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  1. Article ; Online: Identification of the Lipid Antigens Recognized by rHIgM22, a Remyelination-Promoting Antibody.

    Grassi, Sara / Cabitta, Livia / Prioni, Simona / Mauri, Laura / Ciampa, Maria Grazia / Yokoyama, Noriko / Iwabuchi, Kazuhisa / Zorina, Yana / Prinetti, Alessandro

    Neurochemical research

    2023  Volume 48, Issue 6, Page(s) 1783–1797

    Abstract: Failure of the immune system to discriminate myelin components from foreign antigens plays a critical role in the pathophysiology of multiple sclerosis. In fact, the appearance of anti-myelin autoantibodies, targeting both proteins and glycolipids, is ... ...

    Abstract Failure of the immune system to discriminate myelin components from foreign antigens plays a critical role in the pathophysiology of multiple sclerosis. In fact, the appearance of anti-myelin autoantibodies, targeting both proteins and glycolipids, is often responsible for functional alterations in myelin-producing cells in this disease. Nevertheless, some of these antibodies were reported to be beneficial for remyelination. Recombinant human IgM22 (rHIgM22) binds to myelin and to the surface of O4-positive oligodendrocytes, and promotes remyelination in mouse models of chronic demyelination. Interestingly, the identity of the antigen recognized by this antibody remains to be elucidated. The preferential binding of rHIgM22 to sulfatide-positive cells or tissues suggests that sulfatide might be part of the antigen pattern recognized by the antibody, however, cell populations lacking sulfatide expression are also responsive to rHIgM22. Thus, we assessed the binding of rHIgM22 in vitro to purified lipids and lipid extracts from various sources to identify the antigen(s) recognized by this antibody. Our results show that rHIgM22 is indeed able to bind both sulfatide and its deacylated form, whereas no significant binding for other myelin sphingolipids has been detected. Remarkably, binding of rHIgM22 to sulfatide in lipid monolayers can be positively or negatively regulated by the presence of other lipids. Moreover, rHIgM22 also binds to phosphatidylinositol, phosphatidylserine and phosphatidic acid, suggesting that not only sulfatide, but also other membrane lipids might play a role in the binding of rHIgM22 to oligodendrocytes and to other cell types not expressing sulfatide.
    MeSH term(s) Animals ; Humans ; Mice ; Immunoglobulin M ; Myelin Sheath/metabolism ; Oligodendroglia/metabolism ; Remyelination ; Sulfoglycosphingolipids/metabolism ; Lipids/immunology
    Chemical Substances Immunoglobulin M ; Sulfoglycosphingolipids ; Lipids
    Language English
    Publishing date 2023-01-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 199335-5
    ISSN 1573-6903 ; 0364-3190
    ISSN (online) 1573-6903
    ISSN 0364-3190
    DOI 10.1007/s11064-023-03859-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1368: Show issues Location:
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  2. Article ; Online: Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons.

    Hergenreder, Emiliano / Minotti, Andrew P / Zorina, Yana / Oberst, Polina / Zhao, Zeping / Munguba, Hermany / Calder, Elizabeth L / Baggiolini, Arianna / Walsh, Ryan M / Liston, Conor / Levitz, Joshua / Garippa, Ralph / Chen, Shuibing / Ciceri, Gabriele / Studer, Lorenz

    Nature biotechnology

    2024  

    Abstract: The maturation of human pluripotent stem cell (hPSC)-derived neurons mimics the protracted timing of human brain development, extending over months to years for reaching adult-like function. Prolonged in vitro maturation presents a major challenge to ... ...

    Abstract The maturation of human pluripotent stem cell (hPSC)-derived neurons mimics the protracted timing of human brain development, extending over months to years for reaching adult-like function. Prolonged in vitro maturation presents a major challenge to stem cell-based applications in modeling and treating neurological disease. Therefore, we designed a high-content imaging assay based on morphological and functional readouts in hPSC-derived cortical neurons which identified multiple compounds that drive neuronal maturation including inhibitors of lysine-specific demethylase 1 and disruptor of telomerase-like 1 and activators of calcium-dependent transcription. A cocktail of four factors, GSK2879552, EPZ-5676, N-methyl-D-aspartate and Bay K 8644, collectively termed GENtoniK, triggered maturation across all parameters tested, including synaptic density, electrophysiology and transcriptomics. Maturation effects were further validated in cortical organoids, spinal motoneurons and non-neural lineages including melanocytes and pancreatic β-cells. The effects on maturation observed across a broad range of hPSC-derived cell types indicate that some of the mechanisms controlling the timing of human maturation might be shared across lineages.
    Language English
    Publishing date 2024-01-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/s41587-023-02031-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2167: Show issues Location:
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  3. Article ; Online: Human IgM antibody rHIgM22 promotes phagocytic clearance of myelin debris by microglia.

    Zorina, Yana / Stricker, Jason / Caggiano, Anthony O / Button, Donald C

    Scientific reports

    2018  Volume 8, Issue 1, Page(s) 9392

    Abstract: In multiple sclerosis (MS), demyelinated CNS lesions fail to sufficiently remyelinate, despite the presence of oligodendrocyte precursor cells (OPCs) capable of differentiating into mature oligodendrocytes. MS lesions contain damaged myelin debris that ... ...

    Abstract In multiple sclerosis (MS), demyelinated CNS lesions fail to sufficiently remyelinate, despite the presence of oligodendrocyte precursor cells (OPCs) capable of differentiating into mature oligodendrocytes. MS lesions contain damaged myelin debris that can inhibit OPC maturation and hinder repair. rHIgM22 is an experimental human recombinant IgM antibody that promotes remyelination in animal models and is being examined in patients with MS. rHIgM22 binds to CNS myelin and partially rescues OPC process outgrowth on myelin. Since rHIgM22 does not affect OPC process outgrowth in vitro on permissive substrate, we examined the possibility that it acts by enhancing phagocytic clearance of myelin debris by microglia. In this study, we tested if rHIgM22 binding could tag myelin for microglial phagocytosis. A mouse microglial cell line and primary rat microglia were treated with myelin and rHIgM22 and assayed for myelin phagocytosis. We found that: 1) rHIgM22 stimulates myelin phagocytosis in a dose-dependent manner; 2) rHIgM22-mediated myelin phagocytosis requires actin polymerization; and 3) rHIgM22-stimulation of myelin phagocytosis requires activity of rHIgM22 Fc domain and activation of Complement Receptor 3. Since myelin inhibits OPC differentiation, stimulation of phagocytic clearance of damaged myelin may be an important means by which rHIgM22 promotes remyelination.
    MeSH term(s) Animals ; Antibodies/immunology ; Antibodies/metabolism ; Cell Differentiation/physiology ; Cell Line ; Cells, Cultured ; Humans ; Immunoglobulin M/immunology ; Mice ; Microglia/cytology ; Microglia/metabolism ; Myelin Sheath/metabolism ; Phagocytes/cytology ; Phagocytes/metabolism ; Phagocytosis/physiology ; Rats
    Chemical Substances Antibodies ; Immunoglobulin M
    Language English
    Publishing date 2018-06-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-018-27559-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: A spatially specified systems pharmacology therapy for axonal recovery after injury.

    Siddiq, Mustafa M / Johnson, Nicholas P / Zorina, Yana / Yadaw, Arjun Singh / Toro, Carlos A / Hansen, Jens / Rabinovich, Vera / Gregorich, Sarah M / Xiong, Yuguang / Tolentino, Rosa E / Hannila, Sari S / Kaplan, Ehud / Blitzer, Robert D / Filbin, Marie T / Cardozo, Christopher P / Passaglia, Christopher L / Iyengar, Ravi

    Frontiers in pharmacology

    2023  Volume 14, Page(s) 1225759

    Abstract: There are no known drugs or drug combinations that promote substantial central nervous system axonal regeneration after injury. We used systems pharmacology approaches to model pathways underlying axonal growth and identify a four-drug combination that ... ...

    Abstract There are no known drugs or drug combinations that promote substantial central nervous system axonal regeneration after injury. We used systems pharmacology approaches to model pathways underlying axonal growth and identify a four-drug combination that regulates multiple subcellular processes in the cell body and axons using the optic nerve crush model in rats. We intravitreally injected agonists HU-210 (cannabinoid receptor-1) and IL-6 (interleukin 6 receptor) to stimulate retinal ganglion cells for axonal growth. We applied, in gel foam at the site of nerve injury, Taxol to stabilize growing microtubules, and activated protein C to clear the debris field since computational models predicted that this drug combination regulating two subcellular processes at the growth cone produces synergistic growth. Physiologically, drug treatment restored or preserved pattern electroretinograms and some of the animals had detectable visual evoked potentials in the brain and behavioral optokinetic responses. Morphology experiments show that the four-drug combination protects axons or promotes axonal regrowth to the optic chiasm and beyond. We conclude that spatially targeted drug treatment is therapeutically relevant and can restore limited functional recovery.
    Language English
    Publishing date 2023-09-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2023.1225759
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  5. Article: Cannabinoid 1 Receptor and Interleukin-6 Receptor Together Induce Integration of Protein Kinase and Transcription Factor Signaling to Trigger Neurite Outgrowth

    Zorina, Yana / Iyengar, Ravi / Bromberg, Kenneth D

    Journal of biological chemistry. 2010 Jan. 8, v. 285, no. 2

    2010  

    Abstract: Activation of the Go/i-coupled cannabinoid 1 receptor (CB1R) has been shown to induce neurite outgrowth in Neuro2A cells through activation of Src kinase and STAT3 transcription factor. Signaling by the interleukin 6 receptor (IL-6R) also activates STAT3 ...

    Abstract Activation of the Go/i-coupled cannabinoid 1 receptor (CB1R) has been shown to induce neurite outgrowth in Neuro2A cells through activation of Src kinase and STAT3 transcription factor. Signaling by the interleukin 6 receptor (IL-6R) also activates STAT3 through Jak kinase. We studied if signals from the two pathways could be integrated in a synergistic manner to trigger neurite outgrowth in Neuro2A cells. At low concentrations, when agonist at either receptor by itself has no effect, we found that CB1R and IL-6R stimulation together induced synergistic neurite outgrowth. Signal integration requires activation of transcription factors by Src, Jak, and mitogen-activated protein kinases. Mitogen-activated protein kinase can be activated by both receptors and shows enhanced early activation in the presence of both ligands. CREB and STAT3 transcription factors are required for synergy and show enhanced DNA-binding activity when both receptors are activated. STAT3 plays a critical role in integration of the signals downstream of the two receptors. When both pathways are activated, STAT3 phosphorylation is sustained for 6 h. This prolonged activation of STAT3 requires deactivation of SHP2 phosphatase. Reduction of SHP2 levels by RNA interference results in greater synergy in neurite outgrowth. Simultaneous knockdown of both SHP2 and STAT3 blocks the synergistic triggering of neurite outgrowth, indicating that STAT3 is downstream of SHP2. CB1R and IL-6R co-stimulation enhanced the differentiation of rat cortical neuron primary cultures. These results provide a mechanism where multiple protein kinases and transcription factors interact to integrate signals from G protein-coupled and cytokine receptor to evoke neurite outgrowth in Neuro2A cells.
    Language English
    Dates of publication 2010-0108
    Size p. 1358-1370.
    Publishing place American Society for Biochemistry and Molecular Biology
    Document type Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    Database NAL-Catalogue (AGRICOLA)

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  6. Article ; Online: Cannabinoid 1 receptor and interleukin-6 receptor together induce integration of protein kinase and transcription factor signaling to trigger neurite outgrowth.

    Zorina, Yana / Iyengar, Ravi / Bromberg, Kenneth D

    The Journal of biological chemistry

    2009  Volume 285, Issue 2, Page(s) 1358–1370

    Abstract: Activation of the G(o/i)-coupled cannabinoid 1 receptor (CB1R) has been shown to induce neurite outgrowth in Neuro2A cells through activation of Src kinase and STAT3 transcription factor. Signaling by the interleukin 6 receptor (IL-6R) also activates ... ...

    Abstract Activation of the G(o/i)-coupled cannabinoid 1 receptor (CB1R) has been shown to induce neurite outgrowth in Neuro2A cells through activation of Src kinase and STAT3 transcription factor. Signaling by the interleukin 6 receptor (IL-6R) also activates STAT3 through Jak kinase. We studied if signals from the two pathways could be integrated in a synergistic manner to trigger neurite outgrowth in Neuro2A cells. At low concentrations, when agonist at either receptor by itself has no effect, we found that CB1R and IL-6R stimulation together induced synergistic neurite outgrowth. Signal integration requires activation of transcription factors by Src, Jak, and mitogen-activated protein kinases. Mitogen-activated protein kinase can be activated by both receptors and shows enhanced early activation in the presence of both ligands. CREB and STAT3 transcription factors are required for synergy and show enhanced DNA-binding activity when both receptors are activated. STAT3 plays a critical role in integration of the signals downstream of the two receptors. When both pathways are activated, STAT3 phosphorylation is sustained for 6 h. This prolonged activation of STAT3 requires deactivation of SHP2 phosphatase. Reduction of SHP2 levels by RNA interference results in greater synergy in neurite outgrowth. Simultaneous knockdown of both SHP2 and STAT3 blocks the synergistic triggering of neurite outgrowth, indicating that STAT3 is downstream of SHP2. CB1R and IL-6R co-stimulation enhanced the differentiation of rat cortical neuron primary cultures. These results provide a mechanism where multiple protein kinases and transcription factors interact to integrate signals from G protein-coupled and cytokine receptor to evoke neurite outgrowth in Neuro2A cells.
    MeSH term(s) Animals ; Cell Differentiation/physiology ; Cell Line ; Cyclic AMP Response Element-Binding Protein/genetics ; Cyclic AMP Response Element-Binding Protein/metabolism ; Janus Kinases/genetics ; Janus Kinases/metabolism ; MAP Kinase Signaling System/physiology ; Mitogen-Activated Protein Kinase Kinases/genetics ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Neurites/metabolism ; Phosphorylation/physiology ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism ; Rats ; Receptor, Cannabinoid, CB1/genetics ; Receptor, Cannabinoid, CB1/metabolism ; Receptors, Interleukin-6/genetics ; Receptors, Interleukin-6/metabolism ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Time Factors ; src-Family Kinases/genetics ; src-Family Kinases/metabolism
    Chemical Substances Cnr1 protein, rat ; Cyclic AMP Response Element-Binding Protein ; Receptor, Cannabinoid, CB1 ; Receptors, Interleukin-6 ; STAT3 Transcription Factor ; Stat3 protein, rat ; Janus Kinases (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2) ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48)
    Language English
    Publishing date 2009-10-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M109.049841
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.108: Show issues Location:
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  7. Article ; Online: Extracellular histones, a new class of inhibitory molecules of CNS axonal regeneration.

    Siddiq, Mustafa M / Hannila, Sari S / Zorina, Yana / Nikulina, Elena / Rabinovich, Vera / Hou, Jianwei / Huq, Rumana / Richman, Erica L / Tolentino, Rosa E / Hansen, Jens / Velenosi, Adam / Kwon, Brian K / Tsirka, Stella E / Maze, Ian / Sebra, Robert / Beaumont, Kristin G / Toro, Carlos A / Cardozo, Christopher P / Iyengar, Ravi /
    Filbin, Marie T

    Brain communications

    2021  Volume 3, Issue 4, Page(s) fcab271

    Abstract: Axonal regeneration in the mature CNS is limited by extracellular inhibitory factors. Triple knockout mice lacking the major myelin-associated inhibitors do not display spontaneous regeneration after injury, indicating the presence of other inhibitors. ... ...

    Abstract Axonal regeneration in the mature CNS is limited by extracellular inhibitory factors. Triple knockout mice lacking the major myelin-associated inhibitors do not display spontaneous regeneration after injury, indicating the presence of other inhibitors. Searching for such inhibitors, we have detected elevated levels of histone H3 in human CSF 24 h after spinal cord injury. Following dorsal column lesions in mice and optic nerve crushes in rats, elevated levels of extracellular histone H3 were detected at the injury site. Similar to myelin-associated inhibitors, these extracellular histones induced growth cone collapse and inhibited neurite outgrowth. Histones mediate inhibition through the transcription factor Y-box-binding protein 1 and Toll-like receptor 2, and these effects are independent of the Nogo receptor. Histone-mediated inhibition can be reversed by the addition of activated protein C
    Language English
    Publishing date 2021-11-13
    Publishing country England
    Document type Journal Article
    ISSN 2632-1297
    ISSN (online) 2632-1297
    DOI 10.1093/braincomms/fcab271
    Database MEDical Literature Analysis and Retrieval System OnLINE

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