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Alice G Vassiliou, Anastasia Kotanidou, Zafeiria Mastora, Carlo Tascini, Gianluigi Cardinali, Stylianos E Orfanos
INTRODUCTION: A soluble (s) form of the endothelial protein C receptor (EPCR) circulates in plasma and inhibits activated protein C (APC) activities. The clinical impact of sEPCR and its involvement in the septic process is under investigation. This study determined the frequencies of EPCR haplotypes H1 and H3 to investigate possible associations with plasma admission levels of sEPCR in an intensive care unit (ICU) cohort of septic patients. METHODS: Three polymorphisms in the EPCR gene were genotyped in 239 Caucasian critically ill patients, and their plasma sEPCR levels were also measured at the time of admission to the ICU...
March 2018: Infectious Diseases and Therapy
Alborz Karimzadeh, Vanessa M Scarfone, Erika Varady, Connie Chao, Karin Grathwohl, John W Fathman, David A Fruman, Thomas Serwold, Matthew A Inlay
Hematopoietic stem cells (HSCs) are the self-renewing multipotent progenitors to all blood cell types. Identification and isolation of HSCs for study has depended on the expression of combinations of surface markers on HSCs that reliably distinguish them from other cell types. However, the increasing number of markers required to isolate HSCs has made it tedious, expensive, and difficult for newcomers, suggesting the need for a simpler panel of HSC markers. We previously showed that phenotypic HSCs could be separated based on expression of CD11a and that only the CD11a negative fraction contained true HSCs...
March 15, 2018: Stem Cells Translational Medicine
Hironosuke Watanabe, Hisashi Sahara, Shunichiro Nomura, Tatsu Tanabe, Dilrukshi K Ekanayake-Alper, Lennan K Boyd, Nathan J Louras, Arsenoi Asfour, Makenzie A Danton, Siu-Hong Ho, Scott J Arn, Robert J Hawley, Akira Shimizu, Takeshi Nagayasu, David Ayares, Marc I Lorber, Megan Sykes, David H Sachs, Kazuhiko Yamada
BACKGROUND: Despite recent progress in survival times of xenografts in non-human primates, there are no reports of survival beyond 5 days of histologically well-aerated porcine lung grafts in baboons. Here, we report our initial results of pig-to-baboon xeno-lung transplantation (XLTx). METHODS: Eleven baboons received genetically modified porcine left lungs from either GalT-KO alone (n = 3), GalT-KO/humanCD47(hCD47)/hCD55 (n = 3), GalT-KO/hD47/hCD46 (n = 4), or GalT-KO/hCD39/hCD46/hCD55/TBM/EPCR (n = 1) swine...
March 12, 2018: Xenotransplantation
Qingling Wang, Hongli Yang, Qian Zhuo, Yanyan Xu, Peng Zhang
Endothelial protein C receptor (EPCR) has been implicated in the carcinogenesis of diverse tumor types. This tumor-promoting effect of EPCR is associated with the upregulation of activated protein C and the activation of protease-activated receptor 1 (PAR-1). However, the exact role of EPCR in gastric cancer (GC) and the mechanisms underlying the regulation of EPCR remain elusive. In the present study, we investigated the effects of EPCR on human GC cells, as well as the underlying mechanisms. An siRNA inference system was used to knock down the expression of EPCR in GC cells, and CCK-8, colony formation and Transwell assays were performed to determine the effects of EPCR knockdown on the proliferation and migration of the tumor cells...
February 21, 2018: Oncology Reports
Usha R Pendurthi, L Vijaya Mohan Rao
PURPOSE OF REVIEW: Endothelial cell protein C receptor (EPCR), a transmembrane glycoprotein present on the surface of endothelial cells and other cell types, is an essential component of the protein C (PC) anticoagulant system. EPCR is also shown to play a critical role in mediating activated protein C (APC)-induced cytoprotective signaling. The purpose of this review is to outline the mechanisms of EPCR-dependent cell signaling and discuss recent findings made in this area. RECENT FINDINGS: Recent studies showed that the cleavage of protease-activated receptor (PAR)1 at a noncanonical site by APC-EPCR or the canonical site by thrombin when PC occupies EPCR induces β-arrestin-2-mediated biased cytoprotective signaling...
February 15, 2018: Current Opinion in Hematology
Rebecca W Olsen, Gertrude Ecklu-Mensah, Anja Bengtsson, Michael F Ofori, John P A Lusingu, Filip C Castberg, Lars Hviid, Yvonne Adams, Anja T R Jensen
Cerebral malaria (CM) is a potentially deadly outcome of Plasmodium falciparum malaria that is precipitated by sequestration of infected erythrocytes (IEs) in the brain. The adhesion of IEs to brain endothelial cells is mediated by a subtype of parasite-encoded PfEMP1 that facilitate dual binding to host ICAM-1 and EPCR. The PfEMP1 subtype is characterized by the presence of a particular motif (DBLβ_motif) in the constituent ICAM-1-binding DBLβ domain. The rate of natural acquisition of DBLβ_motif-specific IgG and the ability to induce such antibodies by vaccination are unknown, and the aim of this study was to provide such data...
February 5, 2018: Infection and Immunity
Shosaku Nomura, Tomoki Ito, Hideaki Yoshimura, Masaaki Hotta, Takahisa Nakanishi, Shinya Fujita, Aya Nakaya, Atsushi Satake, Kazuyoshi Ishii
Background: Thrombosis is one of the complications in the clinical course of multiple myeloma (MM). Vascular endothelial cells and/or the hemostatic-coagulatory system are thought to play an important role in thrombosis of MM. In addition to melphalan-prednisone (Mel-P) therapy, several new therapeutic drugs such as lenalidomide or bortezomib have been developed and show effectiveness against MM. However, these new drugs also have risk of therapy-related thrombosis. Methods: We assessed 103 MM patients and 30 healthy controls, using enzyme-linked immunosorbent assays to evaluate five biomarkers: platelet-derived microparticles (PDMP), plasminogen activator inhibitor-1 (PAI-1), high mobility group box protein-1 (HMGB1), endothelial protein C receptor (EPCR), and soluble vascular cell adhesion molecule-1 (sVCAM-1)...
2018: Journal of Blood Medicine
Yvonne Azasi, Gabriella Lindergard, Ashfaq Ghumra, Jianbing Mu, Louis H Miller, J Alexandra Rowe
Recent advances have identified a new paradigm for cerebral malaria pathogenesis in which endothelial protein C receptor (EPCR) is a major host receptor for sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the brain and other vital organs. The parasite adhesins that bind EPCR are members of the IE variant surface antigen family Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) containing specific adhesion domains called domain cassette (DC) 8 and DC13. The binding interaction site between PfEMP1 and EPCR has been mapped by biophysical and crystallography studies using recombinant proteins...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Kakunoshin Yoshida, Nobuyuki Akita, Takayuki Okamoto, Kunihiro Asanuma, Atsumasa Uchida, Akihiro Sudo, Motomu Shimaoka, Koji Suzuki, Tatsuya Hayashi
INTRODUCTION: Bone remodeling relies on a delicate balance between formation and resorption of bone tissues, processes in which bone-forming osteoblasts and bone-resorbing osteoclasts play central roles. Recently, we reported that anticoagulant activated protein C (APC) promotes osteoblast proliferation, but the role of the blood coagulation system in bone remodeling remains unclear. In this study, to further elucidate the relationship between bone remodeling and blood coagulation, we investigated the effect of APC on osteoclast differentiation...
January 3, 2018: Thrombosis Research
Dongmei Zhao, Renyu Ding, Yina Liu, Xiaohan Yin, Zhidan Zhang, Xiaochun Ma
Activation of protein C is greatly enhanced by the presence of thrombomodulin (TM) and endothelial protein C receptor (EPCR) on the endothelial surface. Impairment of the anticoagulant protein C system occurs during endotoxemia and contributes to sepsis-associated hypercoagulability. Previous studies have demonstrated that unfractionated heparin (UFH) can attenuate coagulation in endotoxemic mice. However, whether UFH has an effect on the protein C system remains to be elucidated. The current study evaluated the therapeutic effect of UFH on the protein C system in a mouse model of lipopolysaccharide (LPS)-induced sepsis, and further investigated the effect of UFH on the expression of TM and EPCR in vitro using human umbilical vein endothelial cells (HUVECs)...
December 2017: Experimental and Therapeutic Medicine
Xuhong Lin, Huichao Wang, Yuxia Li, Jingnan Yang, Ruilin Yang, Dandan Wei, Junjie Zhang, Desheng Yang, Bin Wang, Xuequn Ren, Guanchang Cheng
The present study aimed to explore the role of CXCR4 and protein C system (PCS) in the experimental ulcerative colitis (UC). The expression of CXCR3, CCR10, and CXCR4 in dextran sulfate sodium (DSS)-induced colitis mouse model was measured by immunohistochemistry and western blot analysis. In vitro studies with microvascular endothelial cells (MVECs) were performed. The expression of endothelial protein C receptor (EPCR) and thrombomodulin (TM) were detected by RT-PCR and western blot analysis. Activities of protein C (PC), protein S (PS), activated PC (APC) were evaluated in cells pre-treated with JNK inhibitor SP600125 and c-Jun silencing...
2017: American Journal of Translational Research
Anne Kessler, Selasi Dankwa, Maria Bernabeu, Visopo Harawa, Samuel A Danziger, Fergal Duffy, Sam D Kampondeni, Michael J Potchen, Nicholas Dambrauskas, Vladimir Vigdorovich, Brian G Oliver, Sarah E Hochman, Wenzhu B Mowrey, Ian J C MacCormick, Wilson L Mandala, Stephen J Rogerson, D Noah Sather, John D Aitchison, Terrie E Taylor, Karl B Seydel, Joseph D Smith, Kami Kim
Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy...
November 8, 2017: Cell Host & Microbe
Estela Shabani, Benjamin Hanisch, Robert O Opoka, Thomas Lavstsen, Chandy C John
BACKGROUND: Expression of group A and the A-like subset of group B Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is associated with severe malaria (SM). The diversity of var sequences combined with the challenges of distinct classification of patient pathologies has made studying the role of distinct PfEMP1 variants on malaria disease severity challenging. The application of retinopathy in the recent years has provided a further method to clinically evaluate children with cerebral malaria (CM)...
October 13, 2017: BMC Medicine
Mathilde Borg Dahl, Asker Daniel Brejnrod, Martin Unterseher, Thomas Hoppe, Yun Feng, Yuri Novozhilov, Søren Johannes Sørensen, Martin Schnittler
Unicellular, eukaryotic organisms (protists) play a key role in soil food webs as major predators of microorganisms. However, due to the polyphyletic nature of protists no single universal barcode can be established for this group, and the structure of many protistean communities remains unresolved. Plasmodial slime molds (Myxogastria or Myxomycetes) stand out among protists by their formation of fruit bodies, which allow for a morphological species concept. By Sanger sequencing of a large collection of morphospecies, this study presents the largest database to date of dark-spored myxomycetes and evaluate a partial 18S SSU gene marker for species annotation...
October 12, 2017: Molecular Ecology Resources
Agapi Kataki, Ioannis Karagiannidis, Nikolaos Memos, Efthymios Koniaris, P Antonakis, Apostolos Papalois, George C Zografos, Manoussos M Konstadoulakis
The present study focuses on the profile of 'endogeneous' caveolin-1 protein in septic lung (CLP model).Caveolin-1, CD25, pP38, pAkt and 14-3-3b protein expression profiles were studied using flow cytometry and immunohistochemistry 6 h, 12 h, 24 h, 36 h and 48 h following sepsis induction. Cell viability was determined by 7-AAD staining and fibrosis by Masson trichrome stain. The effect of protein C zymogen concentrate (PC) on caveolin-1 expression was also investigated given that PC, once dissociated from caveolin-1, elicits a PAR-1-mediated protective signaling by forming a complex with endothelial protein C receptor (EPCR)...
September 27, 2017: Shock
Shiva Keshava, Jagan Sundaram, Anuradha Rajulapati, Charles Esmon, Usha Pendurthi, L Vijaya Mohan Rao
Recent studies established that clotting factor VIIa (FVIIa) binds endothelial cell protein C receptor (EPCR). It has been speculated that FVIIa interaction with EPCR might augment the hemostatic effect of rFVIIa in therapeutic conditions. The present study is carried out to investigate the mechanism by which FVIIa interaction with EPCR contributes to the hemostatic effect of rFVIIa in hemophilia therapy. Active-site inhibited FVIIa, which is capable of binding to EPCR but has no ability to activate factor X, reduced the concentration of rFVIIa required to correct the bleeding following the saphenous vein injury in mouse hemophilia model systems...
June 27, 2017: Blood Advances
Wei Yang, Søren Berg Padkjær, Jishu Wang, Zhe Sun, Bing Shan, Li Yang, Haibin Chen, Lishan Kang, Dennis Madsen, Xun Li, Chenxi Shen, Bingke Yu, Haisun Zhu, Tzu-Yuan Chao, Zhuoxiao Cao, Dapeng Li, Wei Liu, Yanping Du, Jinjing Xu, Dongxia Hao, Fengting Xu, Lujia Peng, Tengkun Li, Lin Wang, Lin Li, Haimei Xing, Di Liu, Zibing Liu, Zhishuang Guan, Wan Wang, Hong Cheng, Henrik Østergaard, Chihchuan Chang, Zhiru Yang, Esper Boel, Jing Su
Interactions between protein ligands and receptors play crucial roles in cell-cell signalling. Most of the human cell surface receptors have been identified in the post-Human Genome Project era but many of their corresponding ligands remain unknown. To facilitate the pairing of orphan receptors, 2762 sequences encoding all human single-pass transmembrane proteins were selected for inclusion into a mammalian-cell expression library. This expression library, consisting of all the individual extracellular domains (ECDs), was constructed as a Fab fusion for each protein...
September 1, 2017: Journal of Biotechnology
Nicaise Tuikue Ndam, Azizath Moussiliou, Thomas Lavstsen, Claire Kamaliddin, Anja T R Jensen, Atikatou Mama, Rachida Tahar, Christian W Wang, Jakob S Jespersen, Jules M Alao, Benoit Gamain, Thor G Theander, Philippe Deloron
Background: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates the binding and accumulation of infected erythrocytes (IE) to blood vessels and tissues. Specific interactions have been described between PfEMP1 and human endothelial proteins CD36, intercellular adhesion molecule-1 (ICAM-1), and endothelial protein C receptor (EPCR); however, cytoadhesion patterns typical for pediatric malaria syndromes and the associated PfEMP1 members are still undefined. Methods: In a cohort of 94 hospitalized children with malaria, we characterized the binding properties of IE collected on admission, and var gene transcription using quantitative polymerase chain reaction...
June 15, 2017: Journal of Infectious Diseases
E M Gleeson, C J McDonnell, E E Soule, O Willis Fox, H Rushe, A Rehill, O P Smith, J S O'Donnell, R J S Preston
Essentials The basis of cytoprotective protease-activated receptor 1 (PAR1) signaling is not fully understood. Activated protein C chimera (APC(FVII-82) ) was used to identify requirements for PAR1 signaling. APC(FVII-82) did not initiate PAR1 signaling, but conferred monocyte anti-inflammatory activity. APC-specific light chain residues are required for cytoprotective PAR1 signaling. SUMMARY: Background Activated protein C (APC) cell signaling is largely reliant upon its ability to mediate protease-activated receptor (PAR) 1 proteolysis when bound to the endothelial cell (EC) protein C (PC) receptor (EPCR)...
August 20, 2017: Journal of Thrombosis and Haemostasis: JTH
Yu Ma, Yi Zhao, Ran Zhang, Xiaoxia Liang, Zhongqiong Yin, Yi Geng, Gang Shu, Xu Song, Yuanfeng Zou, Lixia Li, Lizi Yin, Guizhou Yue, Yinglun Li, Gang Ye, Changliang He
α-Cyperone, a sesquiterpene compound represents 25.23% of the total oil and is the most abundant compound in Cyperus rotundus oil. Endothelial cell protein C receptor (EPCR) is a main member in protein C (PC) anti-coagulation system. EPCR could be shed from cell surface, and is mediated by tumor necrosis factor-α converting enzyme (TACE). Nothing that EPCR is a marker of vascular barrier integrity in vascular inflammatory disease and takes part in systemic inflammatory disease. In this study, we investigated whether α-cyperone could inhibit EPCR shedding...
October 1, 2017: Biological & Pharmaceutical Bulletin
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