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  1. Article: Endothelial Progenitor Cells: New Targets for Therapeutics for Inflammatory Conditions With High Cardiovascular Risk.

    Edwards, Nicola / Langford-Smith, Alexander W W / Wilkinson, Fiona L / Alexander, M Yvonne

    Frontiers in medicine

    2018  Volume 5, Page(s) 200

    Abstract: Over the past decade, we have witnessed an exponential growth of interest into the role of endothelial progenitor cells (EPCs) in cardiovascular disease. While the major thinking revolves around EPC angiogenic repair properties, we have used a hypothesis- ...

    Abstract Over the past decade, we have witnessed an exponential growth of interest into the role of endothelial progenitor cells (EPCs) in cardiovascular disease. While the major thinking revolves around EPC angiogenic repair properties, we have used a hypothesis-driven approach to discover disease-related defects in their characteristics and based on these findings, have identified opportunities for functional enhancement, which offer an exciting avenue for translation into clinical intervention. In this review, we focus on two groups; circulating myeloid angiogenic cells (MACs) and late outgrowth endothelial colony forming cells (ECFCs), and will discuss the unique properties and defects of each population, as new insights have been gained into the potential function of each sub-type using current techniques and multiomic technology. We will discuss their role in inflammatory disorders and alterations in mitochondrial function. In addition, we share key insights into the glycocalyx, and propose this network of membrane-bound proteoglycans and glycoproteins, covering the endothelium warrants further investigation in order to clarify its significance in ECFC regulation of vascularization and angiogenesis and ultimately for potential translational therapeutic aspects.
    Language English
    Publishing date 2018-07-10
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2775999-4
    ISSN 2296-858X
    ISSN 2296-858X
    DOI 10.3389/fmed.2018.00200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Inter-α-inhibitor heavy chain-1 has an integrin-like 3D structure mediating immune regulatory activities and matrix stabilization during ovulation.

    Briggs, David C / Langford-Smith, Alexander W W / Birchenough, Holly L / Jowitt, Thomas A / Kielty, Cay M / Enghild, Jan J / Baldock, Clair / Milner, Caroline M / Day, Anthony J

    The Journal of biological chemistry

    2020  Volume 295, Issue 16, Page(s) 5278–5291

    Abstract: Inter-α-inhibitor is a proteoglycan essential for mammalian reproduction and also plays a less well-characterized role in inflammation. It comprises two homologous "heavy chains" (HC1 and HC2) covalently attached to chondroitin sulfate on the bikunin ... ...

    Abstract Inter-α-inhibitor is a proteoglycan essential for mammalian reproduction and also plays a less well-characterized role in inflammation. It comprises two homologous "heavy chains" (HC1 and HC2) covalently attached to chondroitin sulfate on the bikunin core protein. Before ovulation, HCs are transferred onto the polysaccharide hyaluronan (HA) to form covalent HC·HA complexes, thereby stabilizing an extracellular matrix around the oocyte required for fertilization. Additionally, such complexes form during inflammatory processes and mediate leukocyte adhesion in the synovial fluids of arthritis patients and protect against sepsis. Here using X-ray crystallography, we show that human HC1 has a structure similar to integrin β-chains, with a von Willebrand factor A domain containing a functional metal ion-dependent adhesion site (MIDAS) and an associated hybrid domain. A comparison of the WT protein and a variant with an impaired MIDAS (but otherwise structurally identical) by small-angle X-ray scattering and analytical ultracentrifugation revealed that HC1 self-associates in a cation-dependent manner, providing a mechanism for HC·HA cross-linking and matrix stabilization. Surprisingly, unlike integrins, HC1 interacted with RGD-containing ligands, such as fibronectin, vitronectin, and the latency-associated peptides of transforming growth factor β, in a MIDAS/cation-independent manner. However, HC1 utilizes its MIDAS motif to bind to and inhibit the cleavage of complement C3, and small-angle X-ray scattering-based modeling indicates that this occurs through the inhibition of the alternative pathway C3 convertase. These findings provide detailed structural and functional insights into HC1 as a regulator of innate immunity and further elucidate the role of HC·HA complexes in inflammation and ovulation.
    MeSH term(s) Alpha-Globulins/chemistry ; Extracellular Matrix/metabolism ; Humans ; Immunity, Innate ; Integrin beta Chains/chemistry ; Molecular Dynamics Simulation ; Ovulation ; Protein Domains ; von Willebrand Factor/chemistry
    Chemical Substances Alpha-Globulins ; Integrin beta Chains ; von Willebrand Factor ; inter-alpha-inhibitor (39346-44-6)
    Language English
    Publishing date 2020-03-06
    Publishing country United States
    Document type Journal Article ; 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.RA119.011916
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Diabetic endothelial colony forming cells have the potential for restoration with glycomimetics.

    Langford-Smith, Alexander W W / Hasan, Ahmad / Weston, Ria / Edwards, Nicola / Jones, Alan M / Boulton, Andrew J M / Bowling, Frank L / Rashid, S Tawqeer / Wilkinson, Fiona L / Alexander, M Yvonne

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 2309

    Abstract: Endothelial colony forming progenitor cell (ECFC) function is compromised in diabetes, leading to poor vascular endothelial repair, which contributes to impaired diabetic foot ulcer healing. We have generated novel glycomimetic drugs with protective ... ...

    Abstract Endothelial colony forming progenitor cell (ECFC) function is compromised in diabetes, leading to poor vascular endothelial repair, which contributes to impaired diabetic foot ulcer healing. We have generated novel glycomimetic drugs with protective effects against endothelial dysfunction. We investigated the effect of glycomimetic C3 on the functional capacity of diabetic ECFCs. ECFCs were isolated from healthy controls and patients with diabetes with neuroischaemic (NI) or neuropathic (NP) foot ulcers. Functionally, diabetic ECFCs demonstrated delayed colony formation (p < 0.02), differential proliferative capacity (p < 0.001) and reduced NO bioavailability (NI ECFCs; p < 0.05). Chemokinetic migration and angiogenesis were also reduced in diabetic ECFCs (p < 0.01 and p < 0.001), and defects in wound closure and tube formation were apparent in NP ECFCs (p < 0.01). Differential patterns in mitochondrial activity were pronounced, with raised activity in NI and depressed activity in NP cells (p < 0.05). The application of glycomimetic improved scratch wound closure in vitro in patient ECFCs (p < 0.01), most significantly in NI cells (p < 0.001), where tube formation (p < 0.05) was also improved. We demonstrate restoration of the deficits in NI cells but not NP cells, using a novel glycomimetic agent, which may be advantageous for therapeutic cell transplantation or as a localised treatment for NI but not NP patients.
    MeSH term(s) Aged ; Cell Movement/physiology ; Cell Proliferation/physiology ; Cells, Cultured ; Endothelial Progenitor Cells/cytology ; Endothelial Progenitor Cells/metabolism ; Endothelial Progenitor Cells/pathology ; Female ; Humans ; Male ; Middle Aged ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/pathology ; Neovascularization, Physiologic/physiology
    Language English
    Publishing date 2019-02-19
    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/s41598-019-38921-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: QRISK3 improves detection of cardiovascular disease risk in patients with systemic lupus erythematosus.

    Edwards, Nicola / Langford-Smith, Alexander W W / Parker, Benjamin J / Bruce, Ian N / Reynolds, John A / Alexander, M Yvonne / McCarthy, Eoghan M / Wilkinson, Fiona L

    Lupus science & medicine

    2018  Volume 5, Issue 1, Page(s) e000272

    Abstract: Objective: 10-year cardiovascular disease (CVD) risk scores are calculated using algorithms, including Framingham (worldwide) and QRISK2 (UK). Recently, an updated QRISK3 model was introduced, which considers new variables including SLE and steroid ... ...

    Abstract Objective: 10-year cardiovascular disease (CVD) risk scores are calculated using algorithms, including Framingham (worldwide) and QRISK2 (UK). Recently, an updated QRISK3 model was introduced, which considers new variables including SLE and steroid prescription, not included in QRISK2 and Framingham algorithms. We sought to determine the extent to which QRISK3 improves identification of high-risk patients with SLE and whether the score relates to standard and novel markers of SLE-specific endothelial dysfunction.
    Methods: Framingham and QRISK2/3 scores were calculated in patients with SLE (n=109) and healthy controls (n=29) using clinical measures. In a smaller cohort (n=58), markers of inflammation and endothelial dysfunction, including CD144
    Results: Patients with SLE demonstrated significantly higher QRISK3 scores than controls (5.0%vs0.3%, p<0.001). 21/109 patients with SLE (19%) and 24/109(22%) were newly identified as being at high risk of a CV event when using QRISK3 versus QRISK2 (29vs8patients) and QRISK3 versus Framingham (29vs5patients; p<0.001), respectively. These 'new QRISK3' patients with SLE were more likely to have lupus nephritis, be anticardiolipin antibody positive, currently prescribed corticosteroids, had a higher Body Mass Index and systolic blood pressure (BP) than low-risk patients with SLE. Rates of antiplatelet (8/21) and statin use (5/21) were low in the new QRISK3 group. EMVs, hsCRP and triglyceride levels were significantly higher in new QRISK3 patientscompared with low-risk patients with SLE (p<0.05). Furthermore, pulse wave velocity and VCAM were significantly elevated in all high versus low QRISK3 patients.
    Conclusions: QRISK3 captures significantly more patients with SLE with an elevated 10-year risk of developing CVD, which is associated with measures of endothelial dysfunction; EMVs and systolic BP. The adoption of QRISK3 will enhance management of CVD risk in patients with SLE for improved outcome.
    Language English
    Publishing date 2018-08-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2779620-6
    ISSN 2053-8790
    ISSN 2053-8790
    DOI 10.1136/lupus-2018-000272
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Macrophage enzyme and reduced inflammation drive brain correction of mucopolysaccharidosis IIIB by stem cell gene therapy.

    Holley, Rebecca J / Ellison, Stuart M / Fil, Daniel / O'Leary, Claire / McDermott, John / Senthivel, Nishanthi / Langford-Smith, Alexander W W / Wilkinson, Fiona L / D'Souza, Zelpha / Parker, Helen / Liao, Aiyin / Rowlston, Samuel / Gleitz, Hélène F E / Kan, Shih-Hsin / Dickson, Patricia I / Bigger, Brian W

    Brain : a journal of neurology

    2017  Volume 141, Issue 1, Page(s) 99–116

    Abstract: Mucopolysaccharidosis IIIB is a paediatric lysosomal storage disease caused by deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU), involved in the degradation of the glycosaminoglycan heparan sulphate. Absence of NAGLU leads to accumulation of ... ...

    Abstract Mucopolysaccharidosis IIIB is a paediatric lysosomal storage disease caused by deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU), involved in the degradation of the glycosaminoglycan heparan sulphate. Absence of NAGLU leads to accumulation of partially degraded heparan sulphate within lysosomes and the extracellular matrix, giving rise to severe CNS degeneration with progressive cognitive impairment and behavioural problems. There are no therapies. Haematopoietic stem cell transplant shows great efficacy in the related disease mucopolysaccharidosis I, where donor-derived monocytes can transmigrate into the brain following bone marrow engraftment, secrete the missing enzyme and cross-correct neighbouring cells. However, little neurological correction is achieved in patients with mucopolysaccharidosis IIIB. We have therefore developed an ex vivo haematopoietic stem cell gene therapy approach in a mouse model of mucopolysaccharidosis IIIB, using a high-titre lentiviral vector and the myeloid-specific CD11b promoter, driving the expression of NAGLU (LV.NAGLU). To understand the mechanism of correction we also compared this with a poorly secreted version of NAGLU containing a C-terminal fusion to IGFII (LV.NAGLU-IGFII). Mucopolysaccharidosis IIIB haematopoietic stem cells were transduced with vector, transplanted into myeloablated mucopolysaccharidosis IIIB mice and compared at 8 months of age with mice receiving a wild-type transplant. As the disease is characterized by increased inflammation, we also tested the anti-inflammatory steroidal agent prednisolone alone, or in combination with LV.NAGLU, to understand the importance of inflammation on behaviour. NAGLU enzyme was substantially increased in the brain of LV.NAGLU and LV.NAGLU-IGFII-treated mice, with little expression in wild-type bone marrow transplanted mice. LV.NAGLU treatment led to behavioural correction, normalization of heparan sulphate and sulphation patterning, reduced inflammatory cytokine expression and correction of astrocytosis, microgliosis and lysosomal compartment size throughout the brain. The addition of prednisolone improved inflammatory aspects further. Substantial correction of lysosomal storage in neurons and astrocytes was also achieved in LV.NAGLU-IGFII-treated mice, despite limited enzyme secretion from engrafted macrophages in the brain. Interestingly both wild-type bone marrow transplant and prednisolone treatment alone corrected behaviour, despite having little effect on brain neuropathology. This was attributed to a decrease in peripheral inflammatory cytokines. Here we show significant neurological disease correction is achieved using haematopoietic stem cell gene therapy, suggesting this therapy alone or in combination with anti-inflammatories may improve neurological function in patients.
    MeSH term(s) Animals ; Brain/enzymology ; Cytokines/metabolism ; Disease Models, Animal ; Encephalitis/etiology ; Encephalitis/therapy ; Female ; Genetic Therapy/methods ; Gliosis/therapy ; Glycosaminoglycans/genetics ; Glycosaminoglycans/metabolism ; Humans ; Liver/enzymology ; Macrophages/enzymology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mucopolysaccharidosis III/complications ; Mucopolysaccharidosis III/genetics ; Mucopolysaccharidosis III/pathology ; Mucopolysaccharidosis III/therapy ; Prednisolone/therapeutic use ; Spleen/enzymology ; Stem Cells/physiology ; Sulfatases/genetics ; Sulfatases/metabolism
    Chemical Substances Cytokines ; Glycosaminoglycans ; Prednisolone (9PHQ9Y1OLM) ; Sulfatases (EC 3.1.6.-) ; heparan sulfate sulfatase (EC 3.1.6.-)
    Language English
    Publishing date 2017-11-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awx311
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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