFFECT METABOLIC PROCESSES AND APPETITE REGULATION (LEVIN 2008, ZAMBRANO AND NATHANIELSZ 2013, BURDGE AND LILLYCROP 2014). TAKEN TOGETHER, THESE APPROACHES ARE HELPING TO DEFINE POSSIBLE TREATMENT INTERVENTIONS FOR EATING DISORDERS IN PEOPLE (CASPER, SULLIVAN, AND TECOTT 2008, FOLTIN 2012, VAN GESTEL ET AL. 2014, LUTTER, CROGHAN, AND CUI 2016). THE CHOICE OF ANIMAL USED IS BEST DICTATED BY THE QUESTION BEING ADDRESSED. BECAUSE OF SIMILARITIES IN PHYSIOLOGY AND NEUROBIOLOGY, STUDIES OF CAPTIVE NONHUMAN PRIMATES HAVE BEGUN TO CONTRIBUTE SIGNIFICANTLY TO OUR UNDERSTANDING OF APPETITE REGULATION (SEE WILSON ET AL. 2014 FOR A REVIEW). IMPORTANTLY, THE USE OF NONHUMAN PRIMATE MODELS PROVIDES THE UNIQUE OPPORTUNITY TO EXTEND ANALYSES BEYOND A FOCUS ON THE HOMEOSTATIC REGULATION OF APPETITE. THIS IS PARTICULARLY RELEVANT GIVEN THE WELL-ESTABLISHED NOTION THAT A NUMBER OF PSYCHOSOCIAL FACTORS INFLUENCE FOOD INTAKE IN PEOPLE (BRUCE AND RICCIARDELLI 2015), INCLUDING CHRONIC STRESSOR EXPOSURE (TSENKOVA, BOYLAN, AND RYFF 2013), EVEN IN CHILDREN (NGUYEN-RODRIGUEZ, UNGER, AND SPRUIJT-METZ 2009). WHILE THE IMPORTANCE OF PSYCHOSOCIAL FACTORS CAN BE MODELED IN NONPRIMATE ANIMALS (TAMASHIRO, HEGEMAN, AND SAKAI 2006), SOCIALLY HOUSED NONHUMAN PRIMATES SHARE MANY CHARACTERISTICS IN ADDITION TO PHYSIOLOGY AND NEUROBIOLOGY, WITH HUMANS INCREASING THE TRANSLATIONAL VALUE OF THESE PRE-CLINICAL STUDIES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11 1016  13 CIITA EXPRESSION IS REGULATED BY HISTONE DEACETYLASE ENZYMES AND HAS A ROLE IN ALPHA-SYNUCLEIN PRE-FORMED FIBRIL-INDUCED ANTIGEN PRESENTATION IN MURINE MICROGLIAL CELL LINE. AIM: PARKINSON'S DISEASE (PD) IS A CHRONIC NEURODEGENERATIVE DISORDER RELATED WITH SEVERAL GENETIC AND EPIGENETIC FACTORS. IN THE CONTEXT OF EPIGENETIC FACTORS, HISTONE ACETYLATION IS ONE OF THE MOST ASSOCIATED MECHANISMS WITH PARKINSON'S DISEASE PROGRESSION. THIS STUDY INVESTIGATES THE EFFECTS OF THE INCREASED HISTONE ACETYLATION ON ANTIGEN PRESENTATION IN MICROGLIAL CELLS WHICH WERE INDUCED BY PRE-FORMED FIBRILS OF ALPHA-SYNUCLEIN (PFF ALPHA-SYNUCLEIN). METHODS: PARKINSON'S DISEASE MODEL WAS CREATED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION TO THE BV-2 MICROGLIAL CELLS. BV-2 CELLS WERE CO-TREATED WITH CUDC-907 AND TMP-195 TO INCREASE HISTONE ACETYLATION IN THE PRESENCE OF ALPHA-SYNUCLEIN. ANTIGEN REPRESENTATION WAS EVALUATED BY DETERMINING EXPRESSION LEVELS OF MAJOR HISTOCOMPATIBILITY COMPLEX-II (MHC-II) AND CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX (CIITA). RESULTS: OUR RESULTS SHOWED THAT PFF ALPHA-SYNUCLEIN SIGNIFICANTLY INCREASED MHC-II EXPRESSION, AND THAT EFFECT WAS MOST SEVERE AT 6 H OF ADMINISTRATION OF ALPHA-SYNUCLEIN. INCREASING HISTONE ACETYLATION VIA CUDC-907 AND TMP-195 ENHANCED MHC-II LEVELS EXPRESSION, WHICH WAS MORE SEVERE IN CUDC-907. ADDITIONALLY, CIITA EXPRESSION LEVELS WERE SIGNIFICANTLY INCREASED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION AND INTENSIFIED WITH THE CO-TREATMENT OF CUDC-907 AND TMP-195. FURTHERMORE, PFF ALPHA-SYNUCLEIN CAUSED A TIME-DEPENDENT INCREASE IN THE IFN-GAMMA (IFN-?) AND INTERLEUKIN-16(IL-16) LEVELS, AND THAT INCREASE WAS POTENTIATED WITH CUDC-907 AND TMP-195. CONCLUSION: CHANGES IN MHC-II AND CIITA EXPRESSION INDICATE THAT HISTONE ACETYLATION INCREASES THE ANTIGEN PRESENTATION PROPERTIES OF MICROGLIAL CELLS AFTER PFF ALPHA-SYNUCLEIN OR HISTONE DEACETYLASE INHIBITOR (HDACI) ADMINISTRATION. OUR RESULTS SHOW THAT MICROGLIAL ANTIGEN PRESENTATION MIGHT HAVE AN ESSENTIAL ROLE IN THE PATHOLOGY OF PARKINSON'S DISEASE, AND ALPHA-SYNUCLEIN LIKELY TO PLAY A PRIMARY ROLE IN THIS MECHANISM.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12 2640  14 EPIGENOMIC AND TRANSCRIPTIONAL PROFILING IDENTIFIES IMPAIRED GLYOXYLATE DETOXIFICATION IN NAFLD AS A RISK FACTOR FOR HYPEROXALURIA. EPIGENETIC MODIFICATIONS (E.G. DNA METHYLATION) IN NAFLD AND THEIR CONTRIBUTION TO DISEASE PROGRESSION AND EXTRAHEPATIC COMPLICATIONS ARE POORLY EXPLORED. HERE, WE USE AN INTEGRATED EPIGENOME AND TRANSCRIPTOME ANALYSIS OF MOUSE NAFLD HEPATOCYTES AND IDENTIFY ALTERATIONS IN GLYOXYLATE METABOLISM, A PATHWAY RELEVANT IN KIDNEY DAMAGE VIA OXALATE RELEASE-A HARMFUL WASTE PRODUCT AND KIDNEY STONE-PROMOTING FACTOR. DOWNREGULATION AND HYPERMETHYLATION OF ALANINE-GLYOXYLATE AMINOTRANSFERASE (AGXT), WHICH DETOXIFIES GLYOXYLATE, PREVENTING EXCESSIVE OXALATE ACCUMULATION, IS ACCOMPANIED BY INCREASED OXALATE FORMATION AFTER METABOLISM OF THE PRECURSOR HYDROXYPROLINE. VIRAL-MEDIATED AGXT TRANSFER OR INHIBITING HYDROXYPROLINE CATABOLISM RESCUES EXCESSIVE OXALATE RELEASE. IN HUMAN STEATOTIC HEPATOCYTES, AGXT IS ALSO DOWNREGULATED AND HYPERMETHYLATED, AND IN NAFLD ADOLESCENTS, STEATOSIS SEVERITY CORRELATES WITH URINARY OXALATE EXCRETION. THUS, THIS WORK IDENTIFIES A REDUCED CAPACITY OF THE STEATOTIC LIVER TO DETOXIFY GLYOXYLATE, TRIGGERING ELEVATED OXALATE, AND PROVIDES A MECHANISTIC EXPLANATION FOR THE INCREASED RISK OF KIDNEY STONES AND CHRONIC KIDNEY DISEASE IN NAFLD PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13 1951  22 EPIGENETIC ACTIVATION OF THE TUSC3 GENE AS A POTENTIAL THERAPY FOR XMEN DISEASE. BACKGROUND: X-LINKED MAGT1 DEFICIENCY WITH INCREASED SUSCEPTIBILITY TO EPSTEIN-BARR VIRUS INFECTION AND N-LINKED GLYCOSYLATION DEFECT (XMEN) DISEASE IS A RARE COMBINED IMMUNODEFICIENCY CAUSED BY LOSS-OF-FUNCTION MUTATIONS IN THE MAGNESIUM TRANSPORTER 1 (MAGT1) GENE. MAGT1 DEFICIENCY IMPAIRS MAGNESIUM TRANSPORT AND THE N-LINKED GLYCOSYLATION OF A PANEL OF PROTEINS, WHICH SUBSEQUENTLY ABOLISHES THE EXPRESSION OF KEY IMMUNE RECEPTORS SUCH AS NATURAL KILLER GROUP 2, MEMBER D (AKA NKG2D). THESE EFFECTS INDUCE IMMUNE SYSTEM ABNORMALITIES, CHRONIC EPSTEIN-BARR VIRUS INFECTION, AND NEOPLASIA. RECENT RESEARCH SHOWS THAT MAGT1 AND TUMOR CANDIDATE SUPPRESSOR 3 (TUSC3) SHARE HIGH SEQUENCE AND FUNCTIONAL SIMILARITY. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE FEASIBILITY OF ACTIVATING TUSC3 EXPRESSION TO PROVIDE A POTENTIAL THERAPEUTIC STRATEGY FOR XMEN DISEASE. METHODS: THE EXPRESSION PROFILES OF MAGT1 AND TUSC3 WERE ANALYZED USING MULTIPLE DATABASES, REAL-TIME QUANTITATIVE PCR, AND WESTERN BLOT. THE EFFECTS OF DECITABINE AND PANOBINOSTAT ON THE REGULATION OF TUSC3 EXPRESSION WERE EXPLORED IN BOTH MAGT1 KNOCKOUT (KO)/PATIENT-DERIVED LYMPHOCYTES AND MAGT1 KO HEPATOCYTES. RESULTS: ALTHOUGH TUSC3 IS WIDELY EXPRESSED, IT IS UNDETECTABLE SPECIFICALLY IN THE IMMUNE SYSTEM AND LIVER, CONSISTENT WITH THE MAIN DISEASED TISSUES IN PATIENTS WITH XMEN DISEASE. CRISPR/CAS9-MEDIATED KO OF MAGT1 IN THE NKL CELL LINE SUCCESSFULLY MIMICKED THE PHENOTYPES OF XMEN PATIENT-DERIVED LYMPHOCYTES, AND EXOGENOUS EXPRESSION OF TUSC3 RESCUED THE DEFICIENCIES IN KO NKL CELLS. USING THIS IN VITRO MODEL, WE IDENTIFIED 2 EPIGENETIC DRUGS, DECITABINE AND PANOBINOSTAT, BY SCREENING. COMBINATION TREATMENT USING THESE 2 DRUGS SIGNIFICANTLY UPREGULATED TUSC3 EXPRESSION AND RESCUED THE IMMUNE AND LIVER ABNORMALITIES. CONCLUSIONS: EPIGENETIC ACTIVATION OF TUSC3 EXPRESSION CONSTITUTES AN EFFECTIVE THERAPEUTIC STRATEGY FOR XMEN DISEASE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14 2080  18 EPIGENETIC DNA METHYLATION OF EBI3 MODULATES HUMAN INTERLEUKIN-35 FORMATION VIA NFKB SIGNALING: A PROMISING THERAPEUTIC OPTION IN ULCERATIVE COLITIS. ULCERATIVE COLITIS (UC), A SEVERE CHRONIC DISEASE WITH UNCLEAR ETIOLOGY THAT IS ASSOCIATED WITH INCREASED RISK FOR COLORECTAL CANCER, IS ACCOMPANIED BY DYSREGULATION OF CYTOKINES. EPSTEIN-BARR VIRUS-INDUCED GENE 3 (EBI3) ENCODES A SUBUNIT IN THE UNIQUE HETERODIMERIC IL-12 CYTOKINE FAMILY OF EITHER PRO- OR ANTI-INFLAMMATORY FUNCTION. AFTER HAVING RECENTLY DEMONSTRATED THAT UPREGULATION OF EBI3 BY HISTONE ACETYLATION ALLEVIATES DISEASE SYMPTOMS IN A DEXTRAN SULFATE SODIUM (DSS)-TREATED MOUSE MODEL OF CHRONIC COLITIS, WE NOW AIMED TO EXAMINE A POSSIBLE FURTHER EPIGENETIC REGULATION OF EBI3 BY DNA METHYLATION UNDER INFLAMMATORY CONDITIONS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR (DNMTI) DECITABINE (DAC) AND TNFALPHA LED TO SYNERGISTIC UPREGULATION OF EBI3 IN HUMAN COLON EPITHELIAL CELLS (HCEC). USE OF DIFFERENT SIGNALING PATHWAY INHIBITORS INDICATED NFKAPPAB SIGNALING WAS NECESSARY AND PROPORTIONAL TO THE SYNERGISTIC EBI3 INDUCTION. MALDI-TOF/MS AND HPLC-ESI-MS/MS ANALYSIS OF DAC/TNFALPHA-TREATED HCEC IDENTIFIED IL-12P35 AS THE MOST PROBABLE BINDING PARTNER TO FORM A FUNCTIONAL PROTEIN. EBI3/IL-12P35 HETERODIMERS (IL-35) INDUCE THEIR OWN GENE UPREGULATION, SOMETHING THAT WAS INDEED OBSERVED IN HCEC CULTURED WITH MEDIA FROM PREVIOUSLY DAC/TNFALPHA-TREATED HCEC. THESE RESULTS SUGGEST THAT UNDER INFLAMMATORY AND DEMETHYLATING CONDITIONS THE UPREGULATION OF EBI3 RESULTS IN THE FORMATION OF ANTI-INFLAMMATORY IL-35, WHICH MIGHT BE CONSIDERED AS A THERAPEUTIC TARGET IN COLITIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15 5511  18 RIBONUCLEASES IN TUMOR GROWTH. THIS REVIEW SUMMARIZES DATA ON AMBIGUOUS BIOLOGICAL FUNCTIONS OF RIBONUCLEASES (RNASES) AT TUMOR GROWTH. IN SOME CASES THE RAISED LEVEL OF ENZYME ACTIVITY IN BIOLOGICAL FLUIDS CAN BE REGARDED AS AN ADDITIONAL MARKER OF MALIGNANT GROWTH (PANCREAS CANCER, CHRONIC MYELOID LEUKEMIA, ETC.). AT THE SAME TIME THE ACTIVITY OF RNASES IS OFTEN LOWERED IN TUMOR TISSUE. HIGH SUBSTRATE SPECIFICITY OF PARTICULAR RNASES PROVIDES METABOLIC BALANCE BETWEEN VARIOUS KINDS OF RNAS WITH VARIOUS HALF-TIME EXCHANGE TURN. RNASES ARE THE IMPORTANT FACTORS OF EPIGENETIC REGULATION OF GENE ACTIVITY IN CELLS. THE ACTIVITY OF RNASES IS ADJUSTABLE BY INHIBITORS AND OTHER FACTORS, AND DEFINES TIME OF EXISTENCE OF DIFFERENT KINDS OF RNAS. RNASES (THE MODIFIED VARIANTS OF RNASE A, RNASES OF SEMEN FLUID OF THE CATTLE, RNASE OF AMPHIBIA OOCYTES) CAN BE USED AS ANTI-TUMOR THERAPEUTIC AGENTS. ON THE OTHER HAND, SOME INHIBITORS OF RNASES OF NATURAL OR SYNTHETIC ORIGIN WERE DEMONSTRATED TO BE PERSPECTIVE DRUGS THAT INHIBIT TUMOR GROWTH.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16 2819  16 FILARIAL AND WOLBACHIA GENOMICS. FILARIAL NEMATODE PARASITES, THE CAUSATIVE AGENTS FOR A SPECTRUM OF ACUTE AND CHRONIC DISEASES INCLUDING LYMPHATIC FILARIASIS AND RIVER BLINDNESS, THREATEN THE WELL-BEING AND LIVELIHOOD OF HUNDREDS OF MILLIONS OF PEOPLE IN THE DEVELOPING REGIONS OF THE WORLD. THE 2007 PUBLICATION ON A DRAFT ASSEMBLY OF THE 95-MB GENOME OF THE HUMAN FILARIAL PARASITE BRUGIA MALAYI- REPRESENTING THE FIRST HELMINTH PARASITE GENOME TO BE SEQUENCED - HAS BEEN FOLLOWED IN RAPID SUCCESSION BY PROJECTS THAT HAVE RESULTED IN THE GENOME SEQUENCING OF SIX ADDITIONAL FILARIAL SPECIES, SEVEN NONFILARIAL NEMATODE PARASITES OF ANIMALS AND NEARLY 30 PLANT PARASITIC AND FREE-LIVING SPECIES. PARALLEL TO THE GENOMIC SEQUENCING, TRANSCRIPTOMIC AND PROTEOMIC PROJECTS HAVE FACILITATED GENOME ANNOTATION, EXPANDED OUR UNDERSTANDING OF STAGE-ASSOCIATED GENE EXPRESSION AND PROVIDED A FIRST LOOK AT THE ROLE OF EPIGENETIC REGULATION OF FILARIAL GENOMES THROUGH MICRORNAS. THE EXPANSION IN FILARIAL GENOMICS WILL ALSO PROVIDE A SIGNIFICANT ENRICHMENT IN OUR KNOWLEDGE OF THE DIVERSITY AND VARIABILITY IN THE GENOMES OF THE ENDOSYMBIOTIC BACTERIUM WOLBACHIA LEADING TO A BETTER UNDERSTANDING OF THE GENETIC PRINCIPLES THAT GOVERN FILARIAL-WOLBACHIA MUTUALISM. THE GOAL HERE IS TO PROVIDE AN OVERVIEW OF THE TRENDS AND ADVANCES IN FILARIAL AND WOLBACHIA GENOMICS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17  216  16 ACUTE BETA-ADRENERGIC ACTIVATION TRIGGERS NUCLEAR IMPORT OF HISTONE DEACETYLASE 5 AND DELAYS G(Q)-INDUCED TRANSCRIPTIONAL ACTIVATION. DURING HEMODYNAMIC STRESS, CATECHOLAMINES AND NEUROHUMORAL STIMULI MAY INDUCE CO-ACTIVATION OF G(Q)-COUPLED RECEPTORS AND BETA-ADRENERGIC RECEPTORS (BETA-AR), LEADING TO CARDIAC REMODELING. DYNAMIC REGULATION OF HISTONE DEACETYLASE 5 (HDAC5), A TRANSCRIPTIONAL REPRESSOR, IS CRUCIAL DURING STRESS SIGNALING DUE TO ITS ROLE IN EPIGENETIC CONTROL OF FETAL GENE MARKERS. LITTLE IS KNOWN ABOUT ITS REGULATION DURING ACUTE AND CHRONIC BETA-AR STIMULATION AND ITS CROSS-INTERACTION WITH G(Q) SIGNALING IN ADULT CARDIAC MYOCYTES. HERE, WE EVALUATE THE POTENTIAL CROSS-TALK BETWEEN G(Q)-DRIVEN AND BETA-AR MEDIATED SIGNALING AT THE LEVEL OF NUCLEOCYTOPLASMIC SHUTTLING OF HDAC5. WE SHOW THE TRANSLOCATION OF GFP-TAGGED WILD TYPE HDAC5 OR MUTANTS (S279A AND S279D) IN RESPONSE TO BETA-AR OR G(Q) AGONISTS. ISOPROTERENOL (ISO) OR PKA ACTIVATION RESULTS IN STRONG NUCLEAR ACCUMULATION OF HDAC5 IN CONTRAST TO NUCLEAR EXPORT DRIVEN BY CA(2+)-CALMODULIN PROTEIN KINASE II AND PROTEIN KINASE D. MOREOVER, NUCLEAR ACCUMULATION OF HDAC5 UNDER ACUTE ISO/PKA SIGNALING IS DEPENDENT ON PHOSPHORYLATION OF SER-279 AND CAN BLOCK SUBSEQUENT G(Q)-MEDIATED NUCLEAR HDAC5 EXPORT. INTRIGUINGLY, THE ATTENUATION OF G(Q)-INDUCED EXPORT IS ABOLISHED AFTER CHRONIC PKA ACTIVATION, YET NUCLEAR HDAC5 REMAINS ELEVATED. LAST, THE EFFECT OF CHRONIC BETA-AR SIGNALING ON HDAC5 TRANSLOCATION WAS EXAMINED IN ADULT MYOCYTES FROM A RABBIT MODEL OF HEART FAILURE, WHERE ISO-INDUCED NUCLEAR IMPORT IS ABLATED, BUT G(Q)-AGONIST MEDIATED EXPORT IS PRESERVED. ACUTE BETA-AR/PKA ACTIVATION PROTECTS AGAINST HYPERTROPHIC SIGNALING BY DELAYING G(Q)-MEDIATED TRANSCRIPTIONAL ACTIVATION. THIS SERVES AS A KEY PHYSIOLOGICAL CONTROL SWITCH BEFORE ALLOWING GENETIC REPROGRAMMING VIA HDAC5 NUCLEAR EXPORT DURING MORE SEVERE STRESS, SUCH AS HEART FAILURE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18 1217  13 CREG PROTECTS FROM MYOCARDIAL ISCHEMIA/REPERFUSION INJURY BY REGULATING MYOCARDIAL AUTOPHAGY AND APOPTOSIS. AIMS: HUMAN CELLULAR REPRESSOR OF E1A-STIMULATED GENES (CREG) IS A SECRETED GLYCOPROTEIN THAT REGULATES TISSUE AND CELL HOMEOSTASIS AND HAS BEEN SHOWN TO ANTAGONIZE HEART FIBROSIS, WHICH INDICATES A POTENTIAL PROTECTIVE EFFECT OF CREG AGAINST CARDIOMYOCYTE CHRONIC DAMAGE. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLE OF CREG IN MYOCARDIAL TISSUE ACUTE INJURY, IN THIS STUDY, WE AIMED TO INVESTIGATE THE ROLE OF CREG IN MYOCARDIAL ISCHEMIA/REPERFUSION (MI/R) INJURY AND CLARIFY THE MECHANISM OF ACTION. METHODS AND RESULTS: WILD-TYPE CREG (CREG(+/+)), HETEROZYGOUS CREG (CREG(+/-)) MICE AND MICE PRETREATED WITH INFUSION OF RECOMBINANT 0.3MG/KG.D CREG PROTEIN (RECREG(+/+)) WERE SUBJECTED TO 30MIN OF LEFT ASCENDING CORONARY ISCHEMIA AND 24H OF REPERFUSION. EVAN'S BLUE-TRIPHENYL- TETRAZOLIUM CHLORIDE (TTC) SOLUTION AND ECHOCARDIOGRAPHY ANALYSIS WERE USED TO EVALUATE THE EFFECTS OF CREG ON MI/R MICE. THE UNDERLYING MECHANISMS WERE FURTHER DETERMINED BY CULTURED MYOCARDIAL CELLS IN VITRO. OUR FINDINGS REVEALED THAT THE LEVEL OF CREG PROTEIN IN MOUSE HEARTS WAS SIGNIFICANTLY DECREASED AFTER MICE WERE SUBJECTED TO MI/R. MOREOVER, CREG(+/-) MICE HAD LARGER INFARCTION SIZE 2H AFTER REPERFUSION AND WORSE CARDIAC FUNCTION 28DAYS AFTER MI/R INJURY COMPARED TO THAT IN CREG(+/+) MICE. HOWEVER, RECREG(+/+) MICE COULD MAINTAIN CREG AT A HIGH LEVEL EVEN AFTER MI/R INJURY, AND MITIGATED INFARCTION SIZE AND IMPROVED CARDIAC FUNCTION SIGNIFICANTLY. IN CREG(+/-) MICE, MYOCARDIAL AUTOPHAGY WAS DYSFUNCTIONAL CHARACTERIZED BY ACCUMULATION OF LC3A AND P62, WHILE APOPTOTIC CELL NUMBER INCREASE WAS DETECTED BY CLEAVED CASPASE-3 BLOTTING AND TUNEL STAINING. CONVERSELY, DECREASED APOPTOSIS AND ACTIVATED AUTOPHAGY WERE DETECTED IN RECREG(+/+) MICE. FURTHERMORE, CHLOROQUINE, A KIND OF AUTOPHAGY BLOCKER, WAS USED TO DEMONSTRATE RECOMBINANT CREG PROTECTED CARDIOMYOCYTES AGAINST APOPTOSIS MEDIATED BY ACTIVATING AUTOPHAGY BOTH IN VIVO AND IN VITRO. FINALLY, WE FOUND CREG WAS INVOLVED INTO LYSOSOMAL PROTEIN TRANSFER AND IMPROVE CELLULAR AUTOPHAGY. CONCLUSION: CREG PROTECTS HEART AGAINST MI/R INJURY-INDUCED CARDIOMYOCYTES APOPTOSIS BY ACTIVATING LYSOSOMAL AUTOPHAGY. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: GENETIC AND EPIGENETIC CONTROL OF HEART FAILURE - EDITED BY JUN REN AND MEGAN YINGMEI ZHANG.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19 1421  16 DIFFERENTIAL BRAIN ADRA2A AND ADRA2C GENE EXPRESSION AND EPIGENETIC REGULATION IN SCHIZOPHRENIA. EFFECT OF ANTIPSYCHOTIC DRUG TREATMENT. POSTSYNAPTIC ALPHA(2A)-ADRENOCEPTOR DENSITY IS ENHANCED IN THE DORSOLATERAL PREFRONTAL CORTEX (DLPFC) OF ANTIPSYCHOTIC-TREATED SCHIZOPHRENIA SUBJECTS. THIS ALTERATION MIGHT BE DUE TO TRANSCRIPTIONAL ACTIVATION, AND COULD BE REGULATED BY EPIGENETIC MECHANISMS SUCH AS HISTONE POSTTRANSLATIONAL MODIFICATIONS (PTMS). THE AIM OF THIS STUDY WAS TO EVALUATE ADRA2A AND ADRA2C GENE EXPRESSION (CODIFYING FOR ALPHA(2)-ADRENOCEPTOR SUBTYPES), AND PERMISSIVE AND REPRESSIVE HISTONE PTMS AT GENE PROMOTER REGIONS IN THE DLPFC OF SUBJECTS WITH SCHIZOPHRENIA AND MATCHED CONTROLS (N = 24 PAIRS). WE STUDIED THE EFFECT OF ANTIPSYCHOTIC (AP) TREATMENT IN AP-FREE (N = 12) AND AP-TREATED (N = 12) SUBGROUPS OF SCHIZOPHRENIA SUBJECTS AND IN RATS ACUTELY AND CHRONICALLY TREATED WITH TYPICAL AND ATYPICAL ANTIPSYCHOTICS. ADRA2A MRNA EXPRESSION WAS SELECTIVELY UPREGULATED IN AP-TREATED SCHIZOPHRENIA SUBJECTS (+93%) WHEREAS ADRA2C MRNA EXPRESSION WAS UPREGULATED IN ALL SCHIZOPHRENIA SUBJECTS (+53%) REGARDLESS OF ANTIPSYCHOTIC TREATMENT. ACUTE AND CHRONIC CLOZAPINE TREATMENT IN RATS DID NOT ALTER BRAIN CORTEX ADRA2A MRNA EXPRESSION BUT INCREASED ADRA2C MRNA EXPRESSION. BOTH ADRA2A AND ADRA2C PROMOTER REGIONS SHOWED EPIGENETIC MODIFICATION BY HISTONE METHYLATION AND ACETYLATION IN HUMAN DLPFC. THE UPREGULATION OF ADRA2A EXPRESSION IN AP-TREATED SCHIZOPHRENIA SUBJECTS MIGHT BE RELATED TO OBSERVED BIVALENT CHROMATIN AT ADRA2A PROMOTER REGION IN SCHIZOPHRENIA (DEPICTED BY INCREASED PERMISSIVE H3K4ME3 AND REPRESSIVE H3K27ME3) AND COULD BE TRIGGERED BY THE ENHANCED H4K16AC AT ADRA2A PROMOTER. IN CONCLUSION, EPIGENETIC PREDISPOSITION DIFFERENTIALLY MODULATED ADRA2A AND ADRA2C MRNA EXPRESSION IN DLPFC OF SCHIZOPHRENIA SUBJECTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
20 5353  20 RE-EVALUATION OF POLIHEXANIDE USE IN WOUND ANTISEPSIS IN ORDER TO CLARIFY AMBIGUITIES OF TWO ANIMAL STUDIES. OBJECTIVE: DUE TO CLASSIFICATION OF THE AGENT POLIHEXANIDE (PHMB) IN CATEGORY 2 'MAY CAUSE CANCER' BY THE COMMITTEE FOR RISK ASSESSMENT OF THE EUROPEAN CHEMICALS AGENCY IN 2011, THE USERS OF WOUND ANTISEPTICS MAY BE HIGHLY CONFUSED. IN 2017, THIS STATEMENT WAS UPDATED, DEFINING PHMB UP TO 0.1% AS A PRESERVATIVE SAFE IN ALL COSMETIC PRODUCTS. IN THE INTEREST OF PATIENT SAFETY, A SCIENTIFIC CLARIFICATION OF THE POTENTIAL CARCINOGENICITY OF PHMB IS NECESSARY. METHODS: A MULTIDISCIPLINARY TEAM (MDT) OF MICROBIOLOGISTS, SURGEONS, DERMATOLOGISTS AND BIOCHEMISTS CONDUCTED A BENEFIT-RISK ASSESSMENT TO CLARIFY THE HAZARD OF ANTISEPTIC USE OF PHMB. RESULTS: IN TWO ANIMAL STUDIES, FROM WHICH THE ASSESSMENT OF A CARCINOGENIC RISK WAS DERIVED, PHMB WAS ADMINISTERED ORALLY OVER TWO YEARS IN EXTREMELY HIGH CONCENTRATIONS FAR ABOVE THE NO(A)EL (NO-OBSERVED-(ADVERSE-) EFFECT LEVEL) IN RATS AND MICE. FEEDING IN THE NO(A)EL RANGE RESULTED IN NO ABNORMAL EFFECTS. IN ONE MALE IN THE HIGHEST DOSE GROUP OF 4000PPM PHMB, AN ADENOCARCINOMA WAS FOUND, WHICH THE AUTHOR ATTRIBUTED TO CHRONIC INFLAMMATION OF THE COLON WITH SYSTEMIC ATYPICAL EXPOSURE. THE INCREASING INCIDENCE OF HEMANGIOSARCOMAS HIGHLY PROBABLY RESULTED FROM INCREASED ENDOTHELIAL PROLIFERATION, TRIGGERED BY THE EXCEEDINGLY HIGH DOSAGE FED, BECAUSE PHMB IS NOT GENOTOXIC AND THERE IS NO EVIDENCE FOR EPIGENETIC EFFECTS. DISCUSSION: IT IS WELL KNOWN THAT PHMB IS NOT ABSORBED WHEN APPLIED TOPICALLY. CONSIDERING THE ABSENCE OF GENOTOXICITY AND EPIGENETIC EFFECTS TOGETHER WITH THE INTERPRETATION OF THE ANIMAL STUDIES, IT IS THE CONSENSUS OF THE MULTIDISCIPLINARY EXPERTS THAT A CARCINOGENIC RISK FROM PHMB-USE FOR WOUND ANTISEPSIS CAN BE RULED OUT. CONCLUSION: ON THIS BASIS AND CONSIDERING THEIR EFFECTIVENESS, TOLERABILITY AND CLINICAL EVIDENCE, THE INDICATIONS FOR PHMB BASED WOUND ANTISEPTICS ARE JUSTIFIED.	2019