Polysaccharides from the root of Angelica sinensis promotes hematopoiesis and thrombopoiesis through the PI3K/AKT pathway

<p>Abstract</p> <p>Background</p> <p>Dozens of Traditional Chinese Medicine (TCM) formulas have been used for promotion of "blood production" for centuries, and we are interested in developing novel thrombopoietic medicines from these TCMs. Our previous studies have demonstrated the hematopoietic effects of DangGui BuXue Tong (DBT), a formula composed of <it>Radix Angelicae Sinensis </it>and <it>Radix Astragali </it>in animal and cellular models. As a step further to identify and characterize the active chemical components of DBT, we tested the hematopoietic and particularly, thrombopoietic effects of polysaccharide-enriched fractions from the root of <it>Radix Angelicae Sinensis </it>(APS) in this study.</p> <p>Methods</p> <p>A myelosuppression mouse model was treated with APS (10 mg/kg/day). Peripheral blood cells from APS, thrombopoietin and vehicle-treated samples were then counted at different time-points. Using the colony-forming unit (CFU) assays, we determined the effects of APS on the proliferation and differentiation of hematopoietic stem/progenitor cells and megakaryocytic lineages. Using a megakaryocytic cell line M-07e as model, we analyzed the cellular apoptosis progression with and without APS treatment by Annexin V, Mitochondrial Membrane Potential and Caspase 3 assays. Last, the anti-apoptotic effect of APS on cells treated with Ly294002, a Phosphatidylinositol 3-Kinse inhibitor (PI3K) was also tested.</p> <p>Results</p> <p>In animal models, APS significantly enhanced not only the recovery of platelets, other blood cells and their progenitor cells, but also the formation of Colony Forming Unit (CFU). In M-07e cells, we observed the anti-apoptotic effect of APS. Treatment by Ly294002 alone increased the percentage of cells undergoing apoptosis. However, addition of APS to Ly294002-treated cells significantly reduced the percentage of cells undergoing apoptosis.</p> <p>Conclusions</p> <p>APS promotes hematopoiesis and thrombopoiesis in the mouse model. This effect likely resulted from the anti-apoptosis activity of APS and is likely to involve the PI3K/AKT pathway.</p

A combined randomised and observational study of surgery for fractures in the distal radius in the elderly (CROSSFIRE) - a study protocol

Introduction: Fractures of the distal radius are common and occur in all age groups. The incidence is high in older populations due to osteoporosis and increased falls risk. Considerable practice variation exists in the management of distal radius fractures in older patients ranging from closed reduction with cast immobilisation to open reduction with plate fixation. Plating is currently the most common surgical treatment. While there is evidence showing no significant advantage for some forms of surgical fixation over conservative treatment, and no difference between different surgical techniques, there is a lack of evidence comparing two of the most common treatments used: closed reduction and casting versus plating. Surgical management involves significant costs and risks compared with conservative management. High-level evidence is required to address practice variation, justify costs and to provide the best clinical outcomes for patients. Methods and Analysis: This pragmatic, multicentre randomised comparative effectiveness trial aims to determine whether plating leads to better pain and function and is more cost-effective than closed reduction and casting of displaced distal radius fractures in adults aged 60 years and older. The trial will compare the two techniques but will also follow consenting patients who are unwilling to be randomised in a separate, observational cohort. Inclusion of non-randomised patients addresses selection bias, provides practice and outcome insights about standard care, and improves the generalisability of the results from the randomised trial.Ian A Harris, Justine M Naylor, Andrew Lawson, Rachelle Buchbinder, Rebecca Ivers, Zsolt Balogh, Paul Smith, Rajat Mittal, Wei Xuan, Kirsten Howard, Arezoo Vafa, Piers Yates, Bertram Rieger, Geoff Smith, Ilia Elkinson, Woosung Kim, Mellick Chehade, Jai Sungaran, Kim Latendresse, James Wong, Sameer Viswanathan, Martin Richardson, Kush Shrestha, Herwig Drobetz, Phong Tran, Jeremy Loveridge, Richard Page, Raphael Hau, Roger Bingham, Jonathan Mulford, Ian Incol

Increased Differentiation of Dermal Mast Cells in Mice Lacking the Mpl Gene

Thrombopoietin interactions with its receptor, Mpl, play an important role in the regulation of hematopoietic stem/progenitor cell proliferation and differentiation. In this study, we report that the mast cell restricted progenitor cells (MCP) and the mast cell precursors in the bone marrow of wild-type mice express Mpl on their surface. Furthermore, targeted deletion of the Mpl gene in mice decreases the number of MCP while increasing the number of mast cell precursors present in the marrow and spleen. It also increases the number of mast cells present in the dermis, in the peritoneal cavity, and in the gut of the mice. In addition, serosal mast cells from Mplnull mice have a distinctive differentiation profile similar to that expressed by wild-type dermal mast cells. These results suggest that not only does ligation of thrombopoietin with the Mpl receptor exert an effect at the mast cell restricted progenitor cell level, but also plays an unexpected yet important role in mast cell maturation

Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes

Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation, resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium-glucose cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes