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https://www.readbyqxmd.com/read/29045015/the-small-molecule-mertk-inhibitor-unc2025-decreases-platelet-activation-and-prevents-thrombosis
#1
Brian R Branchford, Timothy J Stalker, Luke Law, Gilbert Acevedo, Susan Sather, Christine Brzezinski, Katina M Wilson, Katherine Minson, Alisa B Lee-Sherick, Pavel Davizon-Castillo, Christopher Ng, Weihe Zhang, Keith B Neeves, Steven R Lentz, Xiaodong Wang, Stephen V Frye, H Shelton Earp, Deborah DeRyckere, Lawrence F Brass, Douglas K Graham, Jorge A Di Paola
BACKGROUND: Gas6 signals through the TAM (TYRO-3, AXL, MERTK) receptor family mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing αIIb β3 integrin. OBJECTIVE: Here we describe anti-thrombotic effects mediated by UNC2025, a small molecule MERTK tyrosine kinase inhibitor. METHODS: MERTK phosphorylation and downstream signaling were assessed by immunoblot. Light transmission aggregometry, flow cytometry, and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregate formation in vitro...
October 17, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29044808/neuroprotective-effects-of-human-mesenchymal-stem-cells-hmsc-and-platelet-derived-growth-factor-pdgf-on-human-retinal-ganglion-cells-rgcs
#2
Andrew Osborne, Julie Sanderson, Keith R Martin
Optic neuropathies such as glaucoma occur when retinal ganglion cells (RGCs) in the eye are injured. Strong evidence suggests mesenchymal stem cells (MSCs) could be a potential therapy to protect RGCs, however little is known regarding their effect on the human retina. We therefore investigated if human MSCs (hMSCs), or platelet derived growth factor (PDGF) as produced by hMSC, could delay RGC death in a human retinal explant model of optic nerve injury. Our results showed hMSCs and the secreted growth factor PDGF-AB could substantially reduce human RGC loss and apoptosis following axotomy...
October 17, 2017: Stem Cells
https://www.readbyqxmd.com/read/29039563/inhibition-of-human-lung-cancer-proliferation-through-targeting-stromal-fibroblasts-by-dihydromyricetin
#3
Kai-Jie Fan, Bo Yang, Yang Liu, Xiao-Dong Tian, Bo Wang
In the present study, the effects of dihydromyricetin on the proliferative potential of fibroblasts and lung carcinoma cells were investigated. Markedly higher expression levels of smooth muscle actin and platelet derived growth factors (PDGFs) were observed in the fibroblasts using reverse transcription-polymerase chain reaction analysis. The expression levels of PDGF-A and PDGF-B were also higher in the lung cancer cells. Western blot analysis revealed higher expression levels of the receptor for platelet-derived growth factor (PDGFRβ) in the lysates from fibroblasts obtained from normal tissues and carcinoma tissues...
October 17, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29038421/stabilization-of-phosphofructokinase-1-platelet-isoform-by-akt-promotes-tumorigenesis
#4
Jong-Ho Lee, Rui Liu, Jing Li, Chuanbao Zhang, Yugang Wang, Qingsong Cai, Xu Qian, Yan Xia, Yanhua Zheng, Yuji Piao, Qianming Chen, John F de Groot, Tao Jiang, Zhimin Lu
Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis; however, its role and regulation in tumorigenesis are not well understood. Here, we demonstrate that PFK1 platelet isoform (PFKP) is the predominant PFK1 isoform in human glioblastoma cells and its expression correlates with total PFK activity. We show that PFKP is overexpressed in human glioblastoma specimens due to an increased stability, which is induced by AKT activation resulting from phosphatase and tensin homologue (PTEN) loss and EGFR-dependent PI3K activation...
October 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/29029406/lyn-mediates-fip1l1-pdgfra-signal-pathway-facilitating-il-5ra-intracellular-signal-through-fip1l1-pdgfra-jak2-lyn-akt-network-complex-in-cel
#5
Bin Li, Guangsen Zhang, Cui Li, Ruijuan Li, Jingchen Lu, Zhengxi He, Quan Wang, Zhenzi Peng, Jun Wang, Yeping Dong, Chunfang Zhang, Jie Qiong Tan, Nacef Bahri, Yuexiang Wang, Chaojun Duan
The Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha (PDGFRA) (F/P) oncogene can cause chronic eosinophilic leukemia (CEL), but requires IL-5 cytokine participation. In this study, we investigate the mechanism of F/P in collaboration with IL-5 in CEL. The results showed that Lyn, a key effector in the IL-5-motivated eosinophil production, is extensively activated in F/P-positive CEL cells. Lyn can associate and phosphorylate IL-5 receptor α (IL-5RA) in F/P-positive cells. Moreover, the activation of Lyn and IL-5R kinase were strengthened when the cells were stimulated by IL-5...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29021703/ginsenoside-rg3-enriched-red-ginseng-extract-inhibits-platelet-activation-and-in%C3%A2-vivo-thrombus-formation
#6
Dahye Jeong, Muhammad Irfan, Sung-Dae Kim, Suk Kim, Jun-Hwan Oh, Chae-Kyu Park, Hyun-Kyoung Kim, Man Hee Rhee
BACKGROUND: Korean Red Ginseng has been used for several decades to treat many diseases, enhancing both immunity and physical strength. Previous studies have documented the therapeutic effects of ginseng, including its anticancer, antiaging, and anti-inflammatory activities. These activities are mediated by ginsenosides present in the ginseng plant. Ginsenoside Rg3, an effective compound from red ginseng, has been shown to have antiplatelet activity in addition to its anticancer and anti-inflammatory activities...
October 2017: Journal of Ginseng Research
https://www.readbyqxmd.com/read/28984160/r-lipoic-acid-overdosing-affects-platelet-life-span-via-ros-mediated-autophagy
#7
Jing Liu, Qingqing Song, Yanwei Huang, Wu Sun, Dingqiang Lu, Bo Zhou
R-lipoic acid (ALA), a powerful antioxidant valuable for the treatment of diabetes and its complications, has been reported to exhibit an antiplatelet activity in vitro. The aim of this study was to investigate the effect and mechanism of ALA on platelets in vivo. Sprague-Dawley (SD) male rats were intravenously administered with low-dose ALA (20 mg/kg/d), high-dose ALA (80 mg/kg/d) and saline, respectively. Platelets count and bone marrow smear were evaluated and the expressions of markers related to apoptosis and autophagy were measured...
October 6, 2017: Platelets
https://www.readbyqxmd.com/read/28974577/molecular-mechanisms-for-enhancement-of-stromal-cell-derived-factor-1-induced-chemotaxis-by-platelet-endothelial-cell-adhesion-molecule-1-pecam-1
#8
Yoshihiro Umezawa, Hiroki Akiyama, Keigo Okada, Shinya Ishida, Ayako Nogami, Gaku Oshikawa, Tetsuya Kurosu, Osamu Miura
Platelet endothelial cell adhesion molecule 1 (PECAM-1) is a cell adhesion protein involved in the regulation of cell adhesion and migration. Interestingly, several PECAM-1-deficient hematopoietic cells exhibit impaired chemotactic responses to stromal cell-derived factor 1 (SDF-1), a chemokine essential for B lymphopoiesis and bone marrow myelopoiesis. However, whether PECAM-1 is involved in SDF-1-regulated chemotaxis is unknown. We report here that SDF-1 induces tyrosine phosphorylation of PECAM-1 at its immunoreceptor tyrosine-based inhibition motifs in several hematopoietic cell lines via the Src family kinase Lyn, BTK, and JAK2 and that inhibition of these kinases reduced chemotaxis...
October 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28951244/tyrosines-740-751-of-pdgfr%C3%AE-contribute-to-the-activation-of-akt-hif1%C3%AE-tgf%C3%AE-nexus-to-drive-high-glucose-induced-glomerular-mesangial-cell-hypertrophy
#9
Falguni Das, Nandini Ghosh-Choudhury, Balakuntalam S Kasinath, Goutam Ghosh Choudhury
Glomerular mesangial cell hypertrophy contributes to the complications of diabetic nephropathy. The mechanism by which high glucose induces mesangial cell hypertrophy is poorly understood. Here we explored the role of the platelet-derived growth factor receptor-β (PDGFRβ) tyrosine kinase in driving the high glucose-induced mesangial cell hypertrophy. We show that high glucose stimulates the association of the PDGFRβ with PI 3 kinase leading to tyrosine phosphorylation of the latter. High glucose-induced Akt kinase activation was also dependent upon PDGFRβ and its tyrosine phosphorylation at 740/751 residues...
September 23, 2017: Cellular Signalling
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...
September 21, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28942012/activation-of-sry-accounts-for-male-specific-hepatocarcinogenesis-implication-in-gender-disparity-of-hepatocellular-carcinoma
#11
Chang Liu, Yi-Fan Ren, Jian Dong, Meng-Yun Ke, Feng Ma, Satdarshan P S Monga, Rongqian Wu, Yi Lv, Xu-Feng Zhang
Sex affects the risk, treatment responses and outcome of many types of cancers. The mechanism of gender disparity in development of hepatocellular carcinoma (HCC) remains obscure. Sex-determining region on Y chromosome (SRY) was overexpressed in approximate 84% male patient HCC. Moreover, we are the first to generate a liver-specific transgenic (TG) murine model with overexpression of the male specific gene SRY. Subject to a single intraperitoneal injection N-nitrosodiethylamine (DEN) at day 14, TG and wildtype (WT) mice of both genders were sacrificed at different time points (6-13...
September 21, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28939294/the-novel-compound-mp407-inhibits-platelet-aggregation-through-cyclic-amp-dependent-processes
#12
Chung-Shuen Lin, Tso-Hsiao Chen, I-Hsin Lin, An-Rong Lee, Tz-Chong Chou
Platelet hyperactivity plays a critical role for initiating several vascular diseases such as atherothrombosis. Therefore, development of effective antiplatelet agents is necessary for ameliorating platelet-related diseases. In this study, we investigated the effects of the new synthesized compound, MP407 on platelet aggregation and further elucidated the underlying mechanisms. Our results demonstrated that MP407 dose-dependently inhibited collagen-induced platelet aggregation, thromboxane B2 (TXB2) production, intracellular Ca(2+) mobilization, platelet membrane GPIIb/IIIa expression, and the phosphorylation of Akt, GSK3β, p38MAPK, and phospho (Ser) PKC substrate (p47)...
September 19, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28924208/chebulinic-acid-inhibits-smooth-muscle-cell-migration-by-suppressing-pdgf-r%C3%AE-phosphorylation-and-inhibiting-matrix-metalloproteinase-2-expression
#13
In-Sung Song, Yu Jeong Jeong, Jung-Hyun Park, Sungbo Shim, Sung-Wuk Jang
Excessive migration of vascular smooth muscle cells (VSMCs) after vascular injury contributes to the development of occlusive vascular disease. Inhibition of VSMC migration is a validated therapeutic modality for occlusive vascular diseases, such as atherosclerosis and restenosis. We investigated the inhibitory effect of chebulinic acid (CBA) on cell migration and matrix metalloproteinase (MMP)-2 activation in platelet-derived growth factor (PDGF)-BB-induced mouse and human VSMCs. CBA significantly inhibited PDGF-BB-induced migration in mouse and human VSMCs, without inducing cell death...
September 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28910587/trichosanthin-attenuates-vascular-injury-induced-neointimal-hyperplasia-following-balloon-catheter-injury-in-rats
#14
Min Qiu, Zheng Yang, Xiao-Hua Guo, Yu-Ting Song, Ming An, Guo-Jun Zhao, Miao Song, Xiao-Min Zhao, Yun-Shan Zhao, Quan-Li Liu
Trichosanthin (TCS), isolated from the root tuber of Trichosantheskirilowii, a well-known traditional Chinese medicinal plant, belonging to the Cucurbitaceae family, was found to exhibit numerous biological and pharmacological activities including anti-inflammatory. However, the effects of TCS on arterial injury induced neointimal hyperplasia and inflammatory cell infiltration remains poorly understood. The aim of study was to examine the effectiveness of TCS on arterial injury-mediated inflammatory processes and underlying mechanisms...
September 14, 2017: Journal of Toxicology and Environmental Health. Part A
https://www.readbyqxmd.com/read/28905392/cryopreserved-platelets-demonstrate-reduced-activation-responses-and-impaired-signaling-after-agonist-stimulation
#15
Lauren Waters, Matthew P Padula, Denese C Marks, Lacey Johnson
BACKGROUND: Room temperature-stored (20-24°C) platelets (PLTs) have a shelf life of 5 days, making it logistically challenging to supply remote medical centers with PLT products. Cryopreservation of PLTs in dimethyl sulfoxide (DMSO) and storage at -80°C enables an extended shelf life up to 2 years. Although cryopreserved PLTs have been widely characterized under resting conditions, their ability to undergo agonist-induced activation is yet to be fully explored. STUDY DESIGN AND METHODS: Buffy coat PLTs were cryopreserved at -80°C with 5% to 6% DMSO and sampled before freezing and after thawing...
September 14, 2017: Transfusion
https://www.readbyqxmd.com/read/28903387/hyperactivated-mtorc1-downregulation-of-foxo3a-pdgfr%C3%AE-akt-cascade-restrains-tuberous-sclerosis-complex-associated-tumor-development
#16
Li Wang, Zhaofei Ni, Yujie Liu, Shuang Ji, Fuquan Jin, Keguo Jiang, Junfang Ma, Cuiping Ren, Hongbing Zhang, Zhongdong Hu, Xiaojun Zha
Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss-of-function mutations in either the TSC1 or TSC2 gene, leads to the development of tuberous sclerosis complex (TSC), a benign tumor syndrome with multiple affected organs. mTORC1-mediated inhibition of AKT constrains the tumor progression of TSC, but the exact mechanisms remain unclear. Herein we showed that loss of TSC1 or TSC2 downregulation of platelet-derived growth factor receptor α (PDGFRα) expression was mediated by mTORC1...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28902366/heat-shock-protein-27-hspb1-suppresses-the-pdgf-bb-induced-migration-of-osteoblasts
#17
Shingo Kainuma, Haruhiko Tokuda, Naohiro Yamamoto, Gen Kuroyanagi, Kazuhiko Fujita, Tetsu Kawabata, Go Sakai, Rie Matsushima-Nishiwaki, Osamu Kozawa, Takanobu Otsuka
Heat shock protein 27 (HSP27/HSPB1), one of the small heat shock proteins, is constitutively expressed in various tissues. HSP27 and its phosphorylation state participate in the regulation of multiple physiological and pathophysiological cell functions. However, the exact roles of HSP27 in osteoblasts remain unclear. In the present study, we investigated the role of HSP27 in the platelet-derived growth factor‑BB (PDGF‑BB)‑stimulated migration of osteoblast-like MC3T3-E1 cells. PDGF-BB by itself barely upregulated the expression of HSP27 protein, but stimulated the phosphorylation of HSP27 in these cells...
October 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28898758/modular-flow-chamber-for-engineering-bone-marrow-architecture-and-function
#18
Christian A Di Buduo, Paolo M Soprano, Lorenzo Tozzi, Stefania Marconi, Ferdinando Auricchio, David L Kaplan, Alessandra Balduini
The bone marrow is a soft, spongy, gelatinous tissue found in the hollow cavities of flat and long bones that support hematopoiesis in order to maintain the physiologic turnover of all blood cells. Silk fibroin, derived from Bombyx mori silkworm cocoons, is a promising biomaterial for bone marrow engineering, because of its tunable architecture and mechanical properties, the capacity of incorporating labile compounds without loss of bioactivity and demonstrated ability to support blood cell formation. In this study, we developed a bone marrow scaffold consisting of a modular flow chamber made of polydimethylsiloxane, holding a silk sponge, prepared with salt leaching methods and functionalized with extracellular matrix components...
November 2017: Biomaterials
https://www.readbyqxmd.com/read/28878675/inhibition-of-collagen-induced-platelet-aggregation-by-the-secobutanolide-secolincomolide-a-from-lindera-obtusiloba-blume
#19
Sang-Hyuk Jung, Joo-Hui Han, Hyun-Soo Park, Jung-Jin Lee, Seo Young Yang, Young Ho Kim, Kyung-Sun Heo, Chang-Seon Myung
Atherothrombosis is one of the main underlying cause of cardiovascular diseases. In addition to treating atherothrombosis with antithrombotic agents, there is growing interest in the role of natural food products and biologically active ingredients for the prevention and treatment of cardiovascular diseases. This study aimed to investigate the effect of secolincomolide A (3) isolated from Lindera obtusiloba Blume on platelet activity and identify possible signaling pathways. In our study, the antiplatelet activities of 3 were measured by collagen-induced platelet aggregation and serotonin secretion in freshly isolated rabbit platelets...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28842683/a-novel-ruthenium-ii-derived-organometallic-compound-tq-6-potently-inhibits-platelet-aggregation-ex-vivo-and-in-vivo-studies
#20
Chih-Hsuan Hsia, Marappan Velusamy, Joen-Rong Sheu, Themmila Khamrang, Thanasekaran Jayakumar, Wan-Jung Lu, Kuan-Hung Lin, Chao-Chien Chang
Arterial thrombosis plays a key role in cardiovascular diseases. Hence, developing more effective antithrombotic agents is necessary. We designed a ruthenium (II)-derived complex, [Ru(η(6)-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), as a new antiplatelet drug. TQ-6 (0.3 µM) exhibited extremely strong inhibitory activity against platelet aggregation, Src, and Syk phosphorylation stimulated by agonists in human platelets. In collagen-activated platelets, TQ-6 also inhibited ATP-release, [Ca(+2)]i, P-selectin expression, FITC-PAC-1 binding, and hydroxyl radical formation, as well as the phosphorylation of phospholipase Cγ2, protein kinase C, mitogen-activated protein kinases, and Akt...
August 25, 2017: Scientific Reports
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