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Yingchun Qiao, Xixi Tian, Li Men, Shengyu Li, Yufeng Chen, Meiting Xue, Yahui Hu, Pengfei Zhou, Guangfeng Long, Yue Shi, Ruiqing Liu, Yunde Liu, Zhi Qi, Yujie Cui, Yanna Shen
Diabetic nephropathy (DN) is a serious complication of diabetes and can cause an increased mortality risk. It was previously reported that NLR family pyrin domain containing 3 (NLRP3) inflammasome is involved in the pathogenesis of diabetes. However, the underlying mechanism is not clearly understood. In the present study, the effects of spleen tyrosine kinase (Syk) and c‑Jun N‑terminal kinase (JNK) on the NLRP3 inflammasome were examined in vivo and in vitro. Sprague‑Dawley rats were injected intraperitoneally with streptozotocin (65 mg/kg) to induce diabetes...
June 14, 2018: Molecular Medicine Reports
Margareta P Correia, Ana Stojanovic, Katharina Bauer, Dilafruz Juraeva, Lars-Oliver Tykocinski, Hanns-Martin Lorenz, Benedikt Brors, Adelheid Cerwenka
CD8+ T cells are considered prototypical cells of adaptive immunity. Here, we uncovered a distinct CD8+ T cell population expressing the activating natural killer (NK) receptor NKp30 in the peripheral blood of healthy individuals. We revealed that IL-15 could de novo induce NKp30 expression in a population of CD8+ T cells and drive their differentiation toward a broad innate transcriptional landscape. The adaptor FcεRIγ was concomitantly induced and was shown to be crucial to enable NKp30 cell-surface expression and function in CD8+ T cells...
June 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Sang Jae Lee, Jang-Sik Choi, Seoung Min Bong, Hae-Jun Hwang, Jaesang Lee, Ho-Juhn Song, Jaekyoo Lee, Jung-Ho Kim, Jong Sung Koh, Byung Il Lee
Spleen tyrosine kinase (SYK) is a cytosolic non-receptor protein tyrosine kinase. Because SYK mediates key receptor signaling pathways involving the B cell receptor and Fc receptors, SYK is an attractive target for autoimmune disease and cancer treatments. To date, representative oral SYK inhibitors, including fostamatinib (R406 or R788), entospletinib (GS- 9973), cerdulatinib (PRT062070), and TAK-659, have been assessed in clinical trials. Here, we report the crystal structures of SYK in complex with two newly developed inhibitors possessing 4-aminopyrido[4,3-D]pyrimidine moieties (SKI-G-618 and SKI-O-85)...
June 12, 2018: Molecules and Cells
Sumalaxmi Janapati, Jeremy Wurtzel, Carol Dangelmaier, Bhanu Kanth Manne, Dheeraj Bhavanasi, John C Kostyak, Soochong Kim, Michael Holinstat, Satya P Kunapuli, Lawrence E Goldfinger
BACKGROUND: Many RAS family small GTPases are expressed in platelets, including RAC, RHOA, RAP, and H-/N-/RRAS1, but most of their signaling and cellular functions remain poorly understood. Like RRAS1, TC21/RRAS2 reverses HRAS-induced suppression of integrin activation in CHO cells. However, a role for TC21 in platelets has not been explored. OBJECTIVES: To determine TC21 expression in platelets, TC21 activation in response to platelet agonists, and roles of TC21 in platelet function in vitro and in vivo thrombosis...
June 8, 2018: Journal of Thrombosis and Haemostasis: JTH
Jens Staal, Yasmine Driege, Mira Haegman, Alice Borghi, Paco Hulpiau, Laurens Lievens, Ismail Sahin Gul, Srividhya Sundararaman, Amanda Gonçalves, Ineke Dhondt, Jorge H Pinzón, Bart P Braeckman, Ulrich Technau, Yvan Saeys, Frans van Roy, Rudi Beyaert
The CARD-coiled coil (CC)/Bcl10/MALT1-like paracaspase (CBM) signaling complexes composed of a CARD-CC family member (CARD-9, -10, -11, or -14), Bcl10, and the type 1 paracaspase MALT1 (PCASP1) play a pivotal role in immunity, inflammation, and cancer. Targeting MALT1 proteolytic activity is of potential therapeutic interest. However, little is known about the evolutionary origin and the original functions of the CBM complex. Type 1 paracaspases originated before the last common ancestor of planulozoa (bilaterians and cnidarians)...
2018: Frontiers in Immunology
Vinay Lanke, S T R Moolamalla, Dipanjan Roy, P K Vinod
Alzheimer's disease (AD) is a neurodegenerative disorder contributing to rapid decline in cognitive function and ultimately dementia. Most cases of AD occur in elderly and later years. There is a growing need for understanding the relationship between aging and AD to identify shared and unique hallmarks associated with the disease in a region and cell-type specific manner. Although genomic studies on AD have been performed extensively, the molecular mechanism of disease progression is still not clear. The major objective of our study is to obtain a higher-order network-level understanding of aging and AD, and their relationship using the hippocampal gene expression profiles of young (20-50 years), aging (70-99 years), and AD (70-99 years)...
2018: Frontiers in Aging Neuroscience
Muhammad Irfan, Dahye Jeong, Evelyn Saba, Hyuk-Woo Kwon, Jung-Hae Shin, Bo-Ra Jeon, Suk Kim, Sung-Dae Kim, Dong-Ha Lee, Seung-Yeol Nah, Man Hee Rhee
Panax ginseng (P. ginseng), one of the most valuable medicinal plants, is known for its healing and immunobooster properties and has been widely used in folk medicine against cardiovascular diseases, including stroke and heart attack. In this study, we explored the anti-platelet activity of gintonin (a recently discovered non-saponin fraction of ginseng) against agonist-induced platelet activation. In vitro effects of gintonin on agonist-induced human and rat platelet aggregation, granule secretion, integrin αIIb β3 activation, and intracellular calcium ion ([Ca2+ ]i ) mobilization were examined...
June 5, 2018: Platelets
Lei Zhang, Lei Shi, Shafer Soars, Joshua Kamps, Hang Hubert Yin
Excessive NF-κB activation contributes to the pathogenesis of numerous diseases. Small-molecule inhibitors of NF-κB signaling have significant therapeutic potential especially in treating inflammatory diseases and cancers. In this study, we performed a cell-based high-throughput screening to discover novel agents capable of inhibiting NF-κB signaling. Based on two hit scaffolds from the screening, we synthesized 69 derivatives to optimize the potency for inhibition of NF-κB activation, leading to successful discovery of the most potent compound Z9j with over 170-fold enhancement of inhibitory activity...
June 5, 2018: Journal of Medicinal Chemistry
Anthony Markham
Rigel Pharmaceuticals are developing the spleen tyrosine kinase (SYK) inhibitor fostamatinib (TAVALISSE™) as a treatment for immune thrombocytopenia (ITP), autoimmune haemolytic anaemia and IgA nephropathy. Based on positive results in the phase III FIT clinical trial program, the drug was recently approved in the US as a treatment for thrombocytopenia in adult patients with chronic ITP who have had an insufficient response to a previous treatment. This article summarizes the milestones in the development of fostamatinib leading to this first approval...
June 4, 2018: Drugs
Konstantinos Melissaropoulos, Stamatis-Nick Liossis
The objective of the study was to explore the phenotype and intracellular signaling events of B cells in patients with systemic sclerosis (SSc). Peripheral blood B cell surface markers CD19 and CD22 were evaluated by flow cytometry in 23 patients with SSc and seven healthy individuals. Levels of intracellular kinases Lyn, Syk and P-Y 348 Syk along with phosphatase SHP-1 were examined with Western immunoblotting in selected patients. P-Y 822 CD22 was subsequently evaluated flow cytometrically in antigen receptor stimulated B cells...
June 4, 2018: Rheumatology International
Zeina Dagher, Shuying Xu, Paige E Negoro, Nida S Khan, Michael B Feldman, Jennifer L Reedy, Jenny M Tam, David B Sykes, Michael K Mansour
Macrophages play a critical role in the elimination of fungal pathogens. They are sensed via cell surface pattern-recognition receptors and are phagocytosed into newly formed organelles called phagosomes. Phagosomes mature through the recruitment of proteins and lysosomes, resulting in addition of proteolytic enzymes and acidification of the microenvironment. Our earlier studies demonstrated an essential role of Dectin-1-dependent activation of spleen tyrosine kinase (Syk) in the maturation of fungal containing phagosomes...
2018: Frontiers in Immunology
Felicia M Bloemendaal, Pim J Koelink, Karin A van Schie, Theo Rispens, Charlotte P Peters, Christianne J Buskens, Jarmila D van der Bilt, Willem A Bemelman, Hannelie Korf, João G Sabino, Cyriel Y Ponsioen, Anje A Te Velde, Geert R A M D'Haens, Gijs R van den Brink, Manon E Wildenberg
Background and Aims: We have recently shown that the mode of action of IgG1 anti-TNF antibodies in inflammatory bowel disease (IBD) requires Fcγ-receptor (FcR) engagement on macrophages. Here we examine the effect of Fcγ-receptor signaling by anti-TNF on macrophage IL-12/IL-23 secretion. Methods: Cytokine production by human inflammatory macrophages was assessed at the level of RNA and or protein. TNF-anti-TNF immune complex formation was determined by size-exclusion chromatography and signaling visualized by immunofluorescence...
May 30, 2018: Journal of Crohn's & Colitis
Donald MacGlashan
BACKGROUND: Secretion from human basophils and mast cells requires the activity of SYK but expression of SYK is highly variable in the general population and this variability predicts the magnitude of IgE-mediated secretion. One known mechanism of modulating SYK expression in human basophils is aggregation of FceRI. OBJECTIVE: This study examines the possibility that functional auto-antibodies are present in a wide variety of subjects and in particular, subjects whose basophils poorly express SYK...
May 31, 2018: Journal of Allergy and Clinical Immunology
Maaike Rijkers, Anno Saris, Sebastiaan Heidt, Arend Mulder, Leendert Porcelijn, Frans H J Claas, Ruben Bierings, Frank W G Leebeek, A J Gerard Jansen, Gestur Vidarsson, Jan Voorberg, Masja de Haas
HLA antibodies are associated with refractoriness to platelet transfusion, leading to rapid platelet clearance, sometimes coinciding with clinical side effects such as fever and chills. The presence of HLA antibodies does not always present with clinical symptoms. It is currently unclear why refractoriness to platelet transfusion is only observed in a subset of patients. Here, we utilized the availability of a unique panel of human monoclonal antibodies (mAbs) to study whether they were capable of activating platelets...
June 1, 2018: Haematologica
Asher Mullard
No abstract text is available yet for this article.
May 30, 2018: Nature Reviews. Drug Discovery
Omar Elaskalani, Norbaini Binti Abdol Razak, Pat Metharom
BACKGROUND: The release of neutrophil extracellular traps (NETs), a mesh of DNA, histones and neutrophil proteases from neutrophils, was first demonstrated as a host defence against pathogens. Recently it became clear that NETs are also released in pathological conditions. NETs released in the blood can activate thrombosis and initiate a cascade of platelet responses. However, it is not well understood if these responses are mediated through direct or indirect interactions. We investigated whether cell-free NETs can induce aggregation of washed human platelets in vitro and the contribution of NET-derived extracellular DNA and histones to platelet activation response...
May 29, 2018: Cell Communication and Signaling: CCS
Artur Zajkowicz, Agnieszka Gdowicz-Kłosok, Małgorzata Krześniak, Patryk Janus, Barbara Łasut, Marek Rusin
TREM2 mutations evoke neurodegenerative disorders, and recently genetic variants of this gene were correlated to increased risk of Alzheimer's disease. The signaling cascade originating from the TREM2 membrane receptor includes its binding partner TYROBP, BLNK adapter protein, and SYK kinase, which can be activated by p53. Moreover, in silico identification of a putative p53 response element (RE) at the TREM2 promoter led us to hypothesize that TREM2 and other pathway elements may be regulated in p53-dependent manner...
May 26, 2018: Neuroscience Letters
Peer Wille-Jørgensen, Ingvar Syk, Kenneth Smedh, Søren Laurberg, Dennis T Nielsen, Sune H Petersen, Andrew G Renehan, Erzsébet Horváth-Puhó, Lars Påhlman, Henrik T Sørensen
Importance: Intensive follow-up of patients after curative surgery for colorectal cancer is common in clinical practice, but evidence of a survival benefit is limited. Objective: To examine overall mortality, colorectal cancer-specific mortality, and colorectal cancer-specific recurrence rates among patients with stage II or III colorectal cancer who were randomized after curative surgery to 2 alternative schedules for follow-up testing with computed tomography and carcinoembryonic antigen...
May 22, 2018: JAMA: the Journal of the American Medical Association
Jianlin Qiao, Xiaoqing Wu, Qi Luo, Guangyu Wei, Mengdi Xu, Yulu Wu, Yun Liu, Xiaoqian Li, Jie Zi, Wen Ju, Lin Fu, Chong Chen, Qingyun Wu, Shengyun Zhu, Kunming Qi, Depeng Li, Zhenyu Li, Robert K Andrews, Lingyu Zeng, Elizabeth E Gardiner, Kailin Xu
In addition to hemostatic function, platelets play an important role in regulating the inflammatory response. The platelet NLRP3 inflammasome not only promotes IL-1β secretion, but was upregulated during platelet activation and thrombus formation in vitro. However, the role of NLRP3 in platelet function and thrombus formation in vivo remains unclear. In this study, we aimed to investigate the role of NLRP3 in platelet integrin αIIbβ3 signaling transduction. Using NLRP3-/- mice, we showed NLRP3-deficient platelets exhibit no significant differences in expression of the platelet-specific adhesive receptors αIIbβ3 integrin, GPIbα or GPVI, however NLRP3-/- platelets transfused into wild-type mice resulted in prolonged tail-bleeding time and delayed arterial thrombus formation, as well as exhibiting impaired spreading on immobilized fibrinogen and defective clot retraction, concomitant with decreased phosphorylation of c-Src, Syk and PLCγ2 in response to thrombin stimulation...
May 24, 2018: Haematologica
Fabiana N Soki, Ryu Yoshida, David N Paglia, Le T Duong, Marc F Hansen, Hicham Drissi
Osteoarthritis (OA) is a degenerative disease and a major cause of chronic disability in aging individuals. Cathepsin K (CatK), encoded by the Ctsk gene, has been implicated in the pathogenesis of pycnodysostosis and osteoporosis. The use of a selective inhibitor of CatK was recently shown to delay OA progression in rabbits. However, the cellular mechanisms underlying these protective effects remain unexplored. We examined articular cartilage maintenance and joint bone remodeling using Ctsk null mice (Ctsk-/- ) which underwent destabilization of the medial meniscus (DMM)...
May 21, 2018: Journal of Cellular Physiology
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