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https://www.readbyqxmd.com/read/29769259/novel-therapeutics-for-hemophilia-and-other-bleeding-disorders
#1
Michael U Callaghan, Robert Sidonio, Steven W Pipe
Hemophilia and von Willebrand disease are the most common congenital bleeding disorders. Treatment for these disorders has focused on replacement of the missing coagulation factor to prevent or treat bleeding. New technologies and insights into hemostasis have driven the development of many promising new therapies for hemophilia and von Willebrand disease. Emerging bypass agents including zymogen-like factor IXa and Xa molecules are in development and a bispecific antibody, emicizumab, demonstrated efficacy in a phase III trial in people with hemophilia A and inhibitors...
May 16, 2018: Blood
https://www.readbyqxmd.com/read/29722941/-culture-of-rat-corpus-cavernosal-endothelial-cells-using-modified-immunomagnetic-beads-and-cloning
#2
Fan-Bo Zhang, Rui Jiang
Objective: To search for the methods of isolating, purifying and culturing corpus cavernosal endothelial cells (CCECs) from SD rats, observe their growth characteristics, and providing seed cells for the study of erectile dysfunction (ED). METHODS: The corpus cavernosal tissue from the SD rat was digested with 0.1% elastase, followed by purification of CCECs with immunomagnetic beads. After further amplification, monoclonal CCECs were sorted out with the cloning cylinder and their morphological and proliferative characteristics were observed...
June 2017: Zhonghua Nan Ke Xue, National Journal of Andrology
https://www.readbyqxmd.com/read/29694861/coarse-grain-modeling-of-shear-induced-binding-between-von-willebrand-factor-and-collagen
#3
Wei Wei, Chuqiao Dong, Michael Morabito, Xuanhong Cheng, X Frank Zhang, Edmund B Webb, Alparslan Oztekin
Von Willebrand factor (VWF) is a large multimeric protein that aids in blood clotting. Near injury sites, hydrodynamic force from increased blood flow elongates VWF, exposing binding sites for platelets and collagen. To investigate VWF binding to collagen that is exposed on injured arterial surfaces, Brownian dynamics simulations are performed with a coarse-grain molecular model. Accounting for hydrodynamic interactions in the presence of a stationary surface, shear flow conditions are modeled. Binding between beads in coarse-grain VWF and collagen sites on the surface is described via reversible ligand-receptor-type bond formation, which is governed via Bell model kinetics...
April 24, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29619625/effects-of-plasma-glycosyltransferase-on-the-abo-h-blood-group-antigens-of-human-von-willebrand-factor
#4
Taiki Kano, Kazunao Kondo, Jiharu Hamako, Fumio Matsushita, Kazuya Sakai, Taei Matsui
Von Willebrand factor (VWF) is one of the plasma protein carrying ABO(H) blood group antigens, but the combining process of these antigens is not clear. In the present study, we examined whether plasma glycosyltransferase affects the blood group antigens on VWF. VWF expressing H-antigen (H-VWF) from blood group O and bovine serum albumin conjugated with H-antigen (H-BSA) were incubated with recombinant α1-3-N-acetylgalactosaminyltransferase (rA-transferase) and A-plasma with or without an additional UDP-GalNAc...
April 4, 2018: International Journal of Hematology
https://www.readbyqxmd.com/read/29615758/von-willebrand-factor-and-adamts13-activity-in-relation-to-risk-of-dementia-a-population-based-study
#5
Frank J Wolters, Johan Boender, Paul S de Vries, Michelle A Sonneveld, Peter J Koudstaal, Moniek P de Maat, Oscar H Franco, M Kamran Ikram, Frank W Leebeek, M Arfan Ikram
Low ADAMTS13 activity is associated with an increased risk of cardiovascular disease, which is generally attributed to its proteolytic effects on Von Willebrand factor (VWF). Cardiovascular health is an important determinant of cognitive decline, but the association of either VWF or ADAMTS13 with risk of dementia is unknown. Between 1997-2002, we measured VWF antigen and ADAMTS13 activity in 6055 participants of the population-based Rotterdam Study (mean age 69.3 years, 57.2% women). At baseline, 85 participants had dementia, and during 15 years of follow-up 821 developed dementia...
April 3, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29534248/truncation-of-adamts13-by-plasmin-enhances-its-activity-in-plasma
#6
Chantal C Clark, Mirjam M Mebius, Steven de Maat, Aloysius G M Tielens, Philip G de Groot, Rolf T Urbanus, Rob Fijnheer, Bouke P C Hazenberg, Jaap J van Hellemond, Coen Maas
ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) cleaves von Willebrand Factor (VWF) multimers to control their thrombogenicity. The fibrinolytic enzyme plasmin can cleave VWF in a similar manner. However, plasmin can also cleave ADAMTS13, which ultimately inactivates it. This leaves the overall role of plasmin in primary haemostasis uncertain.We investigated the combined molecular effects of plasmin on VWF and ADAMTS13. We first identified that plasmin destroys FRETS-VWF73 substrate by cleaving the ADAMTS13 binding region in a buffered system...
March 2018: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/29510721/heme-oxygenase-1-promoter-region-gt-n-polymorphism-associates-with-increased-neuroimmune-activation-and-risk-for-encephalitis-in-hiv-infection
#7
Alexander J Gill, Rolando Garza, Surendra S Ambegaokar, Benjamin B Gelman, Dennis L Kolson
BACKGROUND: Heme oxygenase-1 (HO-1) is a critical cytoprotective enzyme that limits oxidative stress, inflammation, and cellular injury within the central nervous system (CNS) and other tissues. We previously demonstrated that HO-1 protein expression is decreased within the brains of HIV+ subjects and that this HO-1 reduction correlates with CNS immune activation and neurocognitive dysfunction. To define a potential CNS protective role for HO-1 against HIV, we analyzed a well-characterized HIV autopsy cohort for two common HO-1 promoter region polymorphisms that are implicated in regulating HO-1 promoter transcriptional activity, a (GT)n dinucleotide repeat polymorphism and a single nucleotide polymorphism (A(-413)T)...
March 6, 2018: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29507883/autoregulation-of-von-willebrand-factor-function-by-a-disulfide-bond-switch
#8
Diego Butera, Freda Passam, Lining Ju, Kristina M Cook, Heng Woon, Camilo Aponte-Santamaría, Elizabeth Gardiner, Amanda K Davis, Deirdre A Murphy, Agnieszka Bronowska, Brenda M Luken, Carsten Baldauf, Shaun Jackson, Robert Andrews, Frauke Gräter, Philip J Hogg
Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this "mechanopresentation" remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring...
February 2018: Science Advances
https://www.readbyqxmd.com/read/29251812/the-physical-spacing-between-the-von-willebrand-factor-d-d3-and-a1-domains-regulates-platelet-adhesion-in-vitro-and-in-vivo
#9
C Zhang, A Kelkar, M Nasirikenari, J T Y Lau, M Sveinsson, U C Sharma, S Pokharel, S Neelamegham
Essentials The role of von Willebrand factor (VWF) domains in regulating platelet adhesion was studied in vivo. Multimeric VWF with spacers at the N- and C-terminus of VWF-A1 were systematically tested. N-terminal modified VWF avidly bound platelet GpIbα, causing VWD Type2B like phenotype in mice. Novel anti-D'D3 mAbs suggest that changes at the D'D3-A1 interface may be biologically relevant. SUMMARY: Background Previous ex vivo studies using truncated VWF (von Willebrand factor) suggest that domain-level molecular architecture may control platelet-GpIbα binding function...
March 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28943410/loss-of-reelin-protects-mice-against-arterial-thrombosis-by-impairing-integrin-activation-and-thrombus-formation-under-high-shear-conditions
#10
Nina Sarah Gowert, Irena Krüger, Meike Klier, Lili Donner, Friederike Kipkeew, Michael Gliem, Nicholas J Bradshaw, David Lutz, Sabrina Köber, Harald Langer, Sebastian Jander, Kerstin Jurk, Michael Frotscher, Carsten Korth, Hans H Bock, Margitta Elvers
Reelin is a secreted glycoprotein and essential for brain development and plasticity. Recent studies provide evidence that Reelin modifies platelet actin cytoskeletal dynamics. In this study we sought to dissect the contribution of Reelin in arterial thrombus formation. Here we analyzed the impact of Reelin in arterial thrombosis ex vivo and in vivo using Reelin deficient (reeler) and wildtype mice. We found that Reelin is secreted upon platelet activation and mediates signaling via glycoprotein (GP)Ib, the amyloid precursor protein (APP) and apolipoprotein E receptor 2 (ApoER2) to induce activation of Akt, extracellular signal-regulated kinase (Erk), SYK and Phospholipase Cγ2...
December 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28930985/visualizing-angiogenesis-by-multiphoton-microscopy-in-vivo-in-genetically-modified-3d-plga-nhap-scaffold-for-calvarial-critical-bone-defect-repair
#11
Jian Li, Holger Jahr, Wei Zheng, Pei-Gen Ren
The reconstruction of critically sized bone defects remains a serious clinical problem because of poor angiogenesis within tissue-engineered scaffolds during repair, which gives rise to a lack of sufficient blood supply and causes necrosis of the new tissues. Rapid vascularization is a vital prerequisite for new tissue survival and integration with existing host tissue. The de novo generation of vasculature in scaffolds is one of the most important steps in making bone regeneration more efficient, allowing repairing tissue to grow into a scaffold...
September 7, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28686347/epo-modified-mscs-can-inhibit-asthmatic-airway-remodeling-in-an-animal-model
#12
Xin-Peng Han, Fang-Qi Zhang, Xiang-Shu Tan, Liang Liu, Wen-Xian Ma, Hai-Feng Ou-Yang, Chang-Gui Wu
There was no effective measures can be obtained at present to reverse or prevent airway remodeling. We investigated the therapeutic effect of Erythropoietin (EPO) gene modified mesenchymal stem cells (MSCs) on asthmatic airway remodeling and the possible underlied molecular mechanisms. EPO gene was transfected into MSCs via lentivirus vector. The transfected cells (EPO-MSCs) were identified by flow cytometry and the EPO secreting function was detected by PCR and Western blot. MSCs or EPO-MSCs were administrated to albumin (OVA)-induced chronic asthmatic mouse model via tail veins...
January 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28629023/heparin-dna-aptamer-co-assembled-multifunctional-catecholamine-coating-for-epc-capture-and-improved-hemocompatibility-of-vascular-devices
#13
Jinchuan Deng, Shuheng Yuan, Xin Li, Kebing Wang, Lingxia Xie, Na Li, Jin Wang, Nan Huang
Good hemocompatibility and rapid endothelialization are two key factors in the success of stent interventional therapy. In this study, aptamers with the ability to capture endothelial progenitors and anticoagulant molecular heparin were successfully immobilized on the surface of dopamine/polyethylenimine (PDA/PEI) copolymer coating via electrostatic interaction. The results of X-ray spectroscopy (XPS), water contact angle (WCA), and immunofluorescence staining tests confirmed the successful introduction of heparin and aptamers...
October 1, 2017: Materials Science & Engineering. C, Materials for Biological Applications
https://www.readbyqxmd.com/read/28596681/effects-of-heme-oxygenase-1-modified-bone-marrow-mesenchymal-stem-cells-on-microcirculation-and-energy-metabolism-following-liver-transplantation
#14
Liu Yang, Zhong-Yang Shen, Rao-Rao Wang, Ming-Li Yin, Wei-Ping Zheng, Bin Wu, Tao Liu, Hong-Li Song
AIM: To investigate the effects of heme oxygenase-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) on the microcirculation and energy metabolism of hepatic sinusoids following reduced-size liver transplantation (RLT) in a rat model. METHODS: BMMSCs were isolated and cultured in vitro using an adherent method, and then transduced with HO-1-bearing recombinant adenovirus to construct HO-1/BMMSCs. A rat acute rejection model following 50% RLT was established using a two-cuff technique...
May 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28577390/feasibility-of-the-von-willebrand-disease-prevent-trial
#15
Margaret V Ragni, Nicoletta Machin, Andra H James, Craig D Seaman, Lynn M Malec, Craig M Kessler, Barbara A Konkle, Peter A Kouides, Anne T Neff, Claire S Philipp, Maria M Brooks
BACKGROUND: Despite treatment, women with von Willebrand disease (VWD) have lower von Willebrand factor (VWF) levels and greater blood loss at delivery than controls. Current weight-based dosing does not account for the ~1.5-fold increase in blood volume in pregnancy. METHODS: To evaluate the feasibility of a trial to prevent postpartum hemorrhage (PPH), we reviewed pre-pregnancy and 8th month VWF levels in women with VWD with and without PPH following vaginal delivery, assessed VWF concentrate use at delivery by U...
May 25, 2017: Thrombosis Research
https://www.readbyqxmd.com/read/28428179/adamts13-controls-vascular-remodeling-by-modifying-vwf-reactivity-during-stroke-recovery
#16
Haochen Xu, Yongliang Cao, Xing Yang, Ping Cai, Lijing Kang, Ximin Zhu, Haiyu Luo, Lu Lu, Lixiang Wei, Xiaofei Bai, Yuanbo Zhu, Bing-Qiao Zhao, Wenying Fan
Angiogenic response is essential for ischemic brain repair. The von Willebrand factor (VWF)-cleaving protease disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) is required for endothelial tube formation in vitro, but there is currently no in vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited reduced neovascularization, brain capillary perfusion, pericyte and smooth muscle cell coverage on microvessels, expression of the tight junction and basement membrane proteins, and accelerated blood-brain barrier (BBB) breakdown and extravascular deposits of serum proteins in the peri-infarct cortex at 14 days after stroke...
July 6, 2017: Blood
https://www.readbyqxmd.com/read/28412143/thermo-sensitive-assembly-of-the-biomaterial-rep-reduces-hematoma-volume-following-collagenase-induced-intracerebral-hemorrhage-in-rats
#17
Joohyun Park, Jong Youl Kim, Seong-Kyoon Choi, Jae Young Kim, Jae Hwan Kim, Won Bae Jeon, Jong Eun Lee
Intracerebral hemorrhage (ICH) frequently results in severe disabilities and high mortality. RGD-containing elastin-like polypeptide (REP), a modified elastin-like polypeptide (ELP), is a thermally responsive biopolymer. REP has high affinity for cells and is known to show non-immunotoxicity, -cytotoxicity, and -inflammatory responses. Here we found that administration of REP in the acute phase of the ICH rat model reduced the hematoma volume, decreased the number of activated microglia, attenuated the expression of von Willebrand Factor (vWF), and prevented the leakage of immunoglobulin G (IgG) into the cerebral parenchyma without any occlusion of intact microvessels...
April 13, 2017: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/28409234/clinical-role-of-von-willebrand-factor-in-acute-ischemic-stroke
#18
Marija Menih, Miljenko Križmarić, Tanja Hojs Fabjan
BACKGROUND: An elevated level of von Willebrand factor (VWF) is associated with an increased risk for coronary heart disease and ischemic stroke. The objective of the study was to determine whether the level of VWF is associated with the cardioembolic subtype of ischemic stroke, stroke severity, and clinical outcome. PATIENTS AND METHODS: In this study 108 patients suffering from acute ischemic stroke (AIS) were included. According to the etiology of the stroke, patients were classified into the subtype of cardioembolic (CE) stroke and the group with non-CE stroke...
July 2017: Wiener Klinische Wochenschrift
https://www.readbyqxmd.com/read/28391888/inflammatory-markers-modify-the-risk-of-recurrent-coronary-events-associated-with-apolipoprotein-a-i-in-postinfarction-patients
#19
Meng Wang, James Corsetti, Scott McNitt, David Q Rich, Charles E Sparks, Arthur J Moss, Wojciech Zareba
BACKGROUND: Laboratory findings have suggested that systemic and vascular inflammation can impair the antiatherogenic function of high-density lipoproteins (HDLs). However, evidence from population studies is sparse. OBJECTIVE: The objective of the study was to assess if blood inflammatory markers modify the risk of recurrent coronary events associated with apolipoprotein A-I (apoA-I) and HDL cholesterol (HDL-C) among postinfarction patients. METHODS: ApoA-I, HDL-C, and inflammatory markers (C-reactive protein [CRP], serum amyloid A (SAA), fibrinogen, von Willebrand factor [vWF], and D-dimer) were measured from blood samples of 1028 patients drawn 2 months after an index myocardial infarction (MI)...
January 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/28370891/adamts-13-glycans-and-conformation-dependent-activity
#20
A A Nowak, H E R O'Brien, P Henne, A Doerr, K Vanhoorelbeke, M A Laffan, T A J McKinnon
Essentials The impact of N-linked glycosylation on ADAMTS-13 function has not been fully explored. The activity of glycan modified ADAMTS-13 was investigated under static and shear stress conditions. Terminal sialic acid on the metalloprotease domain glycans are important for ADAMTS-13 activity. The CUB domain glycans modulate ADAMTS-13 activity. SUMMARY: Background ADAMTS-13 activity can be regulated by its conformation, whereby interactions between the C-terminal CUB domains and the spacer domain maintain ADAMTS-13 in a closed conformation...
June 2017: Journal of Thrombosis and Haemostasis: JTH
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