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  • 1
    Online Resource
    Online Resource
    The CX3C chemokine fractalkine mediates platelet adhesion via the von Willebrand receptor glycoprotein Ib
    American Society of Hematology ; 2011
    In:  Blood Vol. 117, No. 18 ( 2011-05-05), p. 4999-5008
    Details
    In: Blood, American Society of Hematology, Vol. 117, No. 18 ( 2011-05-05), p. 4999-5008
    Abstract: The membrane-anchored CX3C chemokine fractalkine (FKN) is expressed on activated endothelium and is associated with the development of atherosclerosis. The potential of FKN in mediating platelet adhesion beyond platelet activation remains unexplored to date. A flow-based adhesion assay was used to study the adhesion of platelets to immobilized FKN under physiologic flow conditions. Platelet adhesion to von Willebrand factor (VWF) was increased in the presence of FKN at 600 inverse seconds. Additional platelet adhesion to FKN coimmobilized with VWF was dependent on the FKN receptor CX3CR1 and activation of glycoprotein (GP) IIb/IIIa. The number of platelets rolling on VWF was likewise enhanced in the presence of FKN. The enhancement of rolling on FKN and VWF was insensitive to anti-CX3CR1 antibody but was fully inhibited by neutralizing GPIbα function. The extracellular domain of GPIbα was covalently coupled to fluorescent microspheres, and microsphere binding was significantly higher in the presence of FKN. Platelet adhesion to activated endothelium in vitro and to intact human arteries was substantially increased in an FKN-dependent manner. These data demonstrate that endothelial expressed FKN activates platelets via its cognate receptor CX3CR1, whereas platelet adhesion is predominantly mediated by GPIbα and independent of CX3CR1.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2011-02-335471
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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    detail.hit.zdb_id: 80069-7
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  • 2
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    Lack of Microsomal Prostaglandin E 2 Synthase-1 in Bone Marrow–Derived Myeloid Cells Impairs Left Ventricular Function and Increases Mortality After Acute Myocardial Infarction
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Circulation Vol. 125, No. 23 ( 2012-06-12), p. 2904-2913
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 125, No. 23 ( 2012-06-12), p. 2904-2913
    Abstract: Microsomal prostaglandin E 2 synthase-1 (mPGES-1), encoded by the Ptges gene, catalyzes prostaglandin E 2 biosynthesis and is expressed by leukocytes, cardiac myocytes, and cardiac fibroblasts. Ptges −/− mice develop more left ventricle (LV) dilation, worse LV contractile function, and higher LV end-diastolic pressure than Ptges +/+ mice after myocardial infarction. In this study, we define the role of mPGES-1 in bone marrow–derived leukocytes in the recovery of LV function after coronary ligation. Methods and Results— Cardiac structure and function in Ptges +/+ mice with Ptges +/+ bone marrow ( BM +/+ ) and Ptges +/+ mice with Ptges −/− BM ( BM −/− ) were assessed by morphometric analysis, echocardiography, and invasive hemodynamics before and 7 and 28 days after myocardial infarction. Prostaglandin levels and prostaglandin biosynthetic enzyme gene expression were measured by liquid chromatography–tandem mass spectrometry and real-time polymerase chain reaction, immunoblotting, immunohistochemistry, and immunofluorescence microscopy, respectively. After myocardial infarction, BM −/− mice had more LV dilation, worse LV systolic and diastolic function, higher LV end-diastolic pressure, more cardiomyocyte hypertrophy, and higher mortality but similar infarct size and pulmonary edema compared with BM +/+ mice. BM −/− mice also had higher levels of COX-1 protein and more leukocytes in the infarct, but not the viable LV, than BM +/+ mice. Levels of prostaglandin E 2 were higher in the infarct and viable myocardium of BM −/− mice than in BM +/+ mice. Conclusions— Lack of mPGES-1 in bone marrow–derived leukocytes negatively regulates COX-1 expression, prostaglandin E 2 biosynthesis, and inflammation in the infarct and leads to impaired LV function, adverse LV remodeling, and decreased survival after acute myocardial infarction.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.112.099754
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1466401-X
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  • 3
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    CXCL16/CXCR6-mediated adhesion of human peripheral blood mononuclear cells to inflamed endothelium
    Elsevier BV ; 2019
    In:  Cytokine Vol. 122 ( 2019-10), p. 154081-
    Details
    In: Cytokine, Elsevier BV, Vol. 122 ( 2019-10), p. 154081-
    Type of Medium: Online Resource
    ISSN: 1043-4666
    URL: Article
    DOI: 10.1016/j.cyto.2017.06.008
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 1463198-2
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  • 4
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    Behind the Wall—Compartment-Specific Neovascularisation during Post-Stroke Recovery in Mice
    MDPI AG ; 2022
    In:  Cells Vol. 11, No. 10 ( 2022-05-17), p. 1659-
    Details
    In: Cells, MDPI AG, Vol. 11, No. 10 ( 2022-05-17), p. 1659-
    Abstract: Ischemic stroke is a highly prevalent vascular disease leading to oxygen- and glucose deprivation in the brain. In response, ischemia-induced neovascularization occurs, which is supported by circulating CD34+ endothelial progenitor cells. Here, we used the transient middle cerebral artery occlusion (tMCAO) mouse model to characterize the spatio-temporal alterations within the ischemic core from the acute to the chronic phase using multiple-epitope-ligand cartography (MELC) for sequential immunohistochemistry. We found that around 14 days post-stroke, significant angiogenesis occurs in the ischemic core, as determined by the presence of CD31+/CD34+ double-positive endothelial cells. This neovascularization was accompanied by the recruitment of CD4+ T-cells and dendritic cells as well as IBA1+ and IBA1− microglia. Neighborhood analysis identified, besides pericytes only for T-cells and dendritic cells, a statistically significant distribution as direct neighbors of CD31+/CD34+ endothelial cells, suggesting a role for these cells in aiding angiogenesis. This process was distinct from neovascularization of the peri-infarct area as it was separated by a broad astroglial scar. At day 28 post-stroke, the scar had emerged towards the cortical periphery, which seems to give rise to a neuronal regeneration within the peri-infarct area. Meanwhile, the ischemic core has condensed to a highly vascularized subpial region adjacent to the leptomeningeal compartment. In conclusion, in the course of chronic post-stroke regeneration, the astroglial scar serves as a seal between two immunologically active compartments—the peri-infarct area and the ischemic core—which exhibit distinct processes of neovascularization as a central feature of post-stroke tissue remodeling. Based on our findings, we propose that neovascularization of the ischemic core comprises arteriogenesis as well as angiogenesis originating from the leptomenigeal vasculature.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells11101659
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2661518-6
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  • 5
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    Tumors Provoke Inflammation and Perineural Microlesions at Adjacent Peripheral Nerves
    MDPI AG ; 2020
    In:  Cells Vol. 9, No. 2 ( 2020-01-29), p. 320-
    Details
    In: Cells, MDPI AG, Vol. 9, No. 2 ( 2020-01-29), p. 320-
    Abstract: Cancer-induced pain occurs frequently in patients when tumors or their metastases grow in the proximity of nerves. Although this cancer-induced pain states poses an important therapeutical problem, the underlying pathomechanisms are not understood. Here, we implanted adenocarcinoma, fibrosarcoma and melanoma tumor cells in proximity of the sciatic nerve. All three tumor types caused mechanical hypersensitivity, thermal hyposensitivity and neuronal damage. Surprisingly the onset of the hypersensitivity was independent of physical contact of the nerve with the tumors and did not depend on infiltration of cancer cells in the sciatic nerve. However, macrophages and dendritic cells appeared on the outside of the sciatic nerves with the onset of the hypersensitivity. At the same time point downregulation of perineural tight junction proteins was observed, which was later followed by the appearance of microlesions. Fitting to the changes in the epi-/perineurium, a dramatic decrease of triglycerides and acylcarnitines in the sciatic nerves as well as an altered localization and appearance of epineural adipocytes was seen. In summary, the data show an inflammation at the sciatic nerves as well as an increased perineural and epineural permeability. Thus, interventions aiming to suppress inflammatory processes at the sciatic nerve or preserving peri- and epineural integrity may present new approaches for the treatment of tumor-induced pain.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells9020320
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2661518-6
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  • 6
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    Cysteine-Rich Protein 2, a Novel Downstream Effector of cGMP/cGMP-Dependent Protein Kinase I-Mediated Persistent Inflammatory Pain
    Society for Neuroscience ; 2008
    In:  The Journal of Neuroscience Vol. 28, No. 6 ( 2008-02-06), p. 1320-1330
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 28, No. 6 ( 2008-02-06), p. 1320-1330
    Abstract: The cGMP/cGMP-dependent protein kinase I (cGKI) signaling pathway plays an important role in spinal nociceptive processing. However, downstream targets of cGKI in this context have not been identified to date. Using a yeast two-hybrid screen, we isolated cysteine-rich protein 2 (CRP2) as a novel cGKI interactor in the spinal cord. CRP2 is expressed in laminas I and II of the mouse spinal cord and is colocalized with cGKI, calcitonin gene-related peptide, and isolectin B4. Moreover, the majority of CRP2 mRNA-positive dorsal root ganglion (DRG) neurons express cGKI and peripherin. CRP2 is phosphorylated in a cGMP-dependent manner, and its expression increases in the spinal cord and in DRGs after noxious stimulation of a hindpaw. To elucidate the functional role of CRP2 in nociception, we analyzed mice with a targeted deletion of CRP2. CRP2-deficient (CRP2 −/− ) mice demonstrate normal behavioral responses to acute nociception and after axonal injury of the sciatic nerve, but increased nociceptive behavior in models of inflammatory hyperalgesia compared with wild-type mice. Intrathecal administration of cGMP analogs increases the nociceptive behavior in wild-type but not in CRP2 −/− mice, indicating that the presence of CRP2 is important for cGMP-mediated nociception. These data suggest that CRP2 is a new downstream effector of cGKI-mediated spinal nociceptive processing and point to an inhibitory role of CRP2 in the generation of inflammatory pain.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5037-07.2008
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2008
    detail.hit.zdb_id: 1475274-8
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  • 7
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    Lysophospholipids Contribute to Oxaliplatin-Induced Acute Peripheral Pain
    Society for Neuroscience ; 2020
    In:  The Journal of Neuroscience Vol. 40, No. 49 ( 2020-12-02), p. 9519-9532
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 40, No. 49 ( 2020-12-02), p. 9519-9532
    Abstract: Oxaliplatin, a platinum-based chemotherapeutic drug, which is used as first-line treatment for some types of colorectal carcinoma, causes peripheral neuropathic pain in patients. In addition, an acute peripheral pain syndrome develop in almost 90% of patients immediately after oxaliplatin treatment, which is poorly understood mechanistically but correlates with incidence and severity of the later-occurring neuropathy. Here we investigated the effects of acute oxaliplatin treatment in a murine model, showing that male and female mice develop mechanical hypersensitivity 24 h after oxaliplatin treatment. Interestingly, we found that the levels of several lipids were significantly altered in nervous tissue during oxaliplatin-induced acute pain. Specifically, the linoleic acid metabolite 9,10-EpOME (epoxide of linoleic acid) as well as the lysophospholipids lysophosphatidylcholine (LPC) 18:1 and LPC 16:0 were significantly increased 24 h after oxaliplatin treatment in sciatic nerve, DRGs, or spinal cord tissue as revealed by untargeted and targeted lipidomics. In contrast, inflammatory markers including cytokines and chemokines, ROS markers, and growth factors are unchanged in the respective nervous system tissues. Importantly, LPC 18:1 and LPC 16:0 can induce Ca 2+ transients in primary sensory neurons, and we identify LPC 18:1 as a previously unknown endogenous activator of the ligand-gated calcium channels transient receptor potential V1 and M8 (transient receptor potential vanilloid 1 and transient receptor potential melastatin 8) in primary sensory neurons using both pharmacological inhibition and genetic knockout. Additionally, a peripheral LPC 18:1 injection was sufficient to induce mechanical hypersensitivity in naive mice. Hence, targeting signaling lipid pathways may ameliorate oxaliplatin-induced acute peripheral pain and the subsequent long-lasting neuropathy. SIGNIFICANCE STATEMENT The first-line cytostatic drug oxaliplatin can cause acute peripheral pain and chronic neuropathic pain. The former is causally connected with the chronic neuropathic pain, but its mechanisms are poorly understood. Here, we performed a broad unbiased analysis of cytokines, chemokines, growth factors, and ∼200 lipids in nervous system tissues 24 h after oxaliplatin treatment, which revealed a crucial role of lysophospholipids lysophosphatidylcholine (LPC) 18:1, LPC 16:0, and 9,10-EpOME in oxaliplatin-induced acute pain. We demonstrate for the first time that LPC 18:1 contributes to the activation of the ion channels transient receptor potential vanilloid 1 and transient receptor potential melastatin 8 in sensory neurons and causes mechanical hypersensitivity after peripheral injection in vivo . These findings suggest that the LPC-mediated lipid signaling is involved in oxaliplatin-induced acute peripheral pain.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
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    DOI: 10.1523/JNEUROSCI.1223-20.2020
    DOI: 10.1523/JNEUROSCI.1223-20.2020.f1-1
    DOI: 10.1523/JNEUROSCI.1223-20.2020.f1-2
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    DOI: 10.1523/JNEUROSCI.1223-20.2020.f3-1
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    DOI: 10.1523/JNEUROSCI.1223-20.2020.f5-1
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2020
    detail.hit.zdb_id: 1475274-8
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  • 8
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    Capturing adenylyl cyclases as potential drug targets
    Springer Science and Business Media LLC ; 2009
    In:  Nature Reviews Drug Discovery Vol. 8, No. 4 ( 2009-4), p. 321-335
    Details
    In: Nature Reviews Drug Discovery, Springer Science and Business Media LLC, Vol. 8, No. 4 ( 2009-4), p. 321-335
    Type of Medium: Online Resource
    ISSN: 1474-1776 , 1474-1784
    URL: Article
    DOI: 10.1038/nrd2827
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2009
    detail.hit.zdb_id: 2061062-2
    SSG: 15,3
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  • 9
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    Soluble Epoxide Hydrolase Limits Mechanical Hyperalgesia during Inflammation
    SAGE Publications ; 2011
    In:  Molecular Pain Vol. 7 ( 2011-01-01), p. 1744-8069-7-78-
    Details
    In: Molecular Pain, SAGE Publications, Vol. 7 ( 2011-01-01), p. 1744-8069-7-78-
    Abstract: Cytochrome-P450 (CYP450) epoxygenases metabolise arachidonic acid (AA) into four different biologically active epoxyeicosatrienoic acid (EET) regioisomers. Three of the EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed by the enzyme soluble epoxide hydrolase (sEH). Here, we investigated the role of sEH in nociceptive processing during peripheral inflammation. Results: In dorsal root ganglia (DRG), we found that sEH is expressed in medium and large diameter neurofilament 200-positive neurons. Isolated DRG-neurons from sEH −/− mice showed higher EET and lower DHET levels. Upon AA stimulation, the largest changes in EET levels occurred in culture media, indicating both that cell associated EET concentrations quickly reach saturation and EET-hydrolyzing activity mostly effects extracellular EET signaling. In vivo, DRGs from sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-EET-levels. Interestingly, EET levels did not increase at the site of zymosan-induced inflammation. Cellular imaging experiments revealed direct calcium flux responses to 8,9-EET in a subpopulation of nociceptors. In addition, 8,9-EET sensitized AITC-induced calcium increases in DRG neurons and AITC-induced calcitonin gene related peptide (CGRP) release from sciatic nerve axons, indicating that 8,9-EET sensitizes TRPA1-expressing neurons, which are known to contribute to mechanical hyperalgesia. Supporting this, sEH −/− mice showed increased nociceptive responses to mechanical stimulation during zymosan-induced inflammation and 8,9-EET injection reduced mechanical thresholds in naive mice. Conclusion: Our results show that the sEH can regulate mechanical hyperalgesia during inflammation by inactivating 8,9-EET, which sensitizes TRPA1-expressing nociceptors. Therefore we suggest that influencing the CYP450 pathway, which is actually highly considered to treat cardiovascular diseases, may cause pain side effects.
    Type of Medium: Online Resource
    ISSN: 1744-8069 , 1744-8069
    URL: Article
    DOI: 10.1186/1744-8069-7-78
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2011
    detail.hit.zdb_id: 2174252-2
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  • 10
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    The G2A receptor (GPR132) contributes to oxaliplatin-induced mechanical pain hypersensitivity
    Springer Science and Business Media LLC ; 2017
    In:  Scientific Reports Vol. 7, No. 1 ( 2017-03-27)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2017-03-27)
    Abstract: Chemotherapy-induced peripheral neuropathic pain (CIPN) is a common and severe debilitating side effect of many widely used cytostatics. However, there is no approved pharmacological treatment for CIPN available. Among other substances, oxaliplatin causes CIPN in up to 80% of treated patients. Here, we report the involvement of the G-protein coupled receptor G2A (GPR132) in oxaliplatin-induced neuropathic pain in mice. We found that mice deficient in the G2A-receptor show decreased mechanical hypersensitivity after oxaliplatin treatment. Lipid ligands of G2A were found in increased concentrations in the sciatic nerve and dorsal root ganglia of oxaliplatin treated mice. Calcium imaging and patch-clamp experiments show that G2A activation sensitizes the ligand-gated ion channel TRPV1 in sensory neurons via activation of PKC. Based on these findings, we conclude that targeting G2A may be a promising approach to reduce oxaliplatin-induced TRPV1-sensitization and the hyperexcitability of sensory neurons and thereby to reduce pain in patients treated with this chemotherapeutic agent.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-017-00591-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2615211-3
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