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[PMID]: 29380037 [Au] Autor: Miyashita N; Onozawa M; Hayasaka K; Yamada T; Migita O; Hata K; Okada K; Goto H; Nakagawa M; Hashimoto D; Kahata K; Kondo T; Kunishima S; Teshima T [Ad] Endereço: Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, 0608638, Japan. [Ti] Título: A novel heterozygous ITGB3 p.T720del inducing spontaneous activation of integrin αIIbß3 in autosomal dominant macrothrombocytopenia with aggregation dysfunction. [So] Source: Ann Hematol;97(4):629-640, 2018 Apr. [Is] ISSN: 1432-0584 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: We identified a novel heterozygous ITGB3 p.T720del mutation in a pedigree with macrothrombocytopenia exhibiting aggregation dysfunction. Platelet aggregation induced by ADP and collagen was significantly reduced, while ristocetin aggregation was normal. Integrin αIIbß3 was partially activated in a resting status, but platelet expression of αIIbß3 was downregulated. Functional analysis using a cell line showed spontaneous phosphorylation of FAK in αIIb/ß3 (p.T720del)-transfected 293T cells in suspension conditions. Abnormal cytoplasmic protrusions, membrane ruffling, and cytoplasmic localization of αIIbß3 were observed in αIIb/ß3 (p.T720del)-transfected CHO cells. Such morphological changes were reversed by treatment with an FAK inhibitor. These findings imply spontaneous, but partial, activation of αIIbß3 followed by phosphorylation of FAK as the initial mechanism of abnormal thrombopoiesis. Internalization and decreased surface expression of αIIbß3 would contribute to aggregation dysfunction. We reviewed the literature of congenital macrothrombocytopenia associated with heterozygous ITGA2B or ITGB3 mutations. Reported mutations were highly clustered at the membrane proximal region of αIIbß3, which affected the critical interaction between αIIb R995 and ß3 D723, resulting in a constitutionally active form of the αIIbß3 complex. Macrothrombocytopenia caused by a heterozygous activating mutation of ITGA2B or ITGB3 at the membrane proximal region forms a distinct entity of rare congenital thrombocytopenia. [Mh] Termos MeSH primário: Deleção de Genes Genes Dominantes Heterozigoto Integrina beta3/genética Complexo Glicoproteico GPIIb-IIIa de Plaquetas/agonistas Trombocitopenia/genética [Mh] Termos MeSH secundário: Adulto Animais Células CHO Cricetulus Saúde da Família Feminino Células HEK293 Seres Humanos Integrina beta3/metabolismo Japão Masculino Meia-Idade Mutagênese Sítio-Dirigida Linhagem Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo Proteínas Recombinantes/metabolismo Trombocitopenia/sangue Trombocitopenia/metabolismo Trombocitopenia/fisiopatologia Adulto Jovem [Pt] Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE [Nm] Nome de substância: 0 (ITGB3 protein, human); 0 (Integrin beta3); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Recombinant Proteins) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180309 [Lr] Data última revisão: 180309 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180131 [St] Status: MEDLINE [do] DOI: 10.1007/s00277-017-3214-4

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[PMID]: 29350259 [Au] Autor: Zhu X; Zhang J; Wang Q; Fu H; Chang Y; Kong Y; Lv M; Xu L; Liu K; Huang X; Zhang X [Ad] Endereço: Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China. [Ti] Título: Diminished expression of ß2-GPI is associated with a reduced ability to mitigate complement activation in anti-GPIIb/IIIa-mediated immune thrombocytopenia. [So] Source: Ann Hematol;97(4):641-654, 2018 Apr. [Is] ISSN: 1432-0584 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Anti-GPIIb/IIIa-mediated complement activation has been reported to be important in the pathogenesis of immune thrombocytopenia (ITP). However, the role of the complement system and the involved regulatory mechanism remain equivocal. Beta2-glycoprotein I (ß2-GPI), known as the main target for antiphospholipid autoantibodies, has been demonstrated as a complement regulator. Here, we investigated the complement-regulatory role of ß2-GPI in anti-GPIIb/IIIa-mediated ITP. Plasma complement activation and enhanced complement activation capacity (CAC) were found in ITP patients with anti-GPIIb/IIIa antibodies in vivo and in vitro. Diminished plasma levels of ß2-GPI were shown in patients of this group, which was inversely correlated with C5b-9 deposition. C5b-9 generation was inhibited by approximate physiological concentrations of ß2-GPI, in a dose-dependent manner. Inhibition of C3a generation by ß2-GPI and the existence of ß2-GPI/C3 complexes in plasma indicated a regulation on the level of the C3 convertase. Furthermore, ß2-GPI down-regulated the phosphorylation levels of c-Jun N-terminal kinase (JNK) and cleavage of BH3 interacting domain death agonist (Bid) and ultimately harbored platelet lysis. Our findings may provide a novel link between diminished plasma levels of ß2-GPI and enhanced complement activation, indicating ß2-GPI as a potential diagnostic biomarker and therapeutic target in the treatment of anti-GPIIb/IIIa-mediated ITP. [Mh] Termos MeSH primário: Ativação do Complemento Regulação para Baixo Isoanticorpos/metabolismo Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores Púrpura Trombocitopênica Idiopática/metabolismo beta 2-Glicoproteína I/metabolismo [Mh] Termos MeSH secundário: Adulto Idoso Biomarcadores/sangue Plaquetas/imunologia Plaquetas/metabolismo Plaquetas/patologia China/epidemiologia Convertases de Complemento C3-C5/metabolismo Complemento C3a/metabolismo Feminino Seres Humanos Masculino Meia-Idade Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidores Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo Púrpura Trombocitopênica Idiopática/imunologia Púrpura Trombocitopênica Idiopática/patologia Púrpura Trombocitopênica Idiopática/fisiopatologia Risco Trombocitopenia/sangue Trombocitopenia/imunologia Trombocitopenia/metabolismo Trombose/epidemiologia Trombose/etiologia Adulto Jovem beta 2-Glicoproteína I/sangue [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers); 0 (Isoantibodies); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Platelet Glycoprotein GPIb-IX Complex); 0 (beta 2-Glycoprotein I); 0 (glycoprotein receptor GPIb-IX); 80295-42-7 (Complement C3a); EC 3.4.21.- (Complement C3-C5 Convertases) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180309 [Lr] Data última revisão: 180309 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180120 [St] Status: MEDLINE [do] DOI: 10.1007/s00277-017-3215-3

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[PMID]: 29281734 [Au] Autor: Lee JI; Gliem M; Gerdes G; Turowski B; Kaschner M; Kraus B; Hartung HP; Jander S [Ad] Endereço: Department of Neurology, Heinrich-Heine-University, Medical Faculty, Duesseldorf, Germany. [Ti] Título: Safety of bridging antiplatelet therapy with the gpIIb-IIIa inhibitor tirofiban after emergency stenting in stroke. [So] Source: PLoS One;12(12):e0190218, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: In a proportion of stroke patients with acute large vessel occlusion permanent stent implantation is mandatory to achieve successful recanalization. The optimum platelet inhibition strategy after such emergency stenting is unknown. We therefore analyzed the outcome of early glycoprotein (gp) IIb/IIIa inhibitor treatment after emergency stenting in acute stroke. METHODS: Sixty patients with emergency stenting were identified in our stroke unit registry from 12/2010-06/2014 and analyzed retrospectively. All patients were bridged intravenously with the gpIIb/IIIa antagonist tirofiban immediately after the acute procedure until switching to oral aspirin and clopidogrel was performed. For comparison we studied 135 patients with M1 occlusion undergoing thrombectomy without stent implantation or tirofiban treatment in a propensity score-adjusted analysis. RESULTS: In the acute stenting group receiving tirofiban complications with 6 deaths during the hospital stay (10%), 2 reinfarctions (3%), 12 intracerebral hemorrhages (ICH; 20%) and 5 symptomatic ICH (8%) occurred. Thirty-seven patients (62%) reached a moderate outcome of mRS 0-3 after 90 days. In the thrombectomy group without tirofiban administration the rate of deaths within hospital stay, the rate of ICH and outcome at day 90 were not different. CONCLUSION: In our retrospective study acute stenting with subsequent gpIIb/IIIa inhibition was not associated with an increased risk of ICH or in-hospital death. [Mh] Termos MeSH primário: Inibidores da Agregação de Plaquetas/farmacologia Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores Stents Acidente Vascular Cerebral/tratamento farmacológico [Mh] Termos MeSH secundário: Idoso Feminino Seres Humanos Masculino Meia-Idade [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Platelet Aggregation Inhibitors); 0 (Platelet Glycoprotein GPIIb-IIIa Complex) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180206 [Lr] Data última revisão: 180206 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171228 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0190218

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[PMID]: 28984776 [Au] Autor: Sun B; Liu Z; Yin H; Wang T; Chen T; Yang S; Jiang Z [Ad] Endereço: aDepartment of Cardiology, The Third Hospital of Hebei Medical University bDepartment of Epidemiology and Health Statistics, Center for Disease Control and Prevention of Hebei Province, Shijiazhuang, P.R. China. [Ti] Título: Intralesional versus intracoronary administration of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention in patients with acute coronary syndromes: A meta-analysis of randomized controlled trials. [So] Source: Medicine (Baltimore);96(40):e8223, 2017 Oct. [Is] ISSN: 1536-5964 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Glycoprotein IIb/IIIa inhibitors (GPIs) have been regarded as an adjuvant regimen to deal with no-reflow. However, whether intralesional (IL) administration of GPIs improves myocardial reperfusion without increasing bleeding in patients with acute coronary syndrome (ACS) compared with intracoronary (IC) administration has not been well addressed. Our meta-analysis aimed to evaluate the efficacy and safety of IL versus IC administration of GPIs for patients with ACS during percutaneous coronary intervention. METHODS: We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, and Cambridge Scientific Abstracts from January 2007 to May 2017. Thrombolysis in Myocardial Infarction (TIMI) 3 flow, corrected TIMI frame count (CTFC), and complete ST-segment resolution (>70%) were selected as the primary outcomes. Major adverse cardiac events (MACEs) were the secondary outcome, and major bleeding complications were the safety outcome. Data analysis was conducted using the Review Manager 5.3 software. RESULTS: Six randomized controlled trials were included in our meta-analysis. Compared with IC, IL obtained better results in terms of TIMI grade 3 flow [odds ratio (OR) 2.29; 95% confidence intervals (CIs) 1.31-4.01; P = .004], CTFC [weighted mean difference (WMD) -4.63; 95% CI -8.82 to -0.43; P = .03], and complete ST-segment resolution (OR 1.55; 95% CI 1.12-2.14; P = .008). There was a trend toward decreased MACE in the IL administration groups, which was not of statistical significance (OR 0.63; 95% CI 0.30-1.31; P = .22). No significant difference was found between the two groups in terms of in-hospital major bleeding events (OR 2.52; 95% CI .66 to 9.62; P = .18). CONCLUSION: IL administration yielded favorable outcomes in terms of myocardial tissue reperfusion as evidenced by the improved TIMI flow grade, CTFC, complete ST-segment resolution, and decreased MACE without increasing in-hospital major bleeding events. The IL administration of GPIs can be recommended as the preferred regimen to guard against no-reflow. [Mh] Termos MeSH primário: Síndrome Coronariana Aguda/tratamento farmacológico Injeções Intra-Arteriais/métodos Injeções Intralesionais/métodos Intervenção Coronária Percutânea/métodos Inibidores da Agregação de Plaquetas/administração & dosagem [Mh] Termos MeSH secundário: Síndrome Coronariana Aguda/cirurgia Anticorpos Monoclonais/administração & dosagem Vasos Coronários Sistema de Condução Cardíaco/efeitos dos fármacos Seres Humanos Fragmentos Fab das Imunoglobulinas/administração & dosagem Reperfusão Miocárdica/métodos Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores Ensaios Clínicos Controlados Aleatórios como Assunto Tirosina/administração & dosagem Tirosina/análogos & derivados [Pt] Tipo de publicação: JOURNAL ARTICLE; META-ANALYSIS; REVIEW [Nm] Nome de substância: 0 (Antibodies, Monoclonal); 0 (Immunoglobulin Fab Fragments); 0 (Platelet Aggregation Inhibitors); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 42HK56048U (Tyrosine); GGX234SI5H (tirofiban); X85G7936GV (abciximab) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171012 [Lr] Data última revisão: 171012 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 171007 [St] Status: MEDLINE [do] DOI: 10.1097/MD.0000000000008223

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[PMID]: 28934202 [Au] Autor: Tunjungputri RN; Gasem MH; van der Does W; Sasongko PH; Isbandrio B; Urbanus RT; de Groot PG; van der Ven A; de Mast Q [Ad] Endereço: Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands. [Ti] Título: Platelet dysfunction contributes to bleeding complications in patients with probable leptospirosis. [So] Source: PLoS Negl Trop Dis;11(9):e0005915, 2017 Sep. [Is] ISSN: 1935-2735 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Severe leptospirosis is frequently complicated by a hemorrhagic diathesis, of which the pathogenesis is still largely unknown. Thrombocytopenia is common, but often not to the degree that spontaneous bleeding is expected. We hypothesized that the hemorrhagic complications are not only related to thrombocytopenia, but also to platelet dysfunction, and that increased binding of von Willebrand factor (VWF) to platelets is involved in both platelet dysfunction and increased platelet clearance. METHODOLOGY/PRINCIPAL FINDINGS: A prospective study was carried out in Semarang, Indonesia, enrolling 33 hospitalized patients with probable leptospirosis, of whom 15 developed clinical bleeding, and 25 healthy controls. Platelet activation and reactivity were determined using flow cytometry by measuring the expression of P-selectin and activation of the αIIbß3 integrin by the binding of fibrinogen in unstimulated samples and after ex vivo stimulation by the platelet agonists adenosine-diphosphate (ADP) and thrombin-receptor activating peptide (TRAP). Platelet-VWF binding, before and after VWF stimulation by ristocetin, as well as plasma levels of VWF, active VWF, the VWF-inactivating enzyme ADAMTS13, thrombin-antithrombin complexes (TAT) and P-selectin were also measured. Bleeding complications were graded using the WHO bleeding scale. Our study revealed that platelet activation, with a secondary platelet dysfunction, is a feature of patients with probable leptospirosis, especially in those with bleeding manifestations. There was a significant inverse correlation of bleeding score with TRAP-stimulated P-selectin and platelet-fibrinogen binding (R = -0.72, P = 0.003 and R = -0.66, P = 0.01, respectively) but not with platelet count. Patients with bleeding also had a significantly higher platelet-VWF binding. Platelet counts were inversely correlated with platelet-VWF binding (R = -0.74; P = 0.0009. There were no correlations between platelet-VWF binding and the degree of platelet dysfunction, suggesting that increased platelet-VWF binding does not directly interfere with the platelet αIIbß3 signaling pathway in patients with probable leptospirosis. CONCLUSION/SIGNIFICANCE: Platelet dysfunction is common in probable leptospirosis patients with manifest bleeding. Increased VWF-platelet binding may contribute to the activation and clearance of platelets. [Mh] Termos MeSH primário: Plaquetas/patologia Hemorragia/etiologia Hemorragia/patologia Leptospirose/patologia [Mh] Termos MeSH secundário: Adulto Feminino Fibrinogênio/metabolismo Seres Humanos Indonésia Masculino Meia-Idade Selectina-P/análise Ativação Plaquetária Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo Estudos Prospectivos Ligação Proteica Fator de von Willebrand/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (P-Selectin); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (von Willebrand Factor); 9001-32-5 (Fibrinogen) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171018 [Lr] Data última revisão: 171018 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170922 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pntd.0005915

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[PMID]: 28834730 [Au] Autor: Shams H; Mofrad MRK [Ad] Endereço: Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, Berkeley, California. [Ti] Título: α-Actinin Induces a Kink in the Transmembrane Domain of ß -Integrin and Impairs Activation via Talin. [So] Source: Biophys J;113(4):948-956, 2017 Aug 22. [Is] ISSN: 1542-0086 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Integrin-mediated signaling is crucial for cell-substrate adhesion and can be triggered from both intra- and extracellular interactions. Although talin binding is sufficient for inside-out activation of integrin, other cytoplasmic proteins such as α-actinin and filamin can directly interfere with talin-mediated integrin activation. Specifically, α-actinin plays distinct roles in regulating α ß versus α ß integrin. It has been shown that α-actinin competes with talin for binding to the cytoplasmic tail of ß -integrin, whereas it cooperates with talin for activating integrin α ß . In this study, molecular dynamics simulations were employed to compare and contrast molecular mechanisms of α ß and α ß activation in the presence and absence of α-actinin. Our results suggest that α-actinin impairs integrin signaling by both undermining talin binding to the ß -integrin cytoplasmic tail and inducing a kink in the transmembrane domain of ß -integrin. Furthermore, we showed that α-actinin promote talin association with ß -integrin by restricting the motion of the cytoplasmic tail and reducing the entropic barrier for talin binding. Taken together, our results showed that the interplay between talin and α-actinin regulates signal transmission via controlling the conformation of the transmembrane domain and altering natural response modes of integrins in a type-specific manner. [Mh] Termos MeSH primário: Actinina/metabolismo Membrana Celular/metabolismo Integrina beta3/química Integrina beta3/metabolismo Simulação de Dinâmica Molecular Talina/metabolismo [Mh] Termos MeSH secundário: Citoplasma/metabolismo Integrina alfa5beta1/metabolismo Cinética Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo Ligação Proteica Domínios Proteicos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Integrin alpha5beta1); 0 (Integrin beta3); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Talin); 11003-00-2 (Actinin) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170907 [Lr] Data última revisão: 170907 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170824 [St] Status: MEDLINE

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[PMID]: 28826897 [Au] Autor: Elbadawi A; Elgendy IY; Megaly M; Ha LD; Mahmoud K; Alotaki E; Ogunbayo GO; Baig B; Abuzaid AS; Saad M; Depta JP [Ad] Endereço: Department of Medicine, Rochester General Hospital, Rochester, New York. Electronic address: Ayman.Elbadawi@rochesterregional.org. [Ti] Título: Meta-Analysis of Randomized Trials of Intracoronary Versus Intravenous Glycoprotein IIb/IIIa Inhibitors in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. [So] Source: Am J Cardiol;120(7):1055-1061, 2017 Oct 01. [Is] ISSN: 1879-1913 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The efficacy and safety of glycoprotein IIb/IIIa inhibitors via intracoronary (IC) route versus the intravenous (IV) route are not well known. We conducted this meta-analysis of randomized trials evaluating the role of IC versus IV glycoprotein IIb/IIIa in patients undergoing primary percutaneous coronary intervention. The analysis included 14 trials with a total of 3,754 patients. The primary outcome of major adverse cardiac events (MACE) had no statistically significant difference between the IC and the IV groups (relative risk [RR] 0.74, 95% confidence interval [CI] 0.51 to 1.10). Subgroup analysis showed that short-term MACE (i.e., ≤3 months) was reduced in the IC compared with the IV group; however, long-term MACE (>3 months) was not. IC group was superior in achievement of post-procedural Thrombolysis In Myocardial Infarction 3 flow (RR 1.06, 95% CI 1.01 to 1.11), myocardial blush grade II to III (RR 1.15, 95% CI 1.08 to 1.23), ST-segment resolution rates (RR 1.15, 95% CI 1.03 to 1.29; p = 0.01), and improvement of left ventricular ejection fraction (standardized mean difference = 4.32, 95% CI 0.91 to 7.74). There was a trend for lower stent thrombosis with IC route (RR 0.50, 95% CI 0.24 to 1.03). There was no significant difference between the 2 groups in all-cause mortality, re-infarction, and major bleeding. In conclusion, despite lack of significant difference in overall MACE outcome, IC glycoprotein IIb/IIIa inhibitors may improve short -term MACE, Thrombolysis In Myocardial Infarction 3 flow, myocardial blush grade II- to III rates, ST-segment resolution, and left ventricular ejection fraction compared with the IV route. [Mh] Termos MeSH primário: Intervenção Coronária Percutânea Inibidores da Agregação de Plaquetas/administração & dosagem Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores Ensaios Clínicos Controlados Aleatórios como Assunto Infarto do Miocárdio com Supradesnível do Segmento ST/terapia [Mh] Termos MeSH secundário: Seres Humanos Injeções Intra-Arteriais Injeções Intravenosas [Pt] Tipo de publicação: JOURNAL ARTICLE; META-ANALYSIS; REVIEW [Nm] Nome de substância: 0 (Platelet Aggregation Inhibitors); 0 (Platelet Glycoprotein GPIIb-IIIa Complex) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170914 [Lr] Data última revisão: 170914 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170823 [St] Status: MEDLINE

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[PMID]: 28663280 [Au] Autor: Wang Y; Jiang L; Mo X; Lan Y; Yang X; Liu X; Zhang J; Zhu L; Liu J; Wu X [Ad] Endereço: Department of Laboratory Medicine, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, People's Republic of China (Y.W.); Institute for Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai, People's Republic of China (L.J., X.M.); State Key Laboratory of Pr [Ti] Título: Megakaryocytic Smad4 Regulates Platelet Function through Syk and ROCK2 Expression. [So] Source: Mol Pharmacol;92(3):285-296, 2017 Sep. [Is] ISSN: 1521-0111 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Smad4, a key transcription factor in the transforming growth factor- signaling pathway, is involved in a variety of cell physiologic and pathologic processes. Here, we characterized megakaryocyte/platelet-specific Smad4 deficiency in mice to elucidate its effect on platelet function. We found that megakaryocyte/platelet-specific loss of Smad4 caused mild thrombocytopenia and significantly extended first occlusion time and tail bleeding time in mice. Smad4-deficient platelets showed reduced agonist-induced platelet aggregation. Further studies showed that a severe defect was seen in integrin -mediated bidirectional (inside-out and outside-in) signaling in Smad4-deficient platelets, as evidenced by reduced fibrinogen binding and -granule secretion, suppressed platelet spreading and clot retraction. Microarray analysis showed that the expression levels of multiple genes were altered in Smad4-deficient platelets. Among these genes, spleen tyrosine kinase (Syk) and Rho-associated coiled-coil containing protein kinase 2 (ROCK2) were downregulated several times as confirmed by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Further research showed that Smad4 directly regulates ROCK2 transcription but indirectly regulates Syk. Megakaryocyte/platelet-specific Smad4 deficiency caused decreased expression levels of Syk and ROCK2 in platelets. These results suggest potential links among Smad4 deficiency, attenuated Syk, and ROCK2 expression and defective platelet activation. [Mh] Termos MeSH primário: Plaquetas/fisiologia Megacariócitos/fisiologia Proteína Smad4/fisiologia Quinase Syk/fisiologia Quinases Associadas a rho/fisiologia [Mh] Termos MeSH secundário: Amidas/farmacologia Animais Células HEK293 Seres Humanos Camundongos Niacinamida/análogos & derivados Niacinamida/farmacologia Complexo Glicoproteico GPIIb-IIIa de Plaquetas/fisiologia Piridinas/farmacologia Pirimidinas/farmacologia Quinase Syk/genética Trombocitopenia/etiologia Quinases Associadas a rho/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide); 0 (Amides); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Pyridines); 0 (Pyrimidines); 0 (Smad4 Protein); 0 (Smad4 protein, mouse); 138381-45-0 (Y 27632); 25X51I8RD4 (Niacinamide); EC 2.7.10.2 (Syk Kinase); EC 2.7.10.2 (Syk protein, mouse); EC 2.7.11.1 (Rock2 protein, mouse); EC 2.7.11.1 (rho-Associated Kinases) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170830 [Lr] Data última revisão: 170830 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170701 [St] Status: MEDLINE [do] DOI: 10.1124/mol.116.107417

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[PMID]: 28641286 [Au] Autor: Cao H; Bissinger R; Umbach AT; Gawaz M; Lang F [Ad] Endereço: Department of Internal Medicine III, Tuebingen, Germany. [Ti] Título: Effect of Bexarotene on Platelet Activation and Apoptosis. [So] Source: Cell Physiol Biochem;42(2):838-847, 2017. [Is] ISSN: 1421-9778 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: BACKGROUND/AIMS: The retinoid X receptor (RXRs) stimulator Bexarotene ((4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl] benzoic acid) is used for the treatment of several malignancies. Bexarotene is at least in part effective by stimulation of apoptosis of tumor cells. Moreover, Bexarotene triggers eryptosis, the suicidal death of erythrocytes. Similar to erythrocytes, blood platelets lack nuclei but are nevertheless able to enter an apoptosis-like phenotype, characterized by caspase activation, cell shrinkage and cell membrane scrambling with phospha-tidylserine translocation to the cell surface. Platelet apoptosis is triggered by increase of cytosolic Ca2+-activity ([Ca2+]i), which further leads to degranulation and integrin activation. Platelet activation and apoptosis could be elicited by thrombin or collagen related peptide (CRP). The present study explored whether treatment of platelets with bexarotene modifies platelet activation and apoptosis following exposure to thrombin or CRP. METHODS: Platelets isolated from wild-type mice were exposed for 30 minutes to bexarotene (6 µg/ml) without or with an additional treatment with thrombin (0.01 U/ml) or CRP (2 µg/ml or 5 µg/ml). Flow cytometry was employed to estimate cytosolic Ca2+-activity ([Ca2+]i) from Fluo-3 fluorescence, platelet degranulation from P-selectin abundance, integrin activation from αIIbß3 integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding, and relative platelet volume from forward scatter. RESULTS: In the absence of thrombin or CRP, the administration of bexarotene slightly but significantly increased [Ca2+]i, but did not significantly modify P-selectin abundance, activated αIIbß3 integrin, annexin-V-binding, cell volume, or caspase activity. Exposure of platelets to thrombin or CRP was followed by significant increase of [Ca2+]i, P-selectin abundance, active αIIbß3 integrin, annexin-V-binding, and caspase activity. The effects of thrombin on [Ca2+]i, annexin-V-binding, cell volume, and caspase activity as well as the effects of CRP on [Ca2+]i, P-selectin abundance, activated αIIbß3 integrin, annexin-V-binding, cell volume, and caspase activity were significantly augmented in the presence of bexarotene. CONCLUSIONS: Bexarotene sensitizes blood platelets for thrombin and/or CRP induced activation and apoptosis. [Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos Ativação Plaquetária/efeitos dos fármacos Tetra-Hidronaftalenos/administração & dosagem Trombina/metabolismo [Mh] Termos MeSH secundário: Animais Plaquetas/efeitos dos fármacos Plaquetas/metabolismo Cálcio/metabolismo Colágeno/metabolismo Eritrócitos/metabolismo Citometria de Fluxo Hemólise/efeitos dos fármacos Seres Humanos Camundongos Ativação Plaquetária/genética Complexo Glicoproteico GPIIb-IIIa de Plaquetas Espécies Reativas de Oxigênio/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Reactive Oxygen Species); 0 (Tetrahydronaphthalenes); 9007-34-5 (Collagen); A61RXM4375 (bexarotene); EC 3.4.21.5 (Thrombin); SY7Q814VUP (Calcium) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170804 [Lr] Data última revisão: 170804 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170623 [St] Status: MEDLINE [do] DOI: 10.1159/000478627

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[PMID]: 28619996 [Au] Autor: Unsworth AJ; Bye AP; Tannetta DS; Desborough MJR; Kriek N; Sage T; Allan HE; Crescente M; Yaqoob P; Warner TD; Jones CI; Gibbins JM [Ad] Endereço: From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomed [Ti] Título: Farnesoid X Receptor and Liver X Receptor Ligands Initiate Formation of Coated Platelets. [So] Source: Arterioscler Thromb Vasc Biol;37(8):1482-1493, 2017 Aug. [Is] ISSN: 1524-4636 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OBJECTIVES: The liver X receptors (LXRs) and farnesoid X receptor (FXR) have been identified in human platelets. Ligands of these receptors have been shown to have nongenomic inhibitory effects on platelet activation by platelet agonists. This, however, seems contradictory with the platelet hyper-reactivity that is associated with several pathological conditions that are associated with increased circulating levels of molecules that are LXR and FXR ligands, such as hyperlipidemia, type 2 diabetes mellitus, and obesity. APPROACH AND RESULTS: We, therefore, investigated whether ligands for the LXR and FXR receptors were capable of priming platelets to the activated state without stimulation by platelet agonists. Treatment of platelets with ligands for LXR and FXR converted platelets to the procoagulant state, with increases in phosphatidylserine exposure, platelet swelling, reduced membrane integrity, depolarization of the mitochondrial membrane, and microparticle release observed. Additionally, platelets also displayed features associated with coated platelets such as P-selectin exposure, fibrinogen binding, fibrin generation that is supported by increased serine protease activity, and inhibition of integrin αIIbß3. LXR and FXR ligand-induced formation of coated platelets was found to be dependent on both reactive oxygen species and intracellular calcium mobilization, and for FXR ligands, this process was found to be dependent on cyclophilin D. CONCLUSIONS: We conclude that treatment with LXR and FXR ligands initiates coated platelet formation, which is thought to support coagulation but results in desensitization to platelet stimuli through inhibition of αIIbß3 consistent with their ability to inhibit platelet function and stable thrombus formation in vivo. [Mh] Termos MeSH primário: Benzoatos/farmacologia Benzilaminas/farmacologia Coagulação Sanguínea/efeitos dos fármacos Plaquetas/efeitos dos fármacos Isoxazóis/farmacologia Receptores X do Fígado/agonistas Ativação Plaquetária/efeitos dos fármacos Inibidores da Agregação de Plaquetas/farmacologia Receptores Citoplasmáticos e Nucleares/agonistas [Mh] Termos MeSH secundário: Plaquetas/metabolismo Sinalização do Cálcio/efeitos dos fármacos Micropartículas Derivadas de Células/efeitos dos fármacos Micropartículas Derivadas de Células/metabolismo Ciclofilinas/sangue Relação Dose-Resposta a Droga Fibrina/metabolismo Fibrinogênio/metabolismo Seres Humanos Ligantes Receptores X do Fígado/sangue Potencial da Membrana Mitocondrial/efeitos dos fármacos Selectina-P/sangue Fosfatidilserinas/sangue Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo Espécies Reativas de Oxigênio/sangue Receptores Citoplasmáticos e Nucleares/sangue [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Benzoates); 0 (Benzylamines); 0 (GW 3965); 0 (Isoxazoles); 0 (Ligands); 0 (Liver X Receptors); 0 (P-Selectin); 0 (Phosphatidylserines); 0 (Platelet Aggregation Inhibitors); 0 (Platelet Glycoprotein GPIIb-IIIa Complex); 0 (Reactive Oxygen Species); 0 (Receptors, Cytoplasmic and Nuclear); 0 (SELP protein, human); 0 (farnesoid X-activated receptor); 9001-31-4 (Fibrin); 9001-32-5 (Fibrinogen); EC 5.2.1.- (Cyclophilins); EC 5.2.1.8 (PPID protein, human); SR225WUZ0H (GW 4064) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170617 [St] Status: MEDLINE [do] DOI: 10.1161/ATVBAHA.117.309135

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