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  1. Article ; Online: Haptoglobin Attenuates Cerebrospinal Fluid Hemoglobin-Induced Neurological Deterioration in Sheep.

    Thomson, Bart R / Schwendinger, Nina / Beckmann, Katrin / Gentinetta, Thomas / Couto, Daniel / Wymann, Sandra / Verdon, Valérie / Buzzi, Raphael M / Akeret, Kevin / Kronen, Peter W / Weinberger, Eva M / Held, Ulrike / Seehusen, Frauke / Richter, Henning / Schaer, Dominik J / Hugelshofer, Michael

    Translational stroke research

    2024  

    Abstract: Secondary brain injury (SBI) occurs with a lag of several days post-bleeding in patients with aneurysmal subarachnoid hemorrhage (aSAH) and is a strong contributor to mortality and long-term morbidity. aSAH-SBI coincides with cell-free hemoglobin (Hb) ... ...

    Abstract Secondary brain injury (SBI) occurs with a lag of several days post-bleeding in patients with aneurysmal subarachnoid hemorrhage (aSAH) and is a strong contributor to mortality and long-term morbidity. aSAH-SBI coincides with cell-free hemoglobin (Hb) release into the cerebrospinal fluid. This temporal association and convincing pathophysiological concepts suggest that CSF-Hb could be a targetable trigger of SBI. However, sparse experimental evidence for Hb's neurotoxicity in vivo defines a significant research gap for clinical translation. We modeled the CSF-Hb exposure observed in aSAH patients in conscious sheep, which allowed us to assess neurological functions in a gyrencephalic species. Twelve animals were randomly assigned for 3-day bi-daily intracerebroventricular (ICV) injections of either Hb or Hb combined with the high-affinity Hb scavenger protein haptoglobin (Hb-Hp, CSL888). Repeated CSF sampling confirmed clinically relevant CSF-Hb concentrations. This prolonged CSF-Hb exposure over 3 days resulted in disturbed movement activity, reduced food intake, and impaired observational neuroscores. The Hb-induced neurotoxic effects were significantly attenuated when Hb was administered with equimolar haptoglobin. Preterminal magnetic resonance imaging (MRI) showed no CSF-Hb-specific structural brain alterations. In both groups, histology demonstrated an inflammatory response and revealed enhanced perivascular histiocytic infiltrates in the Hb-Hp group, indicative of adaptive mechanisms. Heme exposure in CSF and iron deposition in the brain were comparable, suggesting comparable clearance efficiency of Hb and Hb-haptoglobin complexes from the intracranial compartment. We identified a neurological phenotype of CSF-Hb toxicity in conscious sheep, which is rather due to neurovascular dysfunction than structural brain injury. Haptoglobin was effective at attenuating CSF-Hb-induced neurological deterioration, supporting its therapeutic potential.
    Language English
    Publishing date 2024-04-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2541897-X
    ISSN 1868-601X ; 1868-4483
    ISSN (online) 1868-601X
    ISSN 1868-4483
    DOI 10.1007/s12975-024-01254-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Activated microglia drive demyelination via CSF1R signaling.

    Marzan, Dave E / Brügger-Verdon, Valérie / West, Brian L / Liddelow, Shane / Samanta, Jayshree / Salzer, James L

    Glia

    2021  Volume 69, Issue 6, Page(s) 1583–1604

    Abstract: Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS), a progressive auto-immune demyelinating disorder. The precise role of microglia, parenchymal central nervous system (CNS) macrophages, ... ...

    Abstract Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS), a progressive auto-immune demyelinating disorder. The precise role of microglia, parenchymal central nervous system (CNS) macrophages, during demyelination, and the relative contributions of peripheral macrophages are incompletely understood. Classical markers used to identify microglia do not reliably discriminate between microglia and peripheral macrophages, confounding analyses. Here, we use a genetic fate mapping strategy to identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Colony-stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF) - a secreted cytokine that regulates microglia development and survival-is upregulated in demyelinated white matter lesions. Depletion of microglia with the CSF1R inhibitor PLX3397 greatly abrogates the demyelination, loss of oligodendrocytes, and reactive astrocytosis that results from CUP treatment. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these CUP-damaged myelin sheaths are lost and robustly phagocytosed upon-repopulation of microglia. Direct injection of CSF1 into CNS white matter induces focal microgliosis and demyelination indicating active CSF1 signaling can promote demyelination. Finally, mice defective in adopting a toxic astrocyte phenotype that is driven by microglia nevertheless demyelinate normally upon CUP treatment implicating microglia rather than astrocytes as the primary drivers of CUP-mediated demyelination. Together, these studies indicate activated microglia are required for and can drive demyelination directly and implicate CSF1 signaling in these events.
    MeSH term(s) Animals ; Cuprizone/toxicity ; Demyelinating Diseases/chemically induced ; Disease Models, Animal ; Macrophages ; Mice ; Microglia ; Receptors, Colony-Stimulating Factor ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics ; Signal Transduction
    Chemical Substances Csf1r protein, mouse ; Receptors, Colony-Stimulating Factor ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ; Cuprizone (5N16U7E0AO)
    Language English
    Publishing date 2021-02-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 639414-0
    ISSN 1098-1136 ; 0894-1491
    ISSN (online) 1098-1136
    ISSN 0894-1491
    DOI 10.1002/glia.23980
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2345: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Modular Platform for the Development of Recombinant Hemoglobin Scavenger Biotherapeutics.

    Buzzi, Raphael M / Owczarek, Catherine M / Akeret, Kevin / Tester, Andrea / Pereira, Natasha / Butcher, Rebecca / Brügger-Verdon, Valérie / Hardy, Matthew P / Illi, Marlies / Wassmer, Andreas / Vallelian, Florence / Humar, Rok / Hugelshofer, Michael / Buehler, Paul W / Gentinetta, Thomas / Schaer, Dominik J

    Molecular pharmaceutics

    2021  Volume 18, Issue 8, Page(s) 3158–3170

    Abstract: Cell-free hemoglobin (Hb) is a driver of disease progression in conditions with intravascular or localized hemolysis. Genetic and acquired anemias or emergency medical conditions such as aneurysmal subarachnoid hemorrhage involve tissue Hb exposure. ... ...

    Abstract Cell-free hemoglobin (Hb) is a driver of disease progression in conditions with intravascular or localized hemolysis. Genetic and acquired anemias or emergency medical conditions such as aneurysmal subarachnoid hemorrhage involve tissue Hb exposure. Haptoglobin (Hp) captures Hb in an irreversible protein complex and prevents its pathophysiological contributions to vascular nitric oxide depletion and tissue oxidation. Preclinical proof-of-concept studies suggest that human plasma-derived Hp is a promising therapeutic candidate for several Hb-driven diseases. Optimizing the efficacy and safety of Hb-targeting biotherapeutics may require structural and functional modifications for specific indications. Improved Hp variants could be designed to achieve the desired tissue distribution, metabolism, and elimination to target hemolytic disease states effectively. However, it is critical to ensure that these modifications maintain the function of Hp. Using transient mammalian gene expression of Hp combined with co-transfection of the pro-haptoglobin processing protease C1r-LP, we established a platform for generating recombinant Hp-variants. We designed an Hpβ-scaffold, which was expressed in this system at high levels as a monomeric unit (mini-Hp) while maintaining the key protective functions of Hp. We then used this Hpβ-scaffold as the basis to develop an initial proof-of-concept Hp fusion protein using human serum albumin as the fusion partner. Next, a hemopexin-Hp fusion protein with bispecific heme and Hb detoxification capacity was generated. Further, we developed a Hb scavenger devoid of CD163 scavenger receptor binding. The functions of these proteins were then characterized for Hb and heme-binding, binding of the Hp-Hb complexes with the clearance receptor CD163, antioxidant properties, and vascular nitric oxide sparing capacity. Our platform is designed to support the generation of innovative Hb scavenger biotherapeutics with novel modes of action and potentially improved formulation characteristics, function, and pharmacokinetics.
    MeSH term(s) Animals ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; Basilar Artery/drug effects ; Biological Products/chemistry ; Biological Products/metabolism ; Biological Products/pharmacology ; Drug Design/methods ; HEK293 Cells ; Haptoglobins/chemistry ; Haptoglobins/genetics ; Haptoglobins/metabolism ; Heme/metabolism ; Hemoglobins/chemistry ; Hemoglobins/metabolism ; Hemolysis ; Hemopexin/chemistry ; Hemopexin/genetics ; Hemopexin/metabolism ; Humans ; Protein Binding ; Receptors, Cell Surface/metabolism ; Receptors, Scavenger/metabolism ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Recombinant Fusion Proteins/pharmacology ; Serum Albumin, Human/chemistry ; Serum Albumin, Human/genetics ; Serum Albumin, Human/metabolism ; Swine ; Transfection ; Vasodilation/drug effects
    Chemical Substances Antigens, CD ; Antigens, Differentiation, Myelomonocytic ; Biological Products ; CD163 antigen ; HP protein, human ; Haptoglobins ; Hemoglobins ; Receptors, Cell Surface ; Receptors, Scavenger ; Recombinant Fusion Proteins ; haptoglobin-hemoglobin complex ; Heme (42VZT0U6YR) ; Hemopexin (9013-71-2) ; Serum Albumin, Human (ZIF514RVZR)
    Language English
    Publishing date 2021-07-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2138405-8
    ISSN 1543-8392 ; 1543-8384
    ISSN (online) 1543-8392
    ISSN 1543-8384
    DOI 10.1021/acs.molpharmaceut.1c00433
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6250: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  4. Article: Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence.

    Gentinetta, Thomas / Belcher, John D / Brügger-Verdon, Valérie / Adam, Jacqueline / Ruthsatz, Tanja / Bain, Joseph / Schu, Daniel / Ventrici, Lisa / Edler, Monika / Lioe, Hadi / Patel, Kalpeshkumar / Chen, Chunsheng / Nguyen, Julia / Abdulla, Fuad / Zhang, Ping / Wassmer, Andreas / Jain, Meena / Mischnik, Marcel / Pelzing, Matthias /
    Martin, Kirstee / Davis, Roslyn / Didichenko, Svetlana / Schaub, Alexander / Brinkman, Nathan / Herzog, Eva / Zürcher, Adrian / Vercellotti, Gregory M / Kato, Gregory J / Höbarth, Gerald

    Journal of clinical medicine

    2022  Volume 11, Issue 3

    Abstract: People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion ... ...

    Abstract People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion proteins on endothelial cells and circulating cells, promoting vaso-occlusion. In this study, plasma-derived hemopexin inhibited heme-mediated cellular externalization of P-selectin and von Willebrand factor, and expression of IL-8, VCAM-1, and heme oxygenase-1 in cultured endothelial cells in a dose-responsive manner. In the Townes SCD mouse model, intravenous injection of free hemoglobin induced vascular stasis (vaso-occlusion) in nearly 40% of subcutaneous blood vessels visualized in a dorsal skin-fold chamber. Hemopexin administered intravenously prevented or relieved stasis in a dose-dependent manner. Hemopexin showed parallel activity in relieving vascular stasis induced by hypoxia-reoxygenation. Repeated IV administration of hemopexin was well tolerated in rats and non-human primates with no adverse findings that could be attributed to human hemopexin. Hemopexin had a half-life in wild-type mice, rats, and non-human primates of 80-102 h, whereas a reduced half-life of hemopexin in Townes SCD mice was observed due to ongoing hemolysis. These data have led to a Phase 1 clinical trial of hemopexin in adults with SCD, which is currently ongoing.
    Language English
    Publishing date 2022-01-26
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662592-1
    ISSN 2077-0383
    ISSN 2077-0383
    DOI 10.3390/jcm11030630
    Database MEDical Literature Analysis and Retrieval System OnLINE

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