1 2754 110 EXPRESSION OF CAVEOLIN 1 IS ENHANCED BY DNA DEMETHYLATION DURING ADIPOCYTE DIFFERENTIATION. STATUS OF INSULIN SIGNALING. CAVEOLIN 1 (CAV-1) IS AN ESSENTIAL CONSTITUENT OF ADIPOCYTE CAVEOLAE WHICH BINDS THE BETA SUBUNIT OF THE INSULIN RECEPTOR (IR) AND IS IMPLICATED IN THE REGULATION OF INSULIN SIGNALING. WE HAVE FOUND THAT, DURING ADIPOCYTE DIFFERENTIATION OF 3T3-L1 CELLS THE PROMOTER, EXON 1 AND FIRST INTRON OF THE CAV-1 GENE UNDERGO A DEMETHYLATION PROCESS THAT IS ACCOMPANIED BY A STRONG INDUCTION OF CAV-1 EXPRESSION, INDICATING THAT EPIGENETIC MECHANISMS MUST HAVE A PIVOTAL ROLE IN THIS DIFFERENTIATION PROCESS. FURTHERMORE, IR, PKB-AKT AND GLUT-4 EXPRESSION ARE ALSO INCREASED DURING THE DIFFERENTIATION PROCESS SUGGESTING A COORDINATED REGULATION WITH CAV-1. ACTIVATION OF CAV-1 PROTEIN BY PHOSPHORYLATION ARISES DURING THE DIFFERENTIATION PROCESS, YET IN FULLY MATURE ADIPOCYTES INSULIN IS NO LONGER ABLE TO SIGNIFICANTLY INCREASE CAV-1 PHOSPHORYLATION. HOWEVER, THESE LONG-TERM DIFFERENTIATED CELLS ARE STILL ABLE TO RESPOND ADEQUATELY TO INSULIN, INCREASING IR AND PKB-AKT PHOSPHORYLATION AND GLUCOSE UPTAKE. THE ACTIVATION OF CAV-1 DURING THE ADIPOCYTE DIFFERENTIATION PROCESS COULD FACILITATE THE MAINTENANCE OF INSULIN SENSITIVITY BY THESE FULLY MATURE ADIPOCYTES ISOLATED FROM ADDITIONAL EXTERNAL STIMULI. HOWEVER, UNDER THE INFLUENCE OF PHYSIOLOGICAL CONDITIONS ASSOCIATED TO OBESITY, SUCH AS CHRONIC INFLAMMATION AND HYPOXIA, INSULIN SENSITIVITY WOULD FINALLY BE COMPROMISED. 2014 2 4482 24 MOLECULAR REGULATION AND CLINICAL SIGNIFICANCE OF CAVEOLIN-1 METHYLATION IN CHRONIC LUNG DISEASES. CHRONIC LUNG DISEASES REPRESENT A LARGELY GLOBAL BURDEN WHOSE PATHOGENESIS REMAINS LARGELY UNKNOWN. RESEARCH INCREASINGLY SUGGESTS THAT EPIGENETIC MODIFICATIONS, ESPECIALLY DNA METHYLATION, PLAY A MECHANISTIC ROLE IN CHRONIC LUNG DISEASES. DNA METHYLATION CAN AFFECT GENE EXPRESSION AND INDUCE VARIOUS DISEASES. OF THE CAVEOLAE IN PLASMA MEMBRANE OF CELL, CAVEOLIN-1 (CAV-1) IS A CRUCIAL STRUCTURAL CONSTITUENT INVOLVED IN MANY IMPORTANT LIFE ACTIVITIES. WITH THE INCREASINGLY ADVANCED PROGRESS OF GENOME-WIDE METHYLATION SEQUENCING TECHNOLOGIES, THE IMPORTANT IMPACT OF CAV-1 DNA METHYLATION HAS BEEN DISCOVERED. THE PRESENT REVIEW OVERVIEWS THE BIOLOGICAL CHARACTERS, FUNCTIONS, AND STRUCTURE OF CAV-1; EPIGENETIC MODIFICATIONS OF CAV-1 IN HEALTH AND DISEASE; EXPRESSION AND REGULATION OF CAV-1 DNA METHYLATION IN THE RESPIRATORY SYSTEM AND ITS SIGNIFICANCE; AS WELL AS CLINICAL POTENTIAL AS DISEASE-SPECIFIC BIOMARKER AND TARGETS FOR EARLY DIAGNOSIS AND THERAPY. 2020 3 4170 17 MEETING REPORT: ISN FOREFRONTS IN NEPHROLOGY ON ENDOTHELIAL BIOLOGY AND RENAL DISEASE: FROM BENCH TO PREVENTION. THIS ISN-SPONSORED FOREFRONT IN NEPHROLOGY MEETING, WHICH HAS BROUGHT TOGETHER 120 SCIENTISTS FROM 21 COUNTRIES, HAS BEEN CONCERNED WITH VARIOUS ASPECTS OF ENDOTHELIAL FUNCTION AND DYSFUNCTION AND THEIR CONTRIBUTION TO PROGRESSION OF CHRONIC KIDNEY DISEASE AND/OR ITS CARDIOVASCULAR COMPLICATIONS. THE FOLLOWING THEMES WERE DISCUSSED IN GREAT DEPTH: (1) PHENOTYPICAL CHANGES IN THE VASCULAR ENDOTHELIUM - PERMEABILITY, SENESCENCE, AND APOPTOSIS; (2) REGULATION OF ENDOTHELIAL NITRIC OXIDE (NO) SYNTHASE FUNCTION - CAVEOLAR AND SHEAR STRESS MECHANISMS, EPIGENETIC REGULATION, S-NITROSYLATION, AND RHO-KINASE REGULATION; (3) OXIDATIVE STRESS AND HYPOXIA-INDUCED CHANGES; (4) ORGANELLAR DYSFUNCTION - LYSOSOMES, MITOCHONDRIA, AND ENDOPLASMIC RETICULUM; (5) NO-INDEPENDENT MECHANISMS OF VASOMOTION - EPOXIDES, HEME OXYGENASE-1 AND CARBON MONOXIDE, THROMBOXANE, TUMOR NECROSIS FACTOR-ALPHA, AND URIC ACID; (6) ENDOTHELIAL CROSSTALK WITH PODOCYTES, MONOCYTES, SMOOTH MUSCLE CELLS, AND PLATELETS; (7) CANDIDATE CLINICAL BIOMARKERS OF ENDOTHELIAL DYSFUNCTION - FUNCTIONAL TESTING OF MACRO- AND MICRO-VASCULAR FUNCTIONS, SURROGATE MARKERS, CIRCULATING DETACHED ENDOTHELIAL CELLS, AND ENDOTHELIAL PRECURSOR CELLS; AND CULMINATED IN ROUND TABLE DISCUSSION ON THE DIAGNOSIS OF ENDOTHELIAL DYSFUNCTION AND ITS TREATMENT OPTIONS. IN CONCLUSION, THIS MEETING HAS FOCUSED ON SEVERAL KEY PROBLEMS OF ENDOTHELIAL CELL PATHOBIOLOGY RELEVANT TO CHRONIC KIDNEY DISEASE. 2006 4 5332 38 PYRUVATE DEHYDROGENASE KINASE 1 AND 2 DEFICIENCY REDUCES HIGH-FAT DIET-INDUCED HYPERTROPHIC OBESITY AND INHIBITS THE DIFFERENTIATION OF PREADIPOCYTES INTO MATURE ADIPOCYTES. OBESITY IS NOW RECOGNIZED AS A DISEASE. THIS STUDY REVEALED A NOVEL ROLE FOR PYRUVATE DEHYDROGENASE KINASE (PDK) IN DIET-INDUCED HYPERTROPHIC OBESITY. MICE WITH GLOBAL OR ADIPOSE TISSUE-SPECIFIC PDK2 DEFICIENCY WERE PROTECTED AGAINST DIET-INDUCED OBESITY. THE WEIGHT OF ADIPOSE TISSUES AND THE SIZE OF ADIPOCYTES WERE REDUCED. ADIPOCYTE-SPECIFIC PDK2 DEFICIENCY SLIGHTLY INCREASED INSULIN SENSITIVITY IN HFD-FED MICE. IN STUDIES WITH 3T3-L1 PREADIPOCYTES, PDK2 AND PDK1 EXPRESSION WAS STRONGLY INCREASED DURING ADIPOGENESIS. EVIDENCE WAS FOUND FOR EPIGENETIC INDUCTION OF BOTH PDK1 AND PDK2. GAIN- AND LOSS-OF-FUNCTION STUDIES WITH 3T3-L1 CELLS REVEALED A CRITICAL ROLE FOR PDK1/2 IN ADIPOCYTE DIFFERENTIATION AND LIPID ACCUMULATION. PDK1/2 INDUCTION DURING DIFFERENTIATION WAS ALSO ACCOMPANIED BY INCREASED EXPRESSION OF HYPOXIA-INDUCIBLE FACTOR-1ALPHA (HIF1ALPHA) AND ENHANCED LACTATE PRODUCTION, BOTH OF WHICH WERE ABSENT IN THE CONTEXT OF PDK1/2 DEFICIENCY. EXOGENOUS LACTATE SUPPLEMENTATION INCREASED THE STABILITY OF HIF1ALPHA AND PROMOTED ADIPOGENESIS. PDK1/2 OVEREXPRESSION-MEDIATED ADIPOGENESIS WAS ABOLISHED BY HIF1ALPHA INHIBITION, SUGGESTING A ROLE FOR THE PDK-LACTATE-HIF1ALPHA AXIS DURING ADIPOGENESIS. IN HUMAN ADIPOSE TISSUE, THE EXPRESSION OF PDK1/2 WAS POSITIVELY CORRELATED WITH THAT OF THE ADIPOGENIC MARKER PPARGAMMA AND INVERSELY CORRELATED WITH OBESITY. SIMILARLY, PDK1/2 EXPRESSION IN MOUSE ADIPOSE TISSUE WAS DECREASED BY CHRONIC HIGH-FAT DIET FEEDING. WE CONCLUDE THAT PDK1 AND 2 ARE NOVEL REGULATORS OF ADIPOGENESIS THAT PLAY CRITICAL ROLES IN OBESITY. 2021 5 460 32 ARACHIDONIC ACID 15-LIPOXYGENASE: EFFECTS OF ITS EXPRESSION, METABOLITES, AND GENETIC AND EPIGENETIC VARIATIONS ON AIRWAY INFLAMMATION. ARACHIDONIC ACID 15-LIPOXYGENASE (ALOX15) IS AN ENZYME THAT CAN OXIDIZE POLYUNSATURATED FATTY ACIDS. ALOX15 IS STRONGLY EXPRESSED IN AIRWAY EPITHELIAL CELLS, WHERE IT CATALYZES THE CONVERSION OF ARACHIDONIC ACID TO 15-HYDROXYEICOSATETRAENOIC ACID (15-HETE) INVOLVED IN VARIOUS AIRWAY INFLAMMATORY DISEASES. INTERLEUKIN (IL)-4 AND IL-13 INDUCE ALOX15 EXPRESSION BY ACTIVATING JAK2 AND TYK2 KINASES AS WELL AS SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION (STATS) 1/3/5/6. ALOX15 UP-REGULATION AND SUBSEQUENT ASSOCIATION WITH PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN 1 (PEBP1) ACTIVATE THE MITOGEN-ACTIVATED EXTRACELLULAR SIGNAL-REGULATED KINASE (MEK)-EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) PATHWAY, THUS INDUCING EOSINOPHIL-MEDIATED AIRWAY INFLAMMATION. IN ADDITION, ALOX15 PLAYS A SIGNIFICANT ROLE IN PROMOTING THE MIGRATION OF IMMUNE CELLS, SUCH AS IMMATURE DENDRITIC CELLS, ACTIVATED T CELLS, AND MAST CELLS, AND AIRWAY REMODELING, INCLUDING GOBLET CELL DIFFERENTIATION. GENOME-WIDE ASSOCIATION STUDIES HAVE REVEALED MULTIPLE ALOX15 VARIANTS AND THEIR SIGNIFICANT CORRELATION WITH THE RISK OF DEVELOPING AIRWAY DISEASES. THE EPIGENETIC MODIFICATIONS OF THE ALOX15 GENE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS, HAVE BEEN SHOWN TO CLOSELY RELATE WITH AIRWAY INFLAMMATION. THIS REVIEW SUMMARIZES THE ROLE OF ALOX15 IN DIFFERENT PHENOTYPES OF ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CHRONIC RHINOSINUSITIS, ASPIRIN-EXACERBATED RESPIRATORY DISEASE, AND NASAL POLYPS, SUGGESTING NEW TREATMENT STRATEGIES FOR THESE AIRWAY INFLAMMATORY DISEASES WITH COMPLEX ETIOLOGY AND POOR TREATMENT RESPONSE. 2021 6 31 19 A CASE OF INFECTION-ASSOCIATED ANTIPROTEINASE-3-NEGATIVE CYTOPLASMIC ANTINEUTROPHIL CYTOPLASMIC ANTIBODY PAUCI-IMMUNE FOCAL NECROTIZING GLOMERULONEPHRITIS. WE PRESENT THE CASE OF A MAN WITH GRAM-NEGATIVE SEPSIS AND EXPOSURE TO ORAL SILICA WHO DEVELOPED PAUCI-IMMUNE FOCAL NECROTIZING GLOMERULONEPHRITIS (PI-FNGN) IN THE SETTING OF A SUBACUTE POLYMICROBIAL CENTRAL VENOUS LINE (CVL) INFECTION. HE DEVELOPED A CYTOPLASMIC ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY (C-ANCA) THAT WAS ANTIPROTEINASE-3 (PR-3) AND ANTIMYELOPEROXIDASE (MPO) ANTIBODY NEGATIVE. WE BELIEVE THIS IS THE FIRST REPORTED CASE OF GRAM-NEGATIVE SEPSIS-ASSOCIATED PI-FNGN. CHRONIC SILICA EXPOSURE IS A LEADING ENVIRONMENTAL RISK FACTOR IN THE DEVELOPMENT OF ANCA VASCULITIS. ORAL SILICA IS A COMMON PHARMACEUTICAL ADDITIVE AND ITS BIOAVAILABILITY IS BEING RECOGNIZED. ORAL SILICA, THEREFORE, MAY ALSO BE A RISK FOR DEVELOPMENT OF AUTOREACTIVITY. THE PI-FNGN RESOLVED WITH ANTIBIOTIC THERAPY ALONE. THE C-ANCA TITER DECLINED AS THE PI-FNGN RESOLVED. THE CASE SUPPORTS EXPERIMENTAL AND OBSERVATIONAL RESEARCH THAT ENVIRONMENTAL EXPOSURES ACT AS ADJUVANTS FOR AN IMMUNE RESPONSE AND ALSO PROVIDE EPIGENETIC TRIGGERS FOR AUTOREACTIVITY. THE C-ANCA WAS NEGATIVE FOR PR-3, ITS MAJOR ANTIGEN. C-ANCA ANTIGEN SPECIFICITY MAY DEPEND ON THE PATHOGENESIS OF THE UNDERLYING DISEASE, POTENTIALLY ELICITED BY A CROSS-REACTION OF AN ANTIBODY TO FOREIGN AND SELF TARGET ANTIGEN SEQUENCE HOMOLOGY OR ALTERNATIVELY ELICITED BY ANTIGENIC EPITOPE SPREAD. 2010 7 768 31 CD47 (CLUSTER OF DIFFERENTIATION 47). CD47, ALSO KNOWN AS INTEGRIN-ASSOCIATED PROTEIN, IS A CONSTITUTIVELY AND UBIQUITOUSLY EXPRESSED TRANSMEMBRANE RECEPTOR. CD47 IS CONSERVED ACROSS AMNIOTES INCLUDING MAMMALS, REPTILES, AND BIRDS. EXPRESSION IS INCREASED IN MANY CANCERS AND, IN NON-MALIGNANT CELLS, BY STRESS AND WITH AGING. THE UP-REGULATION OF CD47 EXPRESSION IS GENERALLY EPIGENETIC, WHEREAS GENE AMPLIFICATION OCCURS WITH LOW FREQUENCY IN SOME CANCERS. CD47 IS A HIGH AFFINITY SIGNALING RECEPTOR FOR THE SECRETED PROTEIN THROMBOSPONDIN-1 (THBS1) AND THE COUNTER-RECEPTOR FOR SIGNAL REGULATORY PROTEIN-ALPHA (SIRPA, SIRPALPHA) AND SIRPGAMMA (SIRPG). CD47 INTERACTION WITH SIRPALPHA SERVES AS A MARKER OF SELF TO INNATE IMMUNE CELLS AND THEREBY PROTECTS CANCER CELLS FROM PHAGOCYTIC CLEARANCE. CONSEQUENTLY, HIGHER CD47 CORRELATES WITH A POOR PROGNOSIS IN SOME CANCERS, AND THERAPEUTIC BLOCKADE CAN SUPPRESS TUMOR GROWTH BY ENHANCING INNATE ANTITUMOR IMMUNITY. CD47 EXPRESSED ON CYTOTOXIC T CELLS, DENDRITIC CELLS, AND NK CELLS MEDIATES INHIBITORY THBS1 SIGNALING THAT FURTHER LIMITS ANTITUMOR IMMUNITY. CD47 LATERALLY ASSOCIATES WITH SEVERAL INTEGRINS AND THEREBY REGULATES CELL ADHESION AND MIGRATION. CD47 HAS ADDITIONAL LATERAL BINDING PARTNERS IN SPECIFIC CELL TYPES, AND LIGATION OF CD47 IN SOME CASES MODULATES THEIR FUNCTION. THBS1-CD47 SIGNALING IN NON-MALIGNANT CELLS INHIBITS NITRIC OXIDE/CGMP, CALCIUM, AND VEGF SIGNALING, MITOCHONDRIAL HOMEOSTASIS, STEM CELL MAINTENANCE, PROTECTIVE AUTOPHAGY, AND DNA DAMAGE RESPONSE, AND PROMOTES NADPH OXIDASE ACTIVITY. CD47 SIGNALING IS A PHYSIOLOGICAL REGULATOR OF PLATELET ACTIVATION, ANGIOGENESIS AND BLOOD FLOW. THBS1/CD47 SIGNALING IS FREQUENTLY DYSREGULATED IN CHRONIC DISEASES. 2021 8 2818 15 FIBROSIS UNDER ARREST. APPROXIMATELY 5% OF PEOPLE THAT ARE HOSPITALIZED FOR ANY REASON DEVELOP ACUTE KIDNEY FAILURE, WHICH, IN SOME CASES, PROGRESSES TO A CHRONIC CONDITION RESULTING IN FIBROSIS OF THE KIDNEY AND PERMANENT CHANGES IN THE ORGAN'S FUNCTION. TWO NEW STUDIES SUGGEST THAT CELL CYCLE ARREST OF EPITHELIAL CELLS AND EPIGENETIC MODIFICATIONS HAVE KEY ROLES IN THE SWITCH TO CHRONIC DISEASE (PAGES 535-543 AND 544-550). 2010 9 760 30 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 10 3353 36 HISTONE DEMETHYLASES REGULATE ADIPOCYTE THERMOGENESIS. ADIPOCYTES PLAY A PIVOTAL ROLE IN THE REGULATION OF ENERGY METABOLISM. WHILE WHITE ADIPOCYTE STORES ENERGY, BROWN ADIPOCYTE DISSIPATES ENERGY BY PRODUCING HEAT. IN ADDITION, ANOTHER TYPE OF HEAT-PRODUCING ADIPOCYTE, BEIGE ADIPOCYTE, EMERGES IN WHITE ADIPOSE TISSUE IN RESPONSE TO CHRONIC COLDNESS. THIS PHENOTYPIC ADAPTATION TO THE COLD ENVIRONMENT IS CONSIDERED TO BE ATTRIBUTED TO THE EPIGENETIC MODIFICATIONS. HISTONE METHYLATION IS A CHEMICALLY STABLE EPIGENETIC MODIFICATION AND THUS A PROPER MECHANISM FOR LONG-LASTING CELLULAR MEMORY. SEVERAL HISTONE METHYL-MODIFYING ENZYMES SUCH AS EHMT1, JMJD1A, JMJD3, AND LSD1 ARE REPORTED TO BE INVOLVED IN THE BEIGE ADIPOSE CELL FATE DETERMINATION. AMONG THESE, A HISTONE DEMETHYLASE JMJD1A SENSES COLD ENVIRONMENT BY BEING PHOSPHORYLATED AT S265 IN RESPONSE TO BETA-ADRENERGIC RECEPTOR STIMULATION. PHOSPHORYLATED JMJD1A REGULATES BOTH ACUTE AND COLD THERMOGENESIS. UNDER ACUTE COLDNESS, PHOSPHORYLATED JMJD1A FORMS A COMPLEX WITH CHROMATIN REMODELER SWI/SNF AND DNA-BOUND PPARGAMMA, WHICH RECRUITS JMJD1A TO THE TARGET GENOMIC REGIONS IN BROWN ADIPOCYTE. THIS COMPLEX FORMATION, IN TURN, INDUCES THE EXPRESSION OF TARGET GENES BY BRINGING THE ENHANCER AND THE PROMOTER INTO CLOSE PROXIMITY. DURING CHRONIC COLDNESS, PHOSPHORYLATED JMJD1A REGULATES BEIGE ADIPOGENESIS THROUGH A TWO-STEP MECHANISM. IN THE FIRST STEP, PHOSPHORYLATED JMJD1A IS RECRUITED TO THE REGULATORY REGIONS OF TARGET GENES BY FORMING A COMPLEX WITH PRDM16, PGC1ALPHA, AND DNA-BOUND PPARGAMMA. IN THE SECOND STEP, JMJD1A DEMETHYLATES HISTONE H3K9ME2 AND INDUCES STABLE EXPRESSION OF BEIGE-SELECTIVE GENES. THE PHENOTYPIC ANALYSES OF JMJD1A-NULL MICE AND NON-PHOSPHORYLATED MUTANT S265A JMJD1A KNOCK-IN MICE INDICATE THAT JMJD1A IS A POTENTIAL THERAPEUTIC TARGET FOR THE TREATMENT OF OBESITY-RELATED DISEASES INCLUDING METABOLIC SYNDROME AND TYPE 2 DIABETES. 2018 11 4048 34 MAINTENANCE AND PHARMACOLOGIC TARGETING OF ROR1 PROTEIN LEVELS VIA UHRF1 IN T(1;19) PRE-B-ALL. EXPRESSION OF THE TRANSMEMBRANE PSEUDOKINASE ROR1 IS REQUIRED FOR SURVIVAL OF T(1;19)-PRE-B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T(1;19) PRE-B-ALL), CHRONIC LYMPHOCYTIC LEUKEMIA, AND MANY SOLID TUMORS. HOWEVER, TARGETING ROR1 WITH SMALL-MOLECULES HAS BEEN CHALLENGING DUE TO THE ABSENCE OF ROR1 KINASE ACTIVITY. TO IDENTIFY GENES THAT REGULATE ROR1 EXPRESSION AND MAY, THEREFORE, SERVE AS SURROGATE DRUG TARGETS, WE EMPLOYED AN SIRNA SCREENING APPROACH AND DETERMINED THAT THE EPIGENETIC REGULATOR AND E3 UBIQUITIN LIGASE, UHRF1, IS REQUIRED FOR T(1;19) PRE-B-ALL CELL VIABILITY IN A ROR1-DEPENDENT MANNER. UPON UHRF1 SILENCING, ROR1 PROTEIN IS REDUCED WITHOUT ALTERING ROR1 MRNA, AND ECTOPICALLY EXPRESSED UHRF1 IS SUFFICIENT TO INCREASE ROR1 LEVELS. ADDITIONALLY, PROTEASOME INHIBITION RESCUES LOSS OF ROR1 PROTEIN AFTER UHRF1 SILENCING, SUGGESTING A ROLE FOR THE PROTEASOME IN THE UHRF1-ROR1 AXIS. FINALLY, WE SHOW THAT ROR1-POSITIVE CELLS ARE TWICE AS SENSITIVE TO THE UHRF1-TARGETING DRUG, NAPHTHAZARIN, AND UNDERGO INCREASED APOPTOSIS COMPARED TO ROR1-NEGATIVE CELLS. NAPHTHAZARIN ELICITS REDUCED EXPRESSION OF UHRF1 AND ROR1, AND COMBINATION OF NAPHTHAZARIN WITH INHIBITORS OF PRE-B CELL RECEPTOR SIGNALING RESULTS IN FURTHER REDUCTION OF CELL SURVIVAL COMPARED WITH EITHER INHIBITOR ALONE. THEREFORE, OUR WORK REVEALS A MECHANISM BY WHICH UHRF1 STABILIZES ROR1, SUGGESTING A POTENTIAL TARGETING STRATEGY TO INHIBIT ROR1 IN T(1;19) PRE-B-ALL AND OTHER MALIGNANCIES. 2018 12 5677 32 SHORT AIP1 (ASK1-INTERACTING PROTEIN-1) ISOFORM LOCALIZES TO THE MITOCHONDRIA AND PROMOTES VASCULAR DYSFUNCTION. OBJECTIVE: VASCULAR ENDOTHELIAL CELLS (ECS) NORMALLY MAINTAIN VASCULAR HOMEOSTASIS AND ARE REGULATED BY PROINFLAMMATORY CYTOKINES AND REACTIVE OXYGEN SPECIES. A HUMAN GENOME-WIDE ASSOCIATION STUDY IDENTIFIED THAT AIP1 (ASK1 [APOPTOSIS SIGNAL-REGULATING KINASE 1]-INTERACTING PROTEIN-1; ALSO IDENTIFIED AS DAB2IP) GENE VARIANTS CONFER SUSCEPTIBILITY TO CARDIOVASCULAR DISEASE, BUT THE UNDERLYING MECHANISM IS UNKNOWN. APPROACH AND RESULTS: WE DETECTED A NORMAL AIP1 FORM (NAMED AIP1A) IN THE HEALTHY AORTA, BUT A SHORTER FORM OF AIP1 (NAMED AIP1B) WAS FOUND IN DISEASED AORTAE THAT CONTAINED ATHEROSCLEROTIC PLAQUES AND GRAFT ARTERIOSCLEROSIS. AIP1B TRANSCRIPTION IN RESTING ECS WAS SUPPRESSED THROUGH EPIGENETIC INHIBITION BY RIF1 (RAP1 [RAS-RELATED PROTEIN 1]-INTERACTING FACTOR 1)/H3K9 (HISTONE H3 LYSINE 9) METHYLTRANSFERASE-MEDIATED H3K9 TRIMETHYLATION, AND THIS INHIBITION WAS RELEASED BY PROINFLAMMATORY CYTOKINES. AIP1A, BUT NOT AIP1B, WAS DOWNREGULATED BY PROTEOLYTIC DEGRADATION THROUGH A SMURF1 (SMAD [SUPPRESSOR OF MOTHERS AGAINST DECAPENTAPLEGIC MISCELLANEOUS] UBIQUITYLATION REGULATORY FACTOR 1)-DEPENDENT PATHWAY IN ECS UNDER INFLAMMATION. THEREFORE, AIP1B WAS THE MAJOR FORM PRESENT DURING INFLAMMATORY CONDITIONS. AIP1B, WHICH LACKS THE N-TERMINAL PLECKSTRIN HOMOLOGY DOMAIN OF AIP1A, LOCALIZED TO THE MITOCHONDRIA AND AUGMENTED TNFALPHA (TUMOR NECROSIS FACTOR ALPHA)-INDUCED MITOCHONDRIAL REACTIVE OXYGEN SPECIES GENERATION AND EC ACTIVATION. AIP1B-ECTG (EC-SPECIFIC AIP1B TRANSGENIC) MICE EXHIBITED AUGMENTED REACTIVE OXYGEN SPECIES PRODUCTION, EC ACTIVATION, AND NEOINTIMA FORMATION IN VASCULAR REMODELING MODELS. CONCLUSIONS: OUR CURRENT STUDY SUGGESTS THAT A SHIFT FROM ANTI-INFLAMMATORY AIP1A TO PROINFLAMMATORY AIP1B DURING CHRONIC INFLAMMATION PLAYS A KEY ROLE IN INFLAMMATORY VASCULAR DISEASES. 2020 13 3862 24 ISOPATHIC USE OF AUTO-SARCODE OF DNA AS ANTI-MIASMATIC HOMEOPATHIC MEDICINE AND MODULATOR OF GENE EXPRESSION? INTRODUCTION: IN ADDITION TO THE FOUR PILLARS OF HOMEOPATHY, VITALISM AND THE MIASMATIC THEORY ARE OFTEN USED TO EXPLAIN THE HEALTH-DISEASE PROCESS. ACCORDING TO HAHNEMANN'S CONCEPTS, HOMEOPATHIC MIASMS ARE THE MAIN OBSTACLE TO THE CURE OF CHRONIC DISEASES, WITH PSORA BEING THE FUNDAMENTAL CAUSE OF ALL FORMS OF DISEASES. ACCORDING TO MODERN GENETICS, THE DISEASE-PROMOTING EPIGENETIC ALTERATIONS ARE THE FUNDAMENTAL CAUSE OF THE MANIFESTATION OF CHRONIC DISEASES. OBJECTIVE: THIS ARTICLE DEVELOPS A PHILOSOPHICAL-SCIENTIFIC CORRELATION BETWEEN CHRONIC MIASMS AND DISEASE-PROMOTING EPIGENETIC MODIFICATIONS, AIMING TO JUSTIFY THE ISOPATHIC USE OF AUTO-SARCODE OF AN INDIVIDUAL'S DNA AS HOMEOPATHIC MEDICINE. RESULTS: BASED ON THE STUDY OF HOMEOPATHIC DOCTRINE AND EPIGENETICS, A CONCEPTUAL AND FUNCTIONAL CORRELATION IS OBSERVED BETWEEN HOMEOPATHIC CHRONIC MIASMS AND DISEASE-PROMOTING EPIGENETIC MODIFICATIONS. ADDITIONALLY, SEVERAL EXPERIMENTAL STUDIES SUGGEST THAT HOMEOPATHY'S MECHANISM OF ACTION MAY BE BY MODULATING GENE EXPRESSION. CONCLUSIONS: BY THE PHILOSOPHICAL-SCIENTIFIC CORRELATIONS DESCRIBED, IT IS INFERRED THAT DISEASE-PROMOTING EPIGENETIC ALTERATIONS ARE THE BIOLOGICAL REPRESENTATION OF THE CHRONIC MIASMS, SUGGESTING THE ISOPATHIC USE OF AUTO-SARCODE OF DNA AS HOMEOPATHIC THERAPEUTIC MODULATOR OF GENE EXPRESSION FOR THE MANAGEMENT OF CHRONIC DISEASES. 2019 14 3152 31 GLUCOSE VARIABILITY: HOW DOES IT WORK? A GROWING BODY OF EVIDENCE POINTS TO THE ROLE OF GLUCOSE VARIABILITY (GV) IN THE DEVELOPMENT OF THE MICROVASCULAR AND MACROVASCULAR COMPLICATIONS OF DIABETES. IN THIS REVIEW, WE SUMMARIZE DATA ON GV-INDUCED BIOCHEMICAL, CELLULAR AND MOLECULAR EVENTS INVOLVED IN THE PATHOGENESIS OF DIABETIC COMPLICATIONS. CURRENT DATA INDICATE THAT THE DETERIORATING EFFECT OF GV ON TARGET ORGANS CAN BE REALIZED THROUGH OXIDATIVE STRESS, GLYCATION, CHRONIC LOW-GRADE INFLAMMATION, ENDOTHELIAL DYSFUNCTION, PLATELET ACTIVATION, IMPAIRED ANGIOGENESIS AND RENAL FIBROSIS. THE EFFECTS OF GV ON OXIDATIVE STRESS, INFLAMMATION, ENDOTHELIAL DYSFUNCTION AND HYPERCOAGULABILITY COULD BE AGGRAVATED BY HYPOGLYCEMIA, ASSOCIATED WITH HIGH GV. OSCILLATING HYPERGLYCEMIA CONTRIBUTES TO BETA CELL DYSFUNCTION, WHICH LEADS TO A FURTHER INCREASE IN GV AND COMPLETES THE VICIOUS CIRCLE. IN CELLS, THE GV-INDUCED CYTOTOXIC EFFECT INCLUDES MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS AND DISTURBANCES IN AUTOPHAGIC FLUX, WHICH ARE ACCOMPANIED BY REDUCED VIABILITY, ACTIVATION OF APOPTOSIS AND ABNORMALITIES IN CELL PROLIFERATION. THESE EFFECTS ARE REALIZED THROUGH THE UP- AND DOWN-REGULATION OF A LARGE NUMBER OF GENES AND THE ACTIVITY OF SIGNALING PATHWAYS SUCH AS PI3K/AKT, NF-KAPPAB, MAPK (ERK), JNK AND TGF-BETA/SMAD. EPIGENETIC MODIFICATIONS MEDIATE THE POSTPONED EFFECTS OF GLUCOSE FLUCTUATIONS. THE MULTIPLE DETERIORATIVE EFFECTS OF GV PROVIDE FURTHER SUPPORT FOR CONSIDERING IT AS A THERAPEUTIC TARGET IN DIABETES. 2021 15 6233 20 THE LONG NONCODING RNA TUG1 CONNECTS METABOLIC CHANGES WITH KIDNEY DISEASE IN PODOCYTES. AN INCREASING AMOUNT OF EVIDENCE SUGGESTS THAT METABOLIC ALTERATIONS PLAY A KEY ROLE IN CHRONIC KIDNEY DISEASE (CKD) PATHOGENESIS. IN THIS ISSUE OF THE JCI, LONG ET AL. REPORT THAT THE LONG NONCODING RNA (LNCRNA) TAURINE-UPREGULATED 1 (TUG1) CONTRIBUTES TO CKD DEVELOPMENT. THE AUTHORS SHOW THAT TUG1 REGULATES MITOCHONDRIAL FUNCTION IN PODOCYTES BY EPIGENETIC TARGETING OF EXPRESSION OF THE TRANSCRIPTION FACTOR PPARGAMMA COACTIVATOR 1ALPHA (PGC-1ALPHA, ENCODED BY PPARGC1A). TRANSGENIC OVEREXPRESSION OF TUG1 SPECIFICALLY IN PODOCYTES AMELIORATED DIABETES-INDUCED CKD IN MICE. TOGETHER, THESE RESULTS HIGHLIGHT AN IMPORTANT CONNECTION BETWEEN LNCRNA-MEDIATED METABOLIC ALTERATIONS IN PODOCYTES AND KIDNEY DISEASE DEVELOPMENT. 2016 16 5009 27 PERK IS A CRITICAL METABOLIC HUB FOR IMMUNOSUPPRESSIVE FUNCTION IN MACROPHAGES. CHRONIC INFLAMMATION TRIGGERS COMPENSATORY IMMUNOSUPPRESSION TO STOP INFLAMMATION AND MINIMIZE TISSUE DAMAGE. STUDIES HAVE DEMONSTRATED THAT ENDOPLASMIC RETICULUM (ER) STRESS AUGMENTS THE SUPPRESSIVE PHENOTYPES OF IMMUNE CELLS; HOWEVER, THE MOLECULAR MECHANISMS UNDERPINNING THIS PROCESS AND HOW IT LINKS TO THE METABOLIC REPROGRAMMING OF IMMUNOSUPPRESSIVE MACROPHAGES REMAIN ELUSIVE. IN THE PRESENT STUDY, WE REPORT THAT THE HELPER T CELL 2 CYTOKINE INTERLEUKIN-4 AND THE TUMOR MICROENVIRONMENT INCREASE THE ACTIVITY OF A PROTEIN KINASE RNA-LIKE ER KINASE (PERK)-SIGNALING CASCADE IN MACROPHAGES AND PROMOTE IMMUNOSUPPRESSIVE M2 ACTIVATION AND PROLIFERATION. LOSS OF PERK SIGNALING IMPEDED MITOCHONDRIAL RESPIRATION AND LIPID OXIDATION CRITICAL FOR M2 MACROPHAGES. PERK ACTIVATION MEDIATED THE UPREGULATION OF PHOSPHOSERINE AMINOTRANSFERASE 1 (PSAT1) AND SERINE BIOSYNTHESIS VIA THE DOWNSTREAM TRANSCRIPTION FACTOR ATF-4. INCREASED SERINE BIOSYNTHESIS RESULTED IN ENHANCED MITOCHONDRIAL FUNCTION AND ALPHA-KETOGLUTARATE PRODUCTION REQUIRED FOR JMJD3-DEPENDENT EPIGENETIC MODIFICATION. INHIBITION OF PERK SUPPRESSED MACROPHAGE IMMUNOSUPPRESSIVE ACTIVITY AND COULD ENHANCE THE EFFICACY OF IMMUNE CHECKPOINT PROGRAMMED CELL DEATH PROTEIN 1 INHIBITION IN MELANOMA. OUR FINDINGS DELINEATE A PREVIOUSLY UNDESCRIBED CONNECTION BETWEEN PERK SIGNALING AND PSAT1-MEDIATED SERINE METABOLISM CRITICAL FOR PROMOTING IMMUNOSUPPRESSIVE FUNCTION IN M2 MACROPHAGES. 2022 17 829 22 CHARACTERIZATION OF P190-BCR-ABL CHRONIC MYELOID LEUKEMIA REVEALS SPECIFIC SIGNALING PATHWAYS AND THERAPEUTIC TARGETS. THE ONCOGENIC PROTEIN BCR-ABL HAS TWO MAJOR ISOFORMS, P190(BCR-ABL) AND P210(BCR-ABL). WHILE P210(BCR-ABL) IS THE HALLMARK OF CHRONIC MYELOID LEUKEMIA (CML), P190(BCR-ABL) OCCURS IN THE MAJORITY OF PHILADELPHIA-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (PH + ALL) PATIENTS. IN CML, P190(BCR-ABL) OCCURS IN A MINORITY OF PATIENTS ASSOCIATING WITH DISTINCT HEMATOLOGICAL FEATURES AND INFERIOR OUTCOMES, YET THE PATHOGENIC ROLE OF P190(BCR-ABL) AND POTENTIAL TARGETING THERAPIES ARE LARGELY UNCHARACTERIZED. WE EMPLOYED NEXT GENERATION SEQUENCING, PHOSPHO-PROTEOMIC PROFILING, AND DRUG SENSITIVITY TESTING TO CHARACTERIZE P190(BCR-ABL) IN CML AND HEMATOPOIETIC PROGENITOR CELL LINE MODELS (BA/F3 AND HPC-LSK). P190(BCR-ABL) CML PATIENTS DEMONSTRATED POOR RESPONSE TO IMATINIB AND FREQUENT MUTATIONS IN EPIGENETIC MODIFIERS GENES. IN CONTRAST WITH P210(BCR-ABL), P190(BCR-ABL) EXHIBITED SPECIFIC TRANSCRIPTIONAL UPREGULATION OF INTERFERON, INTERLEUKIN-1 RECEPTOR, AND P53 SIGNALING PATHWAYS, ASSOCIATED WITH HYPERPHOSPHORYLATION OF RELEVANT SIGNALING MOLECULES INCLUDING JAK1/STAT1 AND PAK1 IN ADDITION TO SRC HYPERPHOSPHORYLATION. COMPARABLE TO P190(BCR-ABL) CML PATIENTS, P190(BCR-ABL) CELL LINES DEMONSTRATED SIMILAR TRANSCRIPTIONAL AND PHOSPHO-SIGNALING SIGNATURES. WITH THE DRUG SENSITIVITY SCREENING WE IDENTIFIED TARGETED DRUGS WITH SPECIFIC ACTIVITY IN P190(BCR-ABL) CELL LINES INCLUDING IAP-, PAK1-, AND SRC INHIBITORS AND GLUCOCORTICOIDS. OUR RESULTS PROVIDE NOVEL INSIGHTS INTO THE MECHANISMS UNDERLYING THE DISTINCT FEATURES OF P190(BCR-ABL) CML AND PROMISING THERAPEUTIC TARGETS FOR THIS HIGH-RISK PATIENT GROUP. 2021 18 2451 22 EPIGENETIC SUPPRESSION OF PGC1ALPHA (PPARGC1A) CAUSES COLLATERAL SENSITIVITY TO HMGCR-INHIBITORS WITHIN BRAF-TREATMENT RESISTANT MELANOMAS. WHILE TARGETED TREATMENT AGAINST BRAF(V600E) IMPROVE SURVIVAL FOR MELANOMA PATIENTS, MANY WILL SEE THEIR CANCER RECUR. HERE WE PROVIDE DATA INDICATING THAT EPIGENETIC SUPPRESSION OF PGC1ALPHA DEFINES AN AGGRESSIVE SUBSET OF CHRONIC BRAF-INHIBITOR TREATED MELANOMAS. A METABOLISM-CENTERED PHARMACOLOGICAL SCREEN FURTHER IDENTIFIES STATINS (HMGCR INHIBITORS) AS A COLLATERAL VULNERABILITY WITHIN PGC1ALPHA-SUPPRESSED BRAF-INHIBITOR RESISTANT MELANOMAS. LOWER PGC1ALPHA LEVELS MECHANISTICALLY CAUSES REDUCED RAB6B AND RAB27A EXPRESSION, WHEREBY THEIR COMBINED RE-EXPRESSION REVERSES STATIN VULNERABILITY. BRAF-INHIBITOR RESISTANT CELLS WITH REDUCED PGC1ALPHA HAVE INCREASED INTEGRIN-FAK SIGNALING AND IMPROVED EXTRACELLULAR MATRIX DETACHED SURVIVAL CUES THAT HELPS EXPLAIN THEIR INCREASED METASTATIC ABILITY. STATIN TREATMENT BLOCKS CELL GROWTH BY LOWERING RAB6B AND RAB27A PRENYLATION THAT REDUCES THEIR MEMBRANE ASSOCIATION AND AFFECTS INTEGRIN LOCALIZATION AND DOWNSTREAM SIGNALING REQUIRED FOR GROWTH. THESE RESULTS SUGGEST THAT CHRONIC ADAPTATION TO BRAF-TARGETED TREATMENTS DRIVE NOVEL COLLATERAL METABOLIC VULNERABILITIES, AND THAT HMGCR INHIBITORS MAY OFFER A STRATEGY TO TREAT MELANOMAS RECURRING WITH SUPPRESSED PGC1ALPHA EXPRESSION. 2023 19 5449 19 REPRESSION OF THE ANTIOXIDANT NRF2 PATHWAY IN PREMATURE AGING. HUTCHINSON-GILFORD PROGERIA SYNDROME (HGPS) IS A RARE, INVARIABLY FATAL PREMATURE AGING DISORDER. THE DISEASE IS CAUSED BY CONSTITUTIVE PRODUCTION OF PROGERIN, A MUTANT FORM OF THE NUCLEAR ARCHITECTURAL PROTEIN LAMIN A, LEADING, THROUGH UNKNOWN MECHANISMS, TO DIVERSE MORPHOLOGICAL, EPIGENETIC, AND GENOMIC DAMAGE AND TO MESENCHYMAL STEM CELL (MSC) ATTRITION IN VIVO. USING A HIGH-THROUGHPUT SIRNA SCREEN, WE IDENTIFY THE NRF2 ANTIOXIDANT PATHWAY AS A DRIVER MECHANISM IN HGPS. PROGERIN SEQUESTERS NRF2 AND THEREBY CAUSES ITS SUBNUCLEAR MISLOCALIZATION, RESULTING IN IMPAIRED NRF2 TRANSCRIPTIONAL ACTIVITY AND CONSEQUENTLY INCREASED CHRONIC OXIDATIVE STRESS. SUPPRESSED NRF2 ACTIVITY OR INCREASED OXIDATIVE STRESS IS SUFFICIENT TO RECAPITULATE HGPS AGING DEFECTS, WHEREAS REACTIVATION OF NRF2 ACTIVITY IN HGPS PATIENT CELLS REVERSES PROGERIN-ASSOCIATED NUCLEAR AGING DEFECTS AND RESTORES IN VIVO VIABILITY OF MSCS IN AN ANIMAL MODEL. THESE FINDINGS IDENTIFY REPRESSION OF THE NRF2-MEDIATED ANTIOXIDATIVE RESPONSE AS A KEY CONTRIBUTOR TO THE PREMATURE AGING PHENOTYPE. 2016 20 1679 25 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