1 6758 141 WNT SIGNALING IN STEM CELL BIOLOGY AND REGENERATIVE MEDICINE. WNT FAMILY MEMBERS ARE SECRETED-TYPE GLYCOPROTEINS TO ORCHESTRATE EMBRYOGENESIS, TO MAINTAIN HOMEOSTASIS, AND TO INDUCE PATHOLOGICAL CONDITIONS. FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, LRP5, LRP6, AND ROR2 ARE TRANSMEMBRANE RECEPTORS TRANSDUCING WNT SIGNALS BASED ON LIGAND-DEPENDENT PREFERENTIALITY FOR CAVEOLIN- OR CLATHRIN-MEDIATED ENDOCYTOSIS. WNT SIGNALS ARE TRANSDUCED TO CANONICAL PATHWAY FOR CELL FATE DETERMINATION, AND TO NON-CANONICAL PATHWAYS FOR REGULATION OF PLANAR CELL POLARITY, CELL ADHESION, AND MOTILITY. MYC, CCND1, AXIN2, FGF20, WISP1, JAG1, DKK1 AND GLUCAGON ARE TARGET GENES OF CANONICAL WNT SIGNALING CASCADE, WHILE CD44, VIMENTIN AND STX5 ARE TARGET GENES OF NON-CANONICAL WNT SIGNALING CASCADES. HOWEVER, TARGET GENES OF WNT SIGNALING CASCADES ARE DETERMINED IN A CONTEXT-DEPENDENT MANNER DUE TO EXPRESSION PROFILE OF TRANSCRIPTION FACTORS AND EPIGENETIC STATUS. WNT SIGNALING CASCADES NETWORK WITH NOTCH, FGF, BMP AND HEDGEHOG SIGNALING CASCADES TO REGULATE THE BALANCE OF STEM CELLS AND PROGENITOR CELLS. HERE WNT SIGNALING IN EMBRYONIC STEM CELLS, NEURAL STEM CELLS, MESENCHYMAL STEM CELLS, HEMATOPOIETIC STEM CELLS, AND INTESTINAL STEM CELLS WILL BE REVIEWED. WNT3, WNT5A AND WNT10B ARE EXPRESSED IN UNDIFFERENTIATED HUMAN EMBRYONIC STEM CELLS, WHILE WNT6, WNT8B AND WNT10B IN ENDODERM PRECURSOR CELLS. WNT6 IS EXPRESSED IN INTESTINAL CRYPT REGION FOR STEM OR PROGENITOR CELLS. TNF/ALPHA-WNT10B SIGNALING IS A NEGATIVE FEEDBACK LOOP TO MAINTAIN HOMEOSTASIS OF ADIPOSE TISSUE AND GASTROINTESTINAL MUCOSA WITH CHRONIC INFLAMMATION. RECOMBINANT WNT PROTEIN OR WNT MIMETIC (CIRCULAR PEPTIDE, SMALL MOLECULE COMPOUND, OR RNA APTAMER) IN COMBINATION WITH NOTCH MIMETIC, FGF PROTEIN, AND BMP PROTEIN OPENS A NEW WINDOW TO TISSUE ENGINEERING FOR REGENERATIVE MEDICINE. 2008 2 3424 23 HUMAN STEM CELLS ISOLATED FROM ADULT SKELETAL MUSCLE DIFFERENTIATE INTO NEURAL PHENOTYPES. MULTIPOTENT NEURAL STEM CELLS HAVE BEEN ISOLATED FROM THE ADULT [KIRSCHENBAUM B, NEDERGAARD M, PREUSS A, BARAMI K, FRASER RA, GOLDMAN SA. IN VITRO NEURONAL PRODUCTION AND DIFFERENTIATION BY PRECURSOR CELLS DERIVED FROM THE ADULT HUMAN FOREBRAIN. CEREB CORTEX 1994;4(6):576-89; LAYWELL ED, KUKEKOV VG, STEINDLER DA. MULTIPOTENT NEUROSPHERES CAN BE DERIVED FROM FOREBRAIN SUBEPENDYMAL ZONE AND SPINAL CORD OF ADULT MICE AFTER PROTRACTED POSTMORTEM INTERVALS. EXP NEUROL 1999;156:430-3; PLUCHINO S, QUATTRINI A, BRAMBILLA E, GRITTI A, SALANI G, DINA G, ET AL. INJECTION OF ADULT NEUROSPHERES INDUCES RECOVERY IN A CHRONIC MODEL OF MULTIPLE SCLEROSIS. NATURE 2003;422:688-94] AND EMBRYONIC [VESCOVI AL, PARATI EA, GRITTI A, POULIN P, FERRARIO M, WANKE E, ET AL. ISOLATION AND CLONING OF MULTIPOTENTIAL STEM CELLS FROM THE EMBRYONIC HUMAN CNS AND ESTABLISHMENT OF TRANSPLANTABLE HUMAN NEURAL STEM CELL LINES BY EPIGENETIC STIMULATION. EXP NEUROL 1999;156:71-83] CENTRAL NERVOUS SYSTEM (CNS). IN ADDITION, NEURAL CELLS CAN BE OBTAINED FROM SOURCES OTHER THAN THE CNS BY DIFFERENTIATING STEM CELLS FROM A NON-NEURAL SOURCE DOWN A NEURAL LINEAGE. THIS HAS PREVIOUSLY BEEN PERFORMED WITH PLURIPOTENT EMBRYONIC STEM CELLS AND ADULT STEM CELLS DERIVED FROM RAT BONE MARROW [WOODBURY D, SCHWARZ EJ, PROCKOP DJ, BLACK IB. ADULT RAT AND HUMAN BONE MARROW STROMAL CELLS DIFFERENTIATE INTO NEURONS. J NEUROSCI RES 2000;61:364-70; WOODBURY D, REYNOLDS K, BLACK IB. ADULT BONE MARROW STROMAL STEM CELLS EXPRESS GERMLINE, ECTODERMAL, ENDODERMAL, AND MESODERMAL GENES PRIOR TO NEUROGENESIS. J NEUROSCI 2002;69(6):908-17] AND SKELETAL MUSCLE [ROMERO-RAMOS M, VOURC'H P, YOUNG HE, LUCAS PA, WU Y, CHIVATAKARN O, ET AL. NEURONAL DIFFERENTIATION OF STEM CELLS ISOLATED FROM ADULT MUSCLE. J NEUROSCI RES 2002;69:894-907]. PREVIOUSLY, WE HAVE ISOLATED ADULT STEM CELLS FROM HUMAN SKELETAL MUSCLE WITH THE POTENTIAL TO DIFFERENTIATE INTO MESODERM, ECTODERM, AND ENDODERM. THE FOLLOWING IN VITRO EXPERIMENTS WERE DESIGNED TO DETERMINE WHETHER HUMAN ADULT STEM CELLS BEHAVED SIMILARLY TO RAT ADULT STEM CELLS WHEN BOTH WERE ISOLATED FROM SKELETAL MUSCLE BY THE SAME PROCEDURE [ROMERO-RAMOS M, VOURC'H P, YOUNG HE, LUCAS PA, WU Y, CHIVATAKARN O, ET AL. NEURONAL DIFFERENTIATION OF STEM CELLS ISOLATED FROM ADULT MUSCLE. J NEUROSCI RES 2002;69:894-907] AND SUBJECTED TO THE SAME PROTOCOLS TO INDUCE NEUROGENESIS. THE NEURAL PHENOTYPES THAT WERE CREATED THROUGH THE NEUROCOCKTAIL OR NEUROSPHERE PROTOCOL WERE ANALYZED FOR NEURAL CHARACTERISTICS THROUGH MORPHOLOGY AND IMMUNOHISTOCHEMISTRY ANTIBODY LABELING FOR PROTEINS TO NEURONS (RT-97, BETA-TUBULIN III, NF-160, NF-200, AND SYNAPSIN), OLIGODENDROCYTES (CNPASE AND RIP), AND ASTROCYTES (GFAP). A CALCIUM UPTAKE ASSAY ALSO SHOWED RESPONSE TO THE NEURONAL EXCITOTOXIC AGENT GLUTAMIC ACID. IN CONCLUSION, THE NEURAL DIFFERENTIATED STEM CELLS DERIVED FROM ADULT SKELETAL MUSCLE MAY BE A LESS INVASIVE ALTERNATIVE FOR THE TREATMENT OF CNS DISORDERS OVER CNS DERIVED NEURAL STEM CELLS. 2006 3 1730 46 DYSREGULATION OF STEM CELL SIGNALING NETWORK DUE TO GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION IN GASTRIC CANCER. GENETIC FACTORS, HELICOBACTER PYLORI INFECTION, SALT OVER-UPTAKE, DECREASED VEGETABLE/FRUIT CONSUMPTION, SMOKING, AND METABOLIC SYNDROME ARE RISK FACTORS OF HUMAN GASTRIC CANCER. GERMLINE MUTATIONS OF CDH1 GENE, AND SNPS OF PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 AND RUNX3 GENES ARE ASSOCIATED WITH GASTRIC CANCER. HELICOBACTER PYLORI ACTIVATES CAGA-SHP2-ERK AND PEPTIDOGLYCAN-NOD1-NFKAPPAB SIGNALING CASCADES IN GASTRIC EPITHELIAL CELLS USING TYPE IV SECRETION SYSTEM, AND ALSO TRAF6-MAP3K7-NFKAPPAB AND TRAF6-MAP3K7-AP-1 SIGNALING CASCADES IN EPITHELIAL AND IMMUNE CELLS THROUGH LIPOPOLYSACCHARIDE RECOGNITION BY TLR2 OR TLR4. IL-1BETA, IL-6, IL-8, TNFALPHA AND IFNGAMMA ARE ELEVATED IN GASTRIC MUCOSA WITH HELICOBACTER PYLORI INFECTION. IL-6 AND TNFALPHA INDUCE UPREGULATION OF WNT5A AND WNT10B, RESPECTIVELY. WNT SIGNALS ARE TRANSDUCED TO BETA-CATENIN-TCF/LEF, RHOA, JNK, PKC, NFAT, AND NLK SIGNALING CASCADES. WNT-BETA-CATENIN-TCF/LEF SIGNALING INDUCES UPREGULATION OF MYC, CCND1, WISP1, FGF20, JAG1 AND DKK1 GENES. NOTCH SIGNALS ARE TRANSDUCED TO CSL-NICD-MAML AND NFKAPPAB SIGNALING CASCADES. FGF SIGNALS ARE TRANSDUCED TO ERK, PI3K-AKT, PKC, AND NFAT SIGNALING CASCADES. HELICOBACTER PYLORI INFECTION INDUCES SHH UPREGULATION IN PARIETAL CELL LINEAGE, WHILE BMP SIGNALS INDUCE IHH UPREGULATION IN PIT CELL LINEAGE. HEDGEHOG SIGNALS INDUCE UPREGULATION OF GLI1, PTCH1, CCND2, FOXL1, JAG2 AND SFRP1 GENES. JAG1 AND JAG2 ACTIVATE NOTCH SIGNALING, WHILE DKK1 AND SFRP1 INHIBIT WNT SIGNALING. STEM CELL SIGNALING NETWORK, CONSISTING OF WNT, NOTCH, FGF, HEDGEHOG AND BMP SIGNALING PATHWAYS, IS ACTIVATED DURING CHRONIC HELICOBACTER PYLORI INFECTION. EPIGENETIC SILENCING OF SFRP1 GENE OCCURS IN THE EARLIER STAGE OF CARCINOGENESIS IN THE STOMACH, WHILE AMPLIFICATION AND OVEREXPRESSION OF FGFR2 GENE IN THE LATER STAGE. DYSREGULATION OF THE STEM CELL SIGNALING NETWORK DUE TO THE ACCUMULATION OF GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION GIVES RISE TO GASTRIC CANCER. SNP TYPING AND CUSTOM-MADE MICROARRAY ANALYSES ON GENES ENCODING STEM CELL SIGNALING MOLECULES COULD BE UTILIZED FOR THE PERSONALIZED MEDICINE. 2007 4 2138 19 EPIGENETIC INHERITANCE OF FETAL GENES IN ALLERGIC ASTHMA. ASTHMA HAS BEEN ASSOCIATED WITH AN EXAGGERATED T-HELPER TYPE 2 (TH2) OVER TH1 RESPONSES TO ALLERGIC AND NONALLERGIC STIMULI, WHICH LEADS TO CHRONIC AIRWAY INFLAMMATION AND AIRWAY REMODELING. IN THE PRESENT ARTICLE, WE PROPOSE THAT MANY OF THE GENES INVOLVED IN IGE SYNTHESIS AND AIRWAYS (RE)MODELING IN ASTHMA ARE PERSISTENT OR REMINISCENT FETAL GENES WHICH MAY NOT BE SILENCED DURING EARLY INFANCY (OR LATE PREGNANCY). GENES OF THE EMBRYOLOGIC DIFFERENTIATION OF ECTODERMIC AND ENDODERMIC TISSUES MAY EXPLAIN SOME OF THE PATTERNS OF AIRWAY REMODELING IN ASTHMA. IN UTERO PROGRAMMING LEADS TO GENE EXPRESSION, THE PERSISTENCE OF WHICH MAY BE ASSOCIATED WITH EPIGENETIC INHERITANCE PHENOMENA INDUCED BY NONSPECIFIC ENVIRONMENTAL FACTORS. CLEAR DELINEATION OF THESE ISSUES MAY YIELD NEW INFORMATION ON THE MECHANISMS OF ASTHMA AND NEW TARGETS FOR THERAPEUTIC INTERVENTION AND PRIMARY PREVENTION. 2004 5 4158 28 MECHANOTRANSDUCTION DETERMINES THE STRUCTURE AND FUNCTION OF LUNG AND BONE: A THEORETICAL MODEL FOR THE PATHOPHYSIOLOGY OF CHRONIC DISEASE. MULTICELLULAR ORGANISMS HAVE EVOLVED IN ADAPTATION TO THE EARTH'S GRAVITATIONAL AND OXYGEN ENVIRONMENT. THIS EPIGENETIC PROCESS IS DEPENDENT ON THE CAPACITY OF MESODERMAL CELLS TO ACT AS MECHANOSENSORS THAT CAN CONFORM, DEFORM, AND REFORM IN ADAPTATION TO THE ORGANISM'S PHYSICAL ENVIRONMENT. MECHANICAL FORCES, SUCH AS HYDROSTATIC PRESSURE AND GRAVITY, PLAY IMPORTANT ROLES IN THE EMBRYONIC DEVELOPMENT, HOMEOSTASIS, AND REPAIR OF LUNG AND BONE. WE DISCUSS THE ROLE OF PARATHYROID HORMONE-RELATED PROTEIN (PTHRP) AS A MECHANOTRANSDUCER FOR STRETCH IN THESE ORGANS DURING NORMAL DEVELOPMENT, PARTICULARLY AS IT LENDS ITSELF TO HOMEOSTASIS; WE FURTHER DEMONSTRATE THAT "UNCOUPLING" OF SUCH MECHANISMS MAY PLAY A CENTRAL ROLE IN INJURY REPAIR, PARTICULARLY AS IT RELATES TO CHRONIC DISEASES OF LUNG AND BONE. ENDOTHERMAL PTHRP SIGNALING THROUGH ITS G-PROTEIN COUPLED RECEPTOR PROMOTES NORMAL CELL-CELL SIGNALING THAT MAINTAINS THE HOMEOSTATIC PHENOTYPES OF LUNG AND BONE. MOLECULAR DISRUPTION OF THE PTHRP/PTHRP RECEPTOR PATHWAY FROM ENDODERM TO MESODERM, BECAUSE OF SUCH FACTORS AS VOLUTRAUMA, HYPEROXIA, INFLAMMATION, AND MICROGRAVITY, ALTERS INTRACELLULAR SIGNALING, CAUSING MALADAPTIVE CELLULAR CHANGES, RESULTING IN MYOFIBROBLAST PROLIFERATION AND GRANULATION. EXAMPLES OF SUCH PATHOLOGIC CHANGES SPECIFICALLY RELATED TO THIS CELLULAR/MOLECULAR MECHANISM OF MALADAPTATION ARE CHRONIC LUNG DISEASE AND OSTEOPOROSIS. WE SUGGEST A NEW PARADIGM THAT MAY HELP IN THE FUTURE CREATION OF DIAGNOSTIC AND THERAPEUTIC MODALITIES FOR A WIDE RANGE OF DEVELOPMENTAL AND CHRONIC DISEASES RANGING FROM BRONCHOPULMONARY DYSPLASIA IN NEWBORNS TO IDIOPATHIC PULMONARY FIBROSIS AND OSTEOPOROSIS AS A RESULT OF AGING OR MICROGRAVITY. 2003 6 2072 23 EPIGENETIC CONVERSION OF HUMAN ADULT BONE MESODERMAL STROMAL CELLS INTO NEUROECTODERMAL CELL TYPES FOR REPLACEMENT THERAPY OF NEURODEGENERATIVE DISORDERS. TISSUE-SPECIFIC STEM CELLS, SUCH AS BONE MARROW-DERIVED MESODERMAL STROMAL CELLS (MSCS), ARE THOUGHT TO BE LINEAGE RESTRICTED AND, THEREFORE, COULD ONLY BE DIFFERENTIATED INTO CELL TYPES OF THE TISSUE OF ORIGIN. SEVERAL RECENT STUDIES, HOWEVER, SUGGEST THAT THESE TYPES OF STEM CELLS MIGHT BE ABLE TO BREAK BARRIERS OF GERM LAYER COMMITMENT AND DIFFERENTIATE IN VITRO AND/OR IN VIVO INTO CELLS OF DIFFERENT TISSUES, SUCH AS NEUROECTODERMAL CELL TYPES. RECENTLY, PROTOCOLS FOR HIGH-YIELD GENERATION OF UNDIFFERENTIATED NEURAL STEM CELL (NSC)-LIKE CELLS FROM MSCS OF PRIMATE AND HUMAN ORIGIN WERE REPORTED. UNDIFFERENTIATED NSCS ARE COMMONLY USED AND ARE MORE SUITABLE FOR NEUROTRANSPLANTATION COMPARED WITH FULLY DIFFERENTIATED NEURAL CELLS, AS DIFFERENTIATED NEURAL CELLS ARE WELL KNOWN TO POORLY SURVIVE DETACHMENT AND SUBSEQUENT TRANSPLANTATION PROCEDURES. THESE HUMAN MSC-DERIVED NSC-LIKE CELLS (MSC-NSCS) GROW IN NEUROSPHERE-LIKE STRUCTURES AND EXPRESS HIGH LEVELS OF EARLY NEUROECTODERMAL MARKERS, BUT LOSE CHARACTERISTICS OF MSCS. IN THE PRESENCE OF SELECTED GROWTH FACTORS, HUMAN MSC-NSCS CAN BE DIFFERENTIATED INTO THE THREE MAIN NEURAL PHENOTYPES: ASTROGLIA, OLIGODENDROGLIA AND NEURONS. COMPARED WITH DIRECT DIFFERENTIATION OF HUMAN MSCS INTO MATURE NEURAL CELLS, THE CONVERSION STEP SEEMS TO BE ESSENTIAL TO GENERATE MATURE FUNCTIONAL NEUROECTODERMAL CELLS. THIS REVIEW DESCRIBES THE TECHNIQUES FOR THE CONVERSION OF HUMAN MSCS INTO NSCS AND SUMMARISES THE DATA ON EPIGENETIC CONVERSION OF HUMAN MSCS INTO IMMATURE NEUROECTODERMAL CELLS. THESE CELLS PROVIDE A POWERFUL TOOL FOR INVESTIGATING THE MOLECULAR MECHANISMS OF NEURAL DIFFERENTIATION, AND MIGHT SERVE AS AN AUTOLOGOUS CELL SOURCE TO TREAT ACUTE AND CHRONIC NEURODEGENERATIVE DISEASES. 2006 7 1116 25 COMPARATIVE ANALYSIS OF NEUROECTODERMAL DIFFERENTIATION CAPACITY OF HUMAN BONE MARROW STROMAL CELLS USING VARIOUS CONVERSION PROTOCOLS. HUMAN ADULT BONE MARROW-DERIVED MESODERMAL STROMAL CELLS (HMSCS) ARE ABLE TO DIFFERENTIATE INTO MULTIPLE MESODERMAL TISSUES, INCLUDING BONE AND CARTILAGE. THERE IS EVIDENCE THAT THESE CELLS ARE ABLE TO BREAK GERM LAYER COMMITMENT AND DIFFERENTIATE INTO CELLS EXPRESSING NEUROECTODERMAL PROPERTIES. THERE IS STILL DEBATE ABOUT WHETHER THIS RESULTS FROM CELL FUSION, ABERRANT MARKER GENE EXPRESSION OR REAL NEUROECTODERMAL DIFFERENTIATION. HERE WE EXTEND OUR WORK ON NEUROECTODERMAL CONVERSION OF ADULT HMSCS IN VITRO BY EVALUATING VARIOUS EPIGENETIC CONVERSION PROTOCOLS USING QUANTITATIVE RT-PCR AND IMMUNOCYTOCHEMISTRY. UNDIFFERENTIATED HMSCS EXPRESSED HIGH LEVELS OF FIBRONECTIN AS WELL AS SEVERAL NEUROECTODERMAL GENES COMMONLY USED TO CHARACTERIZE NEURAL CELL TYPES, SUCH AS NESTIN, BETA-TUBULIN III, AND GFAP, SUGGESTING THAT HMSCS RETAIN THE ABILITY TO DIFFERENTIATE INTO NEUROECTODERMAL CELL TYPES. PROTOCOLS USING A DIRECT DIFFERENTIATION OF HMSCS INTO A NEURAL PHENOTYPE FAILED TO INDUCE SIGNIFICANT CHANGES IN MORPHOLOGY AND/OR EXPRESSION OF MARKERS OF EARLY AND MATURE GLIAL/NEURONAL CELLS TYPES. IN CONTRAST, A MULTISTEP PROTOCOL WITH CONVERSION OF HMSCS INTO A NEURAL STEM CELL-LIKE POPULATION AND SUBSEQUENT TERMINAL DIFFERENTIATION IN MATURE GLIA AND NEURONS GENERATED RELEVANT MORPHOLOGICAL CHANGES AS WELL AS SIGNIFICANT INCREASE OF EXPRESSION LEVELS OF MARKER GENES FOR EARLY AND LATE NEURAL CELL TYPES, SUCH AS NESTIN, NEUROGENIN2, MBP, AND MAP2AB, ACCOMPANIED BY A LOSS OF THEIR MESENCHYMAL PROPERTIES. OUR DATA PROVIDE AN IMPETUS FOR DIFFERENTIATING HMSCS IN VITRO INTO MATURE NEUROECTODERMAL CELLS. NEUROECTODERMALLY CONVERTED HMSCS MAY THEREFORE ULTIMATELY HELP IN TREATING ACUTE AND CHRONIC NEURODEGENERATIVE DISEASES. ANALYSIS OF MARKER GENE EXPRESSION FOR CHARACTERIZATION OF NEURAL CELLS DERIVED FROM MSCS HAS TO TAKE INTO ACCOUNT THAT SEVERAL EARLY AND LATE NEUROECTODERMAL GENES ARE ALREADY EXPRESSED IN UNDIFFERENTIATED MSCS. 2006 8 80 29 A NEW ROLE FOR THE P2Y-LIKE GPR17 RECEPTOR IN THE MODULATION OF MULTIPOTENCY OF OLIGODENDROCYTE PRECURSOR CELLS IN VITRO. OLIGODENDROCYTE PRECURSOR CELLS (OPCS, ALSO CALLED NG2 CELLS) ARE SCATTERED THROUGHOUT BRAIN PARENCHYMA, WHERE THEY FUNCTION AS A RESERVOIR TO REPLACE LOST OR DAMAGED OLIGODENDROCYTES, THE MYELIN-FORMING CELLS. THE HYPOTHESIS THAT, UNDER SOME CIRCUMSTANCES, OPCS CAN ACTUALLY BEHAVE AS MULTIPOTENT CELLS, THUS GENERATING ASTROCYTES AND NEURONS AS WELL, HAS ARISEN FROM SOME IN VITRO AND IN VIVO EVIDENCE, BUT THE MOLECULAR PATHWAYS CONTROLLING THIS ALTERNATIVE FATE OF OPCS ARE NOT FULLY UNDERSTOOD. THEIR IDENTIFICATION WOULD OPEN NEW OPPORTUNITIES FOR NEURONAL REPLACE STRATEGIES, BY FOSTERING THE INTRINSIC ABILITY OF THE BRAIN TO REGENERATE. HERE, WE SHOW THAT THE ANTI-EPILEPTIC EPIGENETIC MODULATOR VALPROIC ACID (VPA) CAN PROMOTE THE GENERATION OF NEW NEURONS FROM NG2(+) OPCS UNDER NEUROGENIC PROTOCOLS IN VITRO, THROUGH THEIR INITIAL DE-DIFFERENTIATION TO A STEM CELL-LIKE PHENOTYPE THAT THEN EVOLVES TO "HYBRID" CELL POPULATION, SHOWING OPC MORPHOLOGY BUT EXPRESSING THE NEURONAL MARKER BETAIII-TUBULIN AND THE GPR17 RECEPTOR, A KEY DETERMINANT IN DRIVING OPC TRANSITION TOWARDS MYELINATING OLIGODENDROCYTES. UNDER THESE CONDITIONS, THE PHARMACOLOGICAL BLOCKADE OF THE P2Y-LIKE RECEPTOR GPR17 BY CANGRELOR, A DRUG RECENTLY APPROVED FOR HUMAN USE, PARTIALLY MIMICS THE EFFECTS MEDIATED BY VPA THUS ACCELERATING CELLS' NEUROGENIC CONVERSION. THESE DATA SHOW A CO-LOCALIZATION BETWEEN NEURONAL MARKERS AND GPR17 IN VITRO, AND SUGGEST THAT, BESIDES ITS INVOLVEMENT IN OLIGODENDROGENESIS, GPR17 CAN DRIVE THE FATE OF NEURAL PRECURSOR CELLS BY INSTRUCTING PRECURSORS TOWARDS THE NEURONAL LINEAGE. BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL "DRUGGABLE" TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC BRAIN DISEASES. 2016 9 4529 16 MULTIGENERATIONAL GRAPHENE OXIDE INTOXICATION RESULTS IN REPRODUCTION DISORDERS AT THE MOLECULAR LEVEL OF VITELLOGENIN PROTEIN EXPRESSION IN ACHETA DOMESTICUS. THE ANTHROPOGENIC ACTIVITIES MAY LEAD TO ACCUMULATION OF GRAPHENE OXIDE (GO) POLLUTION IN THE ENVIRONMENT. ORGANISMS EXPOSED TO CHRONIC OR MULTIGENERATIONAL GO INTOXICATION CAN PRESENT REPRODUCTION DEPLETION. VITELLOGENIN (VG) HAS BEEN USED AS A PARAMETER FOR EVALUATING FEMALE FERTILITY DUE TO ITS IMPORTANCE IN EMBRYO NUTRITION. IN THIS STUDY, WE USED A PROMISING MODEL ORGANISM, ACHETA DOMESTICUS, WHICH WAS INTOXICATED WITH GO IN FOOD FOR THREE GENERATIONS. THE AIM OF THE STUDY WAS TO INVESTIGATE THE PROCESS OF VG SYNTHESIS IN CRICKETS DEPENDING ON THE EXPOSURE TIME, GO CONCENTRATION, AND AGE OF THE FEMALES. THE RESULTS REVEALED THAT CHRONIC GO INTOXICATION HAD ADVERSE EFFECTS ON THE VG EXPRESSION PATTERN. THE 1ST GENERATION OF INSECTS SHOWING LOW VG EXPRESSION WAS MOST AFFECTED. THE 2ND GENERATION OF A. DOMESTICUS PRESENTED A HIGH VG EXPRESSION. THE LAST INVESTIGATED GENERATION SEEMED TO COPE WITH STRESS CAUSED BY GO, AND THE VG EXPRESSION WAS BALANCED. WE SUGGEST THAT THE EPIGENETIC MECHANISMS MAY PLAY A ROLE IN THE INFORMATION TRANSFER TO THE NEXT GENERATIONS ON HOW TO REACT TO THE RISK FACTOR AND KEEP REPRODUCTION AT A HIGH RATE. WE SUSPECT THAT CHRONIC GO INTOXICATION CAN DISTURB THE REGULAR FORMATION OF THE VG QUATERNARY STRUCTURE, RESULTING IN CONSEQUENCES FOR DEVELOPING AN EMBRYO. 2021 10 6756 44 WNT ANTAGONIST, SFRP1, IS HEDGEHOG SIGNALING TARGET. HEDGEHOG AND WNT SIGNALING PATHWAYS NETWORK TOGETHER DURING EMBRYOGENESIS AND CARCINOGENESIS. HEDGEHOG SIGNALING IN INTESTINAL EPITHELIUM REPRESSES CANONICAL WNT SIGNALING TO RESTRICT EXPRESSION OF WNT TARGET GENES TO STEM OR PROGENITOR CELLS; HOWEVER, THE MECHANISM REMAINS UNCLEAR. THE HEDGEHOG SIGNAL IS TRANSDUCED TO GLI FAMILY TRANSCRIPTION FACTORS THOUGH PATCHED RECEPTOR, SMOOTHENED SIGNAL TRANSDUCER, AND OTHER SIGNALING COMPONENTS, SUCH AS KIF27, KIF7, STK36, SUFU, AND DZIP1. HERE, WE SEARCHED FOR THE GLI-BINDING SITE WITHIN THE PROMOTER REGION OF GENES ENCODING SECRETED-TYPE WNT SIGNAL INHIBITORS, INCLUDING SFRP1, SFRP2, SFRP3, SFRP4, SFRP5, DKK1, DKK2, DKK3, DKK4, AND WIF1. THE GLI-BINDING SITE WAS IDENTIFIED WITHIN THE HUMAN SFRP1 PROMOTER BASED ON BIOINFORMATICS AND HUMAN INTELLIGENCE. THE CHIMPANZEE SFRP1 GENE WAS IDENTIFIED WITHIN THE NW_110515.1 GENOME SEQUENCE. THE GLI-BINDING SITE OF THE HUMAN SFRP1 PROMOTER WAS CONSERVED IN CHIMPANZEE SFRP1, MOUSE SFRP1, AND RAT SFRP1 PROMOTERS. SFRP1 IS THE EVOLUTIONARILY CONSERVED TARGET OF THE HEDGEHOG-GLI SIGNALING PATHWAY. EXPRESSION DOMAIN ANALYSES BASED ON TEXT MINING REVEALED THAT INDIAN HEDGEHOG (IHH), SFRP1, AND WNT6 ARE EXPRESSED IN DIFFERENTIATED INTESTINAL EPITHELIAL CELLS, MESENCHYMAL CELLS, AND STEM/PROGENITOR CELLS, RESPECTIVELY. HEDGEHOG IS SECRETED FROM DIFFERENTIATED EPITHELIAL CELLS TO INDUCE SFRP1 EXPRESSION IN MESENCHYMAL CELLS, WHICH KEEPS DIFFERENTIATED EPITHELIAL CELLS AWAY FROM THE EFFECTS OF CANONICAL WNT SIGNALING. THESE FACTS INDICATE THAT SFRP1 IS THE HEDGEHOG TARGET TO CONFINE CANONICAL WNT SIGNALING WITHIN STEM OR PROGENITOR CELLS. THEREFORE, EPIGENETIC CPG HYPERMETHYLATION OF THE SFRP1 PROMOTER DURING CHRONIC PERSISTENT INFLAMMATION AND AGING LEADS TO THE OCCURRENCE OF GASTROINTESTINAL CANCERS, SUCH AS COLORECTAL CANCER AND GASTRIC CANCER, THROUGH THE BREAKDOWN OF HEDGEHOG-DEPENDENT WNT SIGNAL INHIBITION. 2006 11 2882 22 G-PROTEIN-COUPLED RECEPTOR GPR17 REGULATES OLIGODENDROCYTE DIFFERENTIATION IN RESPONSE TO LYSOLECITHIN-INDUCED DEMYELINATION. OLIGODENDROCYTES ARE THE MYELIN-PRODUCING CELLS OF THE CENTRAL NERVOUS SYSTEM (CNS). A VARIETY OF BRAIN DISORDERS FROM "CLASSICAL" DEMYELINATING DISEASES, SUCH AS MULTIPLE SCLEROSIS, STROKE, SCHIZOPHRENIA, DEPRESSION, DOWN SYNDROME AND AUTISM, ARE SHOWN MYELINATION DEFECTS. OLIGODENDROCYTE MYELINATION IS REGULATED BY A COMPLEX INTERPLAY OF INTRINSIC, EPIGENETIC AND EXTRINSIC FACTORS. GPR17 (G PROTEIN-COUPLED RECEPTOR 17) IS A G PROTEIN-COUPLED RECEPTOR, AND HAS BEEN IDENTIFIED TO BE A REGULATOR FOR OLIGODENDROCYTE DEVELOPMENT. HERE, WE DEMONSTRATE THAT THE ABSENCE OF GPR17 ENHANCES REMYELINATION IN VIVO WITH A TOXIN-INDUCED MODEL WHEREBY FOCAL DEMYELINATED LESIONS ARE GENERATED IN SPINAL CORD WHITE MATTER OF ADULT MICE BY LOCALIZED INJECTION OF LPC(L-A-LYSOPHOSPHATIDYLCHOLINE). THE INCREASED EXPRESSION OF THE ACTIVATED FORM OF ERK1/2 (PHOSPHO-ERK1/2) IN LESION AREAS SUGGESTED THE POTENTIAL ROLE OF ERK1/2 ACTIVITY ON THE GPR17-DEPENDENT MODULATION OF MYELINATION. THE ABSENCE OF GPR17 ENHANCES REMYELINATION IS CORRELATE WITH THE ACTIVATED ERK1/2 (PHOSPHO-ERK1/2).BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL DRUGGABLE TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC CNS DISEASES. 2018 12 5408 24 REGULATION AND SIGNALING OF THE GPR17 RECEPTOR IN OLIGODENDROGLIAL CELLS. REMYELINATION, NAMELY, THE FORMATION OF NEW MYELIN SHEATHS AROUND DENUDED AXONS, COUNTERACTS AXONAL DEGENERATION AND RESTORES NEURONAL FUNCTION. CONSIDERABLE ADVANCES HAVE BEEN MADE IN UNDERSTANDING THIS REGENERATIVE PROCESS THAT OFTEN FAILS IN DISEASES LIKE MULTIPLE SCLEROSIS, LEAVING AXONS DEMYELINATED AND VULNERABLE TO DAMAGE, THUS CONTRIBUTING TO DISEASE PROGRESSION. THE IDENTIFICATION OF THE MEMBRANE RECEPTOR GPR17 ON A SUBSET OF OLIGODENDROCYTE PRECURSOR CELLS (OPCS), WHICH MEDIATE REMYELINATION IN THE ADULT CENTRAL NERVOUS SYSTEM (CNS), HAS LED TO A HUGE AMOUNT OF EVIDENCE THAT VALIDATED THIS RECEPTOR AS A NEW ATTRACTIVE TARGET FOR REMYELINATING THERAPIES. HERE, WE SUMMARIZE THE ROLE OF GPR17 IN OPC FUNCTION, MYELINATION AND REMYELINATION, DESCRIBING ITS ATYPICAL PHARMACOLOGY, ITS DOWNSTREAM SIGNALING, AND THE GENETIC AND EPIGENETIC FACTORS MODULATING ITS ACTIVITY. WE ALSO HIGHLIGHT CRUCIAL INSIGHTS INTO GPR17 PATHOPHYSIOLOGY COMING FROM THE DEMONSTRATION THAT OLIGODENDROCYTE INJURY, ASSOCIATED WITH INFLAMMATION IN CHRONIC NEURODEGENERATIVE CONDITIONS, IS INVARIABLY CHARACTERIZED BY ABNORMAL AND PERSISTENT GPR17 UPREGULATION, WHICH, IN TURN, IS ACCOMPANIED BY A BLOCK OF OPCS AT IMMATURE PREMYELINATING STAGES. FINALLY, WE DISCUSS THE CURRENT LITERATURE IN LIGHT OF THE POTENTIAL EXPLOITMENT OF GPR17 AS A THERAPEUTIC TARGET TO PROMOTE REMYELINATION. 2020 13 2786 17 EZH2 RESTRICTS THE SMOOTH MUSCLE LINEAGE DURING MOUSE LUNG MESOTHELIAL DEVELOPMENT. DURING DEVELOPMENT, THE LUNG MESODERM GENERATES A VARIETY OF CELL LINEAGES, INCLUDING AIRWAY AND VASCULAR SMOOTH MUSCLE. EPIGENETIC CHANGES IN ADULT LUNG MESODERMAL LINEAGES ARE THOUGHT TO CONTRIBUTE TOWARDS DISEASES SUCH AS IDIOPATHIC PULMONARY FIBROSIS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ALTHOUGH THE FACTORS THAT REGULATE EARLY LUNG MESODERM DEVELOPMENT ARE UNKNOWN. WE SHOW IN MOUSE THAT THE PRC2 COMPONENT EZH2 IS REQUIRED TO RESTRICT SMOOTH MUSCLE DIFFERENTIATION IN THE DEVELOPING LUNG MESOTHELIUM. MESODERMAL LOSS OF EZH2 LEADS TO THE FORMATION OF ECTOPIC SMOOTH MUSCLE IN THE SUBMESOTHELIAL REGION OF THE DEVELOPING LUNG MESODERM. LOSS OF EZH2 SPECIFICALLY IN THE DEVELOPING MESOTHELIUM REVEALS A MESOTHELIAL CELL-AUTONOMOUS ROLE FOR EZH2 IN REPRESSION OF THE SMOOTH MUSCLE DIFFERENTIATION PROGRAM. LOSS OF EZH2 DEREPRESSES EXPRESSION OF MYOCARDIN AND TBX18, WHICH ARE IMPORTANT REGULATORS OF SMOOTH MUSCLE DIFFERENTIATION FROM THE MESOTHELIUM AND RELATED CELL LINEAGES. TOGETHER, THESE FINDINGS UNCOVER AN EZH2-DEPENDENT MECHANISM TO RESTRICT THE SMOOTH MUSCLE GENE EXPRESSION PROGRAM IN THE DEVELOPING MESOTHELIUM AND ALLOW APPROPRIATE CELL FATE DECISIONS TO OCCUR IN THIS MULTIPOTENT MESODERM LINEAGE. 2016 14 2468 29 EPIGENETIC TOXICOLOGY AS TOXICANT-INDUCED CHANGES IN INTRACELLULAR SIGNALLING LEADING TO ALTERED GAP JUNCTIONAL INTERCELLULAR COMMUNICATION. COMMUNICATION MECHANISMS [EXTRA-, INTRA-, AND GAP JUNCTIONAL INTER-CELLULAR COMMUNICATION (GJIC)] CONTROL, FROM THE FERTILIZED EGG, THROUGH EMBRYOGENESIS TO MATURITY AND AGING, WHETHER A CELL PROLIFERATES, DIFFERENTIATES, DIES BY APOPTOSIS, OR IF DIFFERENTIATED, ADAPTIVELY RESPONDS TO ENDOGENOUS AND EXOGENOUS SIGNALS. FROM THE EGG TO THE 100 TRILLION CELLS IN THE HUMAN BODY, HEALTH IS MAINTAINED WHEN THESE COMMUNICATION PROCESSES BETWEEN STEM, PROGENITOR AND TERMINALLY DIFFERENTIATED CELLS ARE INTEGRATED. EACH CELL CHOICE INVOLVES 'EPIGENETIC' MECHANISMS TO ALTER THE EXPRESSION OF GENES AT THE TRANSCRIPTIONAL, TRANSLATIONAL OR POST-TRANSLATIONAL LEVELS. DISRUPTION OF THE COMMUNICATION MECHANISMS CAN BE EITHER ADAPTIVE OR MALADAPTIVE. MODULATION OF EXTRA-CELLULAR COMMUNICATION, EITHER BY GENETIC IMBALANCES OF GROWTH FACTORS, HORMONES OR NEUROTRANSMITTERS OR BY ENVIRONMENTAL, EXOGENOUS CHEMICALS CAN TRIGGER SIGNAL TRANSDUCING INTRA-CELLULAR MECHANISMS. THESE INTRA-CELLULAR SIGNALS CAN MODULATE GENE EXPRESSION AT THE TRANSCRIPTIONAL, TRANSLATIONAL OR POST-TRANSLATIONAL LEVELS WHILE ALSO MODULATING GJIC. UNTIMELY OR CHRONIC DISRUPTION OF GJIC DURING EMBRYONIC OR FETAL DEVELOPMENT COULD LEAD TO EMBRYONIC LETHALITY OR TERATOGENESIS. BY MODULATION OF GJIC, HOMEOSTATIC CONTROL OF CELL GROWTH, DIFFERENTIATION OR APOPTOSIS COULD LEAD TO SPECIFIC DISEASES, SUCH AS NEUROLOGICAL, CARDIOVASCULAR, REPRODUCTIVE OR ENDOCRINOLOGICAL DYSFUNCTION. CHEMICAL MODULATION OR ONCOGENE DOWN-REGULATION OF GJIC IN INITIATED TISSUES HAS BEEN SHOWN TO LEAD TO TUMOR PROMOTION. GENETIC SYNDROMES CARRYING A MUTATED GAP JUNCTION GENE, TOGETHER WITH SOME TRANSGENIC AND KNOCK-OUT GAP JUNCTION GENE MICE, PROVIDE EVIDENCE FOR THE IMPORTANCE OF THIS ORGANELLE FOUND ONLY IN METAZOANS. IMPLICATIONS FOR 'THRESHOLDS' TO TOXICANTS AND FOR RISK ASSESSMENT ARE EVIDENT. 1998 15 2772 28 EXTRACELLULAR ATP AND NEURODEGENERATION. ATP IS A POTENT SIGNALING MOLECULE ABUNDANTLY PRESENT IN THE CNS. IT ELICITS A WIDE ARRAY OF PHYSIOLOGICAL EFFECTS AND IS REGARDED AS THE PHYLOGENETICALLY MOST ANCIENT EPIGENETIC FACTOR PLAYING CRUCIAL BIOLOGICAL ROLES IN SEVERAL DIFFERENT TISSUES. THESE CAN RANGE FROM NEUROTRANSMISSION, SMOOTH MUSCLE CONTRACTION, CHEMOSENSORY SIGNALING, SECRETION AND VASODILATATION, TO MORE COMPLEX PHENOMENA SUCH AS IMMUNE RESPONSES, PAIN, MALE REPRODUCTION, FERTILIZATION AND EMBRYONIC DEVELOPMENT. ATP IS RELEASED INTO THE EXTRACELLULAR SPACE EITHER EXOCYTOTICALLY OR FROM DAMAGED AND DYING CELLS. IT IS OFTEN CO-RELEASED WITH OTHER NEUROTRANSMITTERS AND IT CAN INTERACT WITH GROWTH FACTORS AT BOTH RECEPTOR- AND/OR SIGNAL TRANSDUCTION-LEVEL. ONCE IN THE EXTRACELLULAR ENVIRONMENT, ATP BINDS TO SPECIFIC RECEPTORS TERMED P2. BASED ON PHARMACOLOGICAL PROFILES, ON SELECTIVITY OF COUPLING TO SECOND-MESSENGER PATHWAYS AND ON MOLECULAR CLONING, TWO MAIN SUBCLASSES WITH MULTIPLE SUBTYPES HAVE BEEN DISTINGUISHED. THEY ARE P2X, I.E. FAST CATION-SELECTIVE RECEPTOR CHANNELS (NA+, K+, CA2+), POSSESSING LOW AFFINITY FOR ATP AND RESPONSIBLE FOR FAST EXCITATORY NEUROTRANSMISSION, AND P2Y, I.E. SLOW G PROTEIN-COUPLED METABOTROPIC RECEPTORS, POSSESSING HIGHER AFFINITY FOR THE LIGAND. IN THE NERVOUS SYSTEM, THEY ARE BROADLY EXPRESSED IN BOTH NEURONS AND GLIAL CELLS AND CAN MEDIATE DUAL EFFECTS: SHORT-TERM SUCH AS NEUROTRANSMISSION, AND LONG-TERM SUCH AS TROPHIC ACTIONS. SINCE MASSIVE EXTRACELLULAR RELEASE OF ATP OFTEN OCCURS AFTER METABOLIC STRESS, BRAIN ISCHEMIA AND TRAUMA, PURINERGIC MECHANISMS ARE ALSO CORRELATED TO AND INVOLVED IN THE ETIOPATHOLOGY OF MANY NEURODEGENERATIVE CONDITIONS. FURTHERMORE, EXTRACELLULAR ATP PER SE IS TOXIC FOR PRIMARY NEURONAL DISSOCIATED AND ORGANOTYPIC CNS CULTURES FROM CORTEX, STRIATUM AND CEREBELLUM AND P2 RECEPTORS CAN MEDIATE AND AGGRAVATE HYPOXIC SIGNALING IN MANY CNS NEURONS. CONVERSELY, SEVERAL P2 RECEPTOR ANTAGONISTS ABOLISH THE CELL DEATH FATE OF PRIMARY NEURONAL CULTURES EXPOSED TO EXCESSIVE GLUTAMATE, SERUM/POTASSIUM DEPRIVATION, HYPOGLYCEMIA AND CHEMICAL HYPOXIA. IN PARALLEL WITH THESE DETRIMENTAL EFFECTS, ALSO TROPHIC FUNCTIONS HAVE BEEN EXTENSIVELY DESCRIBED FOR EXTRACELLULAR PURINES (BOTH FOR NEURONAL AND NON-NEURONAL CELLS), BUT THESE MIGHT EITHER AGGRAVATE OR AMELIORATE THE NORMAL CELLULAR CONDITIONS. IN SUMMARY, EXTRACELLULAR ATP PLAYS A VERY COMPLEX ROLE NOT ONLY IN THE REPAIR, REMODELING AND SURVIVAL OCCURRING IN THE NERVOUS SYSTEM, BUT EVEN IN CELL DEATH AND THIS CAN OCCUR EITHER AFTER NORMAL DEVELOPMENTAL CONDITIONS, AFTER INJURY, OR ACUTE AND CHRONIC DISEASES. 2003 16 5083 30 PICKING A BONE WITH WISP1 (CCN4): NEW STRATEGIES AGAINST DEGENERATIVE JOINT DISEASE. AS THE WORLD'S POPULATION CONTINUES TO AGE, IT IS ESTIMATED THAT DEGENERATIVE JOINT DISEASE DISORDERS SUCH AS OSTEOARTHRITIS WILL IMPACT AT LEAST 130 MILLION INDIVIDUALS THROUGHOUT THE GLOBE BY THE YEAR 2050. ADVANCED AGE, OBESITY, GENETICS, GENDER, BONE DENSITY, TRAUMA, AND A POOR LEVEL OF PHYSICAL ACTIVITY CAN LEAD TO THE ONSET AND PROGRESSION OF OSTEOARTHRITIS. HOWEVER, FACTORS THAT LEAD TO DEGENERATIVE JOINT DISEASE AND INVOLVE GENDER, GENETICS, EPIGENETIC MECHANISMS, AND ADVANCED AGE ARE NOT WITHIN THE CONTROL OF AN INDIVIDUAL. FURTHERMORE, CURRENT THERAPIES INCLUDING PAIN MANAGEMENT, IMPROVED NUTRITION, AND REGULAR PROGRAMS FOR EXERCISE DO NOT LEAD TO THE RESOLUTION OF OSTEOARTHRITIS. AS A RESULT, NEW AVENUES FOR TARGETING THE TREATMENT OF OSTEOARTHRITIS ARE DESPERATELY NEEDED. WNT1 INDUCIBLE SIGNALING PATHWAY PROTEIN 1 (WISP1), A MATRICELLULAR PROTEIN AND A DOWNSTREAM TARGET OF THE WINGLESS PATHWAY WNT1, IS ONE SUCH TARGET TO CONSIDER THAT GOVERNS CELLULAR PROTECTION, STEM CELL PROLIFERATION, AND TISSUE REGENERATION IN A NUMBER OF DISORDERS INCLUDING BONE DEGENERATION. HOWEVER, INCREASED WISP1 EXPRESSION ALSO HAS BEEN ASSOCIATED WITH THE PROGRESSION OF OSTEOARTHRITIS. WISP1 HAS AN INTRICATE RELATIONSHIP WITH A NUMBER OF PROLIFERATIVE AND PROTECTIVE PATHWAYS THAT INCLUDE PHOSPHOINOSITIDE 3-KINASE (PI 3-K), PROTEIN KINASE B (AKT), NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB), INTERLEUKIN -6 (IL-6), TRANSFORMING GROWTH FACTOR-BETA, MATRIX METALLOPROTEINASE, SMALL NON-CODING RIBONUCLEIC ACIDS (RNAS), SIRTUIN SILENT MATING TYPE INFORMATION REGULATION 2 HOMOLOG 1 (SACCHAROMYCES CEREVISIAE) (SIRT1), AND THE MECHANISTIC TARGET OF RAPAMYCIN (MTOR). TAKEN TOGETHER, THIS COMPLEX ASSOCIATION WISP1 HOLDS WITH THESE SIGNALING PATHWAYS NECESSITATES A FINE BIOLOGICAL REGULATION OF WISP1 ACTIVITY THAT CAN OFFSET THE PROGRESSION OF DEGENERATIVE JOINT DISEASE, BUT NOT LIMIT THE CELLULAR PROTECTIVE CAPABILITIES OF THE WISP1 PATHWAY. 2016 17 5600 22 ROLES OF VOLTAGE-DEPENDENT SODIUM CHANNELS IN NEURONAL DEVELOPMENT, PAIN, AND NEURODEGENERATION. BESIDES INITIATING AND PROPAGATING ACTION POTENTIALS IN ESTABLISHED NEURONAL CIRCUITS, VOLTAGE-DEPENDENT SODIUM CHANNELS SCULPT AND BOLSTER THE FUNCTIONAL NEURONAL NETWORK FROM EARLY IN EMBRYONIC DEVELOPMENT THROUGH ADULTHOOD (E.G., DIFFERENTIATION OF OLIGODENDROCYTE PRECURSOR CELLS INTO OLIGODENDROCYTES, MYELINATING AXON; COMPETITION BETWEEN NEIGHBORING EQUIPOTENTIAL NEURITES FOR DEVELOPMENT INTO A SINGLE AXON; ENHANCING AND OPPOSING FUNCTIONAL INTERACTIONS WITH ATTRACTIVE AND REPULSIVE MOLECULES FOR AXON PATHFINDING; EXTENDING AND RETRACTING TERMINAL ARBORIZATION OF AXON FOR CORRECT SYNAPSE FORMATION; EXPERIENCE-DRIVEN COGNITION; NEURONAL SURVIVAL; AND REMYELINATION OF DEMYELINATED AXONS). SURPRISINGLY, DIFFERENT PATTERNS OF ACTION POTENTIALS DIRECT HOMEOSTASIS-BASED EPIGENETIC SELECTION FOR NEUROTRANSMITTER PHENOTYPE, THUS EXCITABILITY BY SODIUM CHANNELS SPECIFYING EXPRESSION OF INHIBITORY NEUROTRANSMITTERS. MECHANISMS FOR THESE PLEIOTROPIC EFFECTS OF SODIUM CHANNELS INCLUDE RECIPROCAL INTERACTIONS BETWEEN NEURONS AND GLIA VIA NEUROTRANSMITTERS, GROWTH FACTORS, AND CYTOKINES AT SYNAPSES AND AXONS. SODIUM CHANNELOPATHIES CAUSING PAIN (E.G., ALLODYNIA) AND NEURODEGENERATION (E.G., MULTIPLE SCLEROSIS) DERIVE FROM 1) ELECTROPHYSIOLOGICAL DISTURBANCES BY INSULTS (E.G., ISCHEMIA/HYPOXIA, TOXINS, AND ANTIBODIES); 2) LOSS-OF-PHYSIOLOGICAL FUNCTION OR GAIN-OF-PATHOLOGICAL FUNCTION OF MUTANT SODIUM CHANNEL PROTEINS; 3) SPATIOTEMPORAL INAPPROPRIATE EXPRESSION OF NORMAL SODIUM CHANNEL PROTEINS; OR 4) DE-REPRESSED EXPRESSION OF OTHERWISE SILENT SODIUM CHANNEL GENES. NA(V)1.7 PROVED TO ACCOUNT FOR PAIN IN HUMAN ERYTHERMALGIA AND INFLAMMATION, BEING THE CONVINCING MOLECULAR TARGET OF PAIN TREATMENT. 2006 18 4304 25 MICRORNA-223 PROTECTS NEURONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. MULTIPLE SCLEROSIS IS A CHRONIC INFLAMMATORY, DEMYELINATING, AND NEURODEGENERATIVE DISEASE AFFECTING THE BRAIN, SPINAL CORD AND OPTIC NERVES. NEURONAL DAMAGE IS TRIGGERED BY VARIOUS HARMFUL FACTORS THAT ENGAGE DIVERSE SIGNALLING CASCADES IN NEURONS; THUS, THERAPEUTIC APPROACHES TO PROTECT NEURONS WILL NEED TO FOCUS ON AGENTS THAT CAN TARGET MULTIPLE BIOLOGICAL PROCESSES. WE HAVE THEREFORE FOCUSED OUR ATTENTION ON MICRORNAS: SMALL NON-CODING RNAS THAT PRIMARILY FUNCTION AS POST-TRANSCRIPTIONAL REGULATORS THAT TARGET MESSENGER RNAS AND REPRESS THEIR TRANSLATION INTO PROTEINS. A SINGLE MICRORNA CAN TARGET MANY FUNCTIONALLY RELATED MESSENGER RNAS MAKING MICRORNAS POWERFUL EPIGENETIC REGULATORS. DYSREGULATION OF MICRORNAS HAS BEEN DESCRIBED IN MANY NEURODEGENERATIVE DISEASES INCLUDING MULTIPLE SCLEROSIS. HERE, WE REPORT THAT TWO MICRORNAS, MIR-223-3P AND MIR-27A-3P, ARE UPREGULATED IN NEURONS IN THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS MOUSE MODEL OF CNS INFLAMMATION AND IN GREY MATTER-CONTAINING MULTIPLE SCLEROSIS LESIONS. PRIOR WORK HAS SHOWN PERIPHERAL BLOOD MONONUCLEAR CELL CONDITIONED MEDIA CAUSES SUBLETHAL DEGENERATION OF NEURONS IN CULTURE. WE FIND OVEREXPRESSION OF MIR-27A-3P OR MIR-223-3P PROTECTS DISSOCIATED CORTICAL NEURONS FROM CONDITION MEDIA MEDIATED DEGENERATION. INTRODUCTION OF MIR-223-3P IN VIVO IN MOUSE RETINAL GANGLION CELLS PROTECTS THEIR AXONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. IN SILICO ANALYSIS REVEALED THAT MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING ARE ENRICHED AS MIR-27A-3P AND MIR-223-3P TARGETS. WE OBSERVE THAT ANTAGONISM OF NMDA AND AMPA TYPE GLUTAMATE RECEPTORS PROTECTS NEURONS FROM CONDITION MEDIA DEPENDENT DEGENERATION. OUR RESULTS SUGGEST THAT MIR-223-3P AND MIR-27A-3P ARE UPREGULATED IN RESPONSE TO INFLAMMATION TO MEDIATE A COMPENSATORY NEUROPROTECTIVE GENE EXPRESSION PROGRAM THAT DESENSITIZES NEURONS TO GLUTAMATE BY TARGETING MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING. 2019 19 6263 39 THE MULTIPLE WAYS WNT SIGNALING CONTRIBUTES TO ACUTE LEUKEMIA PATHOGENESIS. WNT PROTEINS CONSTITUTE A VERY CONSERVED FAMILY OF SECRETED GLYCOPROTEINS THAT ACT AS SHORT-RANGE LIGANDS FOR SIGNALING WITH CRITICAL ROLES IN HEMATOPOIESIS, EMBRYONIC DEVELOPMENT, AND TISSUE HOMEOSTASIS. THESE PROTEINS TRANSDUCE SIGNALS VIA THE CANONICAL PATHWAY, WHICH IS BETA-CATENIN-MEDIATED AND BETTER-CHARACTERIZED, OR VIA MORE DIVERSE NONCANONICAL PATHWAYS THAT ARE BETA-CATENIN INDEPENDENT AND COMPRISE THE PLANAR CELL POLARITY (PCP) PATHWAY AND THE WNT/CA(++) PATHWAYS. SEVERAL PROTEINS REGULATE WNT SIGNALING THROUGH A VARIETY OF SOPHISTICATED MECHANISMS. DISORDERS WITHIN THE PATHWAY CAN CONTRIBUTE TO VARIOUS HUMAN DISEASES, AND THE DYSREGULATION OF WNT PATHWAYS BY DIFFERENT MOLECULAR MECHANISMS IS IMPLICATED IN THE PATHOGENESIS OF MANY TYPES OF CANCER, INCLUDING THE HEMATOLOGICAL MALIGNANCIES. THE TYPES OF LEUKEMIA DIFFER CONSIDERABLY AND CAN BE SUBDIVIDED INTO CHRONIC, MYELOID OR LYMPHOCYTIC, AND ACUTE, MYELOID OR LYMPHOCYTIC, LEUKEMIA, ACCORDING TO THE DIFFERENTIATION STAGE OF THE PREDOMINANT CELLS, THE PROGENITOR LINEAGE, THE DIAGNOSTIC AGE STRATA, AND THE SPECIFIC MOLECULAR DRIVERS BEHIND THEIR DEVELOPMENT. HERE, WE REVIEW THE ROLE OF WNT SIGNALING IN NORMAL HEMATOPOIESIS AND DISCUSS IN DETAIL THE MULTIPLE WAYS CANONICAL WNT SIGNALING CAN BE DYSREGULATED IN ACUTE LEUKEMIA, INCLUDING ALTERATIONS IN GENE EXPRESSION AND PROTEIN LEVELS, EPIGENETIC REGULATION, AND MUTATIONS. FURTHERMORE, WE HIGHLIGHT THE DIFFERENT IMPACTS OF THESE ALTERATIONS, CONSIDERING THE DISTINCT FORMS OF THE DISEASE, AND THE THERAPEUTIC POTENTIAL OF TARGETING WNT SIGNALING. 2020 20 620 30 BIOCHEMISTRY AND MOLECULAR BIOLOGY OF GELATINASE B OR MATRIX METALLOPROTEINASE-9 (MMP-9): THE NEXT DECADE. RESEARCH ON MATRIX METALLOPROTEINASES (MMPS) AND IN PARTICULAR ON GELATINASE B, ALIAS MMP-9, HAS GROWN EXPONENTIALLY IN THE DECADE 2003-2012. STRUCTURAL DETAILS ABOUT FLEXIBILITY OF MMP-9 MONOMERS, TOGETHER WITH GLYCOSYLATION, OLIGOMERIZATION, HETEROGENEITY AND INSTABILITY OF THE WILDTYPE ENZYME EXPLAIN WHY CRYSTALLOGRAPHY EXPERIMENTS HAVE NOT YET BEEN SUCCESSFUL FOR THE INTACT ENZYME. MMP-9 MAY BE VIEWED AS A MULTIDOMAIN ENZYME IN WHICH THE HEMOPEXIN, THE O-GLYCOSYLATED AND THE CATALYTIC DOMAINS YIELD SUPPORT FOR ATTACHMENT, ARTICULATION AND CATALYSIS, RESPECTIVELY. THE STEPWISE PROTEOLYTIC ACTIVATION OF THE INACTIVE ZYMOGEN INTO A CATALYTICALLY ACTIVE FORM BECOMES GRADUALLY BETTER UNDERSTOOD. PRIMING OF ACTIVATION BY MMP-3 MAY BE EXECUTED BY MEPRINS THAT DESTABILIZE THE INTERACTION OF THE AMINOTERMINUS WITH THE THIRD FIBRONECTIN REPEAT. ALTERNATIVELY, AUTOCATALYTIC ACTIVATION MAY OCCUR IN THE PRESENCE OF MOLECULES THAT TIGHTLY BIND TO THE CATALYTIC SITE AND THAT PUSH THE CYSTEIN RESIDUE IN THE PRODOMAIN AWAY FROM THE CATALYTIC ZINC ION. THANKS TO THE DEVELOPMENT OF DEGRADOMICS TECHNOLOGIES, SUBSTRATE REPERTOIRES OF MMP-9 HAVE BEEN DEFINED, BUT IT REMAINS A CHALLENGE TO DETERMINE AND PROVE WHICH SUBSTRATES ARE BIOLOGICALLY RELEVANT. THE SUBSTRATE REPERTOIRE HAS BEEN ENLARGED FROM EXTRACELLULAR TO MEMBRANE-BOUND AND EFFICIENT INTRACELLULAR SUBSTRATES, SUCH AS CRYSTALLINS, TUBULINS AND ACTINS. BIOLOGICAL STUDIES OF MMP-9 HAVE TUNED THE FIELD FROM BEING PRIMARILY CANCER-ORIENTED TOWARDS VASCULAR AND INFLAMMATORY RESEARCH. IN TUMOR BIOLOGY, IT HAS BEEN INCREASINGLY APPRECIATED THAT MMP-9 FROM INFLAMMATORY CELLS, PARTICULARLY NEUTROPHILS, CO-DETERMINES PROGNOSIS AND OUTCOME. ASIDE FROM THE CATALYTIC FUNCTIONS EXECUTED BY AMINOTERMINAL DOMAINS OF MMP-9, THE CARBOXYTERMINAL HEMOPEXIN (PEX) DOMAIN OF GELATINASE B EXERTS NON-CATALYTIC ANTI-APOPTOTIC SIGNALING EFFECTS. THE RECOGNITION THAT GELATINASE B IS INDUCED BY MANY PRO-INFLAMMATORY CYTOKINES, WHEREAS ITS INHIBITORS ARE INCREASED BY ANTI-INFLAMMATORY CYTOKINES, HAS GENERATED INTEREST TO TARGET MMP-9 IN ACUTE LETHAL CONDITIONS, SUCH AS BACTERIAL MENINGITIS, SEPSIS AND ENDOTOXIN SHOCK, AND IN ACUTE EXACERBATIONS OF CHRONIC DISEASES. PREVIOUSLY DESCRIBED TRANSCRIPTIONAL REGULATION OF MMP-9 IS COMPLEMENTED BY EPIGENETIC CHECKPOINTS, INCLUDING HISTONE MODIFICATIONS AND MICRORNAS. BECAUSE ACTIVATION OF PROMMP-9 MAY BE EXECUTED BY OTHER MMPS, THE THERAPEUTIC DOGMA THAT MMP INHIBITORS NEED TO BE HIGHLY SELECTIVE MAY BE KEYED DOWN FOR THE TREATMENT OF LIFE-THREATENING CONDITIONS. WHEN INFLAMMATION AND MMP-9 FULFILL BENEFICIAL FUNCTIONS TO CLEAR DAMAGING PROTEIN COMPLEXES, SUCH AS IN SYSTEMIC AUTOIMMUNE DISEASES, THERAPEUTIC MMP INHIBITION HAS TO BE AVOIDED. IN MMP9 GENE KNOCKOUT MICE, SPECIFIC SPONTANEOUS PHENOTYPES EMERGED WITH EFFECTS ON THE SKELETAL, REPRODUCTIVE AND NERVOUS SYSTEMS. THESE FINDINGS NOT ONLY HAVE CLINICAL CORRELATES IN BONE GROWTH AND FERTILITY, BUT ALSO STIMULATE RESEARCH ON THE ROLES OF MMPS AND MMP-9 IN ENDOCRINOLOGY, IMMUNOLOGY AND THE NEUROSCIENCES. MMP9-DEFICIENT MICE ARE VALUABLE TOOLS TO DEFINE MMP-9 SUBSTRATES IN VIVO AND TO STUDY THE ROLE OF THIS ENZYME IN ANIMAL MODELS OF INFLAMMATORY, VASCULAR, NEOPLASTIC AND DEGENERATIVE DISEASES. FUTURE CHALLENGES INCLUDE SOLVING THE CRYSTAL STRUCTURE, DEFINITION OF THE FUNCTIONS OF COVALENT OLIGOMERS AND HETEROMERS IN BIOLOGY AND PATHOLOGY, LIFE-IMAGING OF MMP-9 ACTIVITY, SUBSTRATE DETERMINATION IN SITU AND THE STUDY OF INHIBITOR EFFECTS ON FERTILITY, CANCER AND INFLAMMATION AND IN NEUROBIOLOGY AND REGENERATIVE MEDICINE. SUCH STUDIES WILL BETTER DEFINE CONDITIONS IN WHICH INHIBITION OF MMP-9 IS BENEFICIAL OR HAS TO BE AVOIDED. 2013